### Microbiology A yeast. *Cryptococcus* *neoformans*, *C*. deutero*gattii*, *C*. tetra*gattii*, *C*. bacillisporus, *Cryptococcus* *gattii*, *Cryptococcus* *neoformans* var grubii, *Cryptococcus* *tetragattii* (in Africa [^1] and S. India) which must be 4 times worser than *C*. *gattii*. *Cryptococcus* spp other than *C*. *neoformans* and *C*. *gattii*, like *Cryptococcus* *magnus*, *Cryptococcus* *laurentii*, and *Cryptococcus* later rarely cause clinically significant infection in humans. And names keep changing: there two varieties of *C*. *neoformans* have been recognized as species: *C*. *neoformans* (formerly *C*. *neoformans* var *grubii*) and *C*. *deneoformans* (formerly *C*. *neoformans* var *neoformans*). The outbreak in the Great Pacific NW is due to *C*. *deuterogattii* by current nomenclature. A Cryptococcal antigen on CSF and/or blood are the rapid way to make the diagnosis. It can have false-positive results with the *Aspergillus* galactomannan assay in pulmonary cryptococcosis patients. [^2] > "Low-serum CrAg titers (≤1:10) correlated with cryptococcal disease in a substantial proportion of non-HIV immunocompromised patients and should prompt careful clinical workup for cryptococcal infection. [^3] ### Epidemiologic Risks Disease occurs in the immunoincompetent (HIV, transplants) and in the immunocompetent as well, although the ostensibly normal patient may have wonky B cells. [^4] HIV patients do better with the disease. [^5] In one study most cases were in normal people. [^6] Pigeon droppings and Eucalyptus trees. Also found in a variety of decaying soils. Most disease is in the immunoincompetent: transplant patients (although being on a calcineurin-inhibitor has a protective effect[^7] and AIDS (CD4 < 200 as a rule); it can cause disease in people with no apparent immunologic deficiency. In the Great Pacific NW it is found in fir trees. I keep waiting for an outbreak from Christmas trees. 3% of HIV patients with CD < 100 will be CRAG positive, a high enough rate to warrant screening. [^8] Another study suggests 6%, 1/3 of whom are asymptomatic. [^9] Smoking cannabis. [^10] There is an ongoing problem with *Cryptococcus* *neoformans* var *gattii* on Vancouver Island and the Great Pacific NW, perhaps related to environmental changes from global warming (not that global warming exists, at least according to President Very Stable Genius. It is spreading across the US. [^11] More common in 'normal' patients. It arrived from S. America and Australia [^12] and virulence is due in part to same-sex mating: > "However, instead of the classic a--α sexual cycle, the majority outbreak clone appears to have descended from two α mating-type parents." [^13] Alpha males. Always a problem. It prefers the Oregon Pine as the environmental source. *C*. *gattii* is being reported all over the US, including the US South [^14] and in Europe, some acquired locally and some reactivating long after leaving an endemic area. [^15] Genetic clock suggests the *C*. *gattii* reached the South at least 9,000 years ago, long before the introduction in the Great Pacific NW. [^16] And there was a cat that became ill > 8 years after leaving an endemic era. [^17] So this yeast can lurk a long time before rearing its ugly head. *C*. *gattii* is harder to treat, causes more CNS cryptococcomas, and it may be recalcitrant to fluconazole , consider fungal susceptibility testing, and consider it strongly. *Cryptococcus* *neoformans* var grubii is found in Vietnam/SE Asia and is harder to treat. Ibrutinib, an irreversible inhibitor of Bruton tyrosine kinase is a risk. [^18] Auto-antibodies to gamma interferon is a risk for disseminated disease [^19] and portends a poor outcome [^20]; patients act like they have HIV. Also seen in patients with anti-GM-CSF auto-antibodies. [^21] [^22] And there is the idiopathic low CD4 count syndrome, with or without other genetic defects. [^23] ### Syndromes The incubation period for *C*. *gattii* is 6 weeks to 13 months. Pneumonia : usually asymptomatic, but in the transplant or HIV patient it can disseminate. In the normal host, smooth, multiple upper lobe nodules are the most common manifestation; lymphadenitis is unusual. [^24] Check a serum cryptococcal antigen, and, if positive, do an LP. Maybe everyone should get an LP since the fungemia can be transient. I have seen two patients after they had a bit o' lung removed for a mass that turned out to be due to *Cryptococcus* and not the expected tumor. Cryptococcal antigenemia with meningitis symptoms but a negative LP should be treated like meningitis and NOT treated with fluconazole. [^25] Meningitis : usually a granulomatous meningitis: >"Altered mental status at presentation, a high baseline organism load, and a slow rate of clearance of infection are independently associated with increased mortality at 2 and 10 weeks." [^26] In AIDS patients with a positive serum antigen > 160, 1/3 will have asymptomatic CNS involvement, 90% if only a headache. [^27] A negative serum antigen usually excludes meningitis in HIV patients. [^28] As with most diseases, the sicker you are, the worse you do. For *C*. *gattii*, serum CRAG > 512 or CSF > 256 were bad prognostic findings. [^29] > "Despite aggressive antifungal therapies, outcomes of CNS cryptococcosis in people without HIV are characterized by substantial long-term neurological sequelae. [^30] In AIDs, seizures are common with advanced infection and bode ill. [^31] Skin lesions can mimic molluscum contagiosum. ### Treatment Send the organisim for susceptibility testing: > "..mean prevalence of fluconazole resistance was 12.1% for all isolates (n = 4995). Mean fluconazole resistance was 10.6% for the incident isolates (n = 4747) and 24.1% ) for the relapse isolates (n = 248)." [^32] Which antifungal to use and for how long depends on the host and the strain of *Cryptococcus*. It tends to be susceptible to azoles, amphotericin B and 5 flucytocine, but not echinocandidins. *C*. *gattii* probably should be treated more aggressively: > "Induction Amphotericin B , plus 5-flucytosine is indicated for *C*. *gattii* neurologic cryptococcosis (6 weeks) and when localized to lung (2 weeks)" [^33] before moving to an azole. The MIC to fluconazole has been slowly rising and the data is from when the organism was more susceptible. Get an MIC to fluconazole. There is a very compelling argument made that 800 mg a day should be the minimal dose, more as the MIC rises, and that "using low dose fluconazole at 100 mg/day for pre-emptive therapy in asymptomatic CrAg-positive persons does not make rational sense." [^34] DO NOT give adjunctive dexamethasone. Patients do worse, [^35] especially HIV disease [^36], although one patient who went blind got better with steroids. [^37] Every now and again a pulmonary nodule is removed thinking it is a cancer and it turns out to be *Cryptococcus*. Whoops. I have seen a few in my day. How long do they need treatment? Likely 2 months assuming no CNS involvement. [^38] Who may need a shunt? > "By multivariable analysis, baseline opening pressure >30 cm H2O, being a normal host, and hydrocephalus, were associated with increased odds of shunting." [^39] In AIDS patients, wait 4 to 10 weeks after starting before HAART to avoid IRIS OR fluconazole +/- flucytosine. The fluconazole should be 400 mg/d at a minimum and continued for life at 200 mg qd in HIV. Less thrilling would be fluconazole alone. If you can't give flucytosine, then give more amphotericin, longer. Fluconazole resistance was 10.6% for initial isolates and 24.1% for relapse isolates. [^40] In resource-poor areas (Malawi or the US thanks to our lack of health care) 14 days of fluconazole (1200 mg per day) in combination with flucytosine (100 mg/kg per day) followed by fluconazole (800 mg per day) had reasonable outcomes in HIV patients. [^41] In recalcitrant disease, consider adding interferon-gamma. [^42] In one paper they succeeded with liposomal amphotericin B, intravenous voriconazole, and subcutaneous recombinant interferon γ­1b. [^43] ### Notes As is so often the case, patients with ID consultation, while sicker, have decreased mortality. [^44] What flabbers my gaster is there were docs at Washington School of Medicine who would manage the disease without ID consultation. Talk about a dumbass, suffering from the delusion that they know what they are doing. Dunning-Kruger. It kills. [^45] *Cryptococcus* *gattii* is a worser disease: more cryptococcomas, less responsive to fluconazole , slower to respond to Amphotericin B . My bias (supported by the literature of course [^46] is to treat with higher dose Amphotericin B at least 0.8 mg/kg d with flucytosine initially and the change to fluconazole . All the azole antifungals are probably the same (except itraconazole). [^47] The mean duration of therapy for eradication with *C*. *gattii* is 18 months, although some patients can take 2-3 years to eradicate the organism. [^49] All strains of *C*. *gattii* have heteroresistance, with mic's that ranged between 4 μg/ml and 32 μg/ml. More *C*. *gattii* strains (86%) than *Cryptococcus* *neoformans* strains (46%) exhibited mic's that were 16 μg/ml. [^48] This may be particularly true of strains from the great Pacific Northwest [^50] and the MIC to fluconazole is increasing in other parts of the world. [^51] *Cryptococcus* *neoformans* var *grubii* has higher MICs to fluconazole, amphotericin and flucytosine and a worse prognosis. [^52] Higher mic's to fluconazole (>=16) portend a bad outcome; either push the fluconazole or perhaps use voriconazole. And don't use caspofungin; it does not work. AIDS patients will have a positive serum cryptococcal antigen when the disease is in the CNS, transplant patients usually will not. So a negative serum antigen means that HIV patient does not have *Cryptococcus* in the CNS; this is not true in the transplant patient. Usually. The endpoint for treating the non-AIDS patient is normal LP, not some arbitrary duration of therapy as in the two classic NEJM articles on the treatment of cryptococcal meningitis. They are crap and are a study in how to kill as many people as possible. They under-treated both in dose and duration with the amphotericin. I repeat, the articles are crap. In Africa, > "Deferring ART for 5 weeks after the diagnosis of cryptococcal meningitis was associated with significantly improved survival, as compared with initiating ART at 1 to 2 weeks, especially among patients with a paucity of white cells in cerebral spinal fluid." [^53] [^54] Increased intracranial pressure with therapy is not uncommon and treat with LP and remove large volumes of CSF (do if opening pressure >25). May need to do daily.  On one HIV study, at least one therapeutic LP decreased mortality. "The association was observed regardless of opening pressure at baseline." [^55] Normal patients can get an arachnoiditis after therapy presenting with severe lower motor neuron involvement, cognitive changes, gait disturbances, asymmetric weakness and urinary retention.[^56] Long term morbidity and mortality is common ([PubMed](https://www.ncbi.nlm.nih.gov/pubmed/29028957)). 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J Infect. 2016 Jun;72(6):745-752. doi: 10.1016/j.jinf.2016.02.018. Epub 2016 Mar 30. PMID: 27038502. [^2]: Takazono T, Saijo T, Ashizawa N, Oshima K, Nishimura K, Tashiro M, Yamamoto K, Imamura Y, Miyazaki T, Yanagihara K, Mukae H, Izumikawa K, Sheppard DC. Clinical features and cause analysis of false positive results of Aspergillus galactomannan assay in pulmonary cryptococcosis patients. Eur J Clin Microbiol Infect Dis. 2019 Apr;38(4):735-741. doi: 10.1007/s10096-019-03469-3. Epub 2019 Jan 25. PMID: 30684164. [^3]: Dizon E, Seo W, Butler-Wu SM, She RC. Clinical Significance of Low Serum Cryptococcal Antigen Titers by Lateral Flow Assay in Immunocompromised Patients: a Retrospective Case-Control Study. J Clin Microbiol. 2020 Jan 28;58(2):e01648-19. doi: 10.1128/JCM.01648-19. PMID: 31723013; PMCID: PMC6989075. [^4]: Soma Rohatgi and others, Antibody and B Cell Subset Perturbations in Human Immunodeficiency Virus-Uninfected Patients With Cryptococcosis, _Open Forum Infectious Diseases_, Volume 5, Issue 1, January 2018, ofx255, [https://doi.org/10.1093/ofid/ofx255](https://doi.org/10.1093/ofid/ofx255) [^5]: Ige A George and others, Comparative Epidemiology and Outcomes of Human Immunodeficiency virus (HIV), Non-HIV Non-transplant, and Solid Organ Transplant Associated Cryptococcosis: A Population-Based Study, _Clinical Infectious Diseases_, Volume 66, Issue 4, 15 February 2018, Pages 608–611, [https://doi.org/10.1093/cid/cix867](https://doi.org/10.1093/cid/cix867) [^6]: # Presentation and Mortality of Cryptococcal Infection Varies by Predisposing Illness: A Retrospective Cohort Study [^7]: Singh N, Alexander BD, Lortholary O, Dromer F, Gupta KL, John GT, del Busto R, Klintmalm GB, Somani J, Lyon GM, Pursell K, Stosor V, Munoz P, Limaye AP, Kalil AC, Pruett TL, Garcia-Diaz J, Humar A, Houston S, House AA, Wray D, Orloff S, Dowdy LA, Fisher RA, Heitman J, Wagener MM, Husain S; Cryptococcal Collaborative Transplant Study Group. Cryptococcus neoformans in organ transplant recipients: impact of calcineurin-inhibitor agents on mortality. J Infect Dis. 2007 Mar 1;195(5):756-64. doi: 10.1086/511438. Epub 2007 Jan 23. PMID: 17262720; PMCID: PMC2746485. [^8]: McKenney J, Smith RM, Chiller TM, Detels R, French A, Margolick J, Klausner JD; Centers for Disease Control and Prevention. Prevalence and correlates of cryptococcal antigen positivity among AIDS patients--United States, 1986-2012. MMWR Morb Mortal Wkly Rep. 2014 Jul 11;63(27):585-7. PMID: 25006824; PMCID: PMC4584711. [^9]: Temfack E, Bigna JJ, Luma HN, Spijker R, Meintjes G, Jarvis JN, Dromer F, Harrison T, Cohen JF, Lortholary O. Impact of Routine Cryptococcal Antigen Screening and Targeted Preemptive Fluconazole Therapy in Antiretroviral-naive Human Immunodeficiency Virus-infected Adults With CD4 Cell Counts <100/μL: A Systematic Review and Meta-analysis. Clin Infect Dis. 2019 Feb 1;68(4):688-698. doi: 10.1093/cid/ciy567. PMID: 30020446. [^10]: Shapiro BB MD, MPH, Hedrick R, Vanle BC, Becker CA, Nguyen C, Underhill DM, Morgan MA, Kopple JD, Danovitch I, IsHak WW. Cryptococcal meningitis in a daily cannabis smoker without evidence of immunodeficiency. BMJ Case Rep. 2018 Jan 26;2018:bcr2017221435. doi: 10.1136/bcr-2017-221435. PMID: 29374632; PMCID: PMC5787011. [^11]: Harris JR, Lockhart SR, Sondermeyer G, Vugia DJ, Crist MB, D'Angelo MT, Sellers B, Franco-Paredes C, Makvandi M, Smelser C, Greene J, Stanek D, Signs K, Nett RJ, Chiller T, Park BJ. Cryptococcus gattii infections in multiple states outside the US Pacific Northwest. Emerg Infect Dis. 2013 Oct;19(10):1620-6. doi: 10.3201/eid1910.130441. PMID: 24050410; PMCID: PMC3810751. [^12]: Ewa Bielska , Robin C. May, What makes _Cryptococcus gattii_ a pathogen?, _FEMS Yeast Research_, Volume 16, Issue 1, February 2016, fov106, [https://doi.org/10.1093/femsyr/fov106](https://doi.org/10.1093/femsyr/fov106) [^13]: Fraser, J., Giles, S., Wenink, E. _et al._ Same-sex mating and the origin of the Vancouver Island _Cryptococcus gattii_ outbreak. _Nature_ **437**, 1360–1364 (2005). https://doi.org/10.1038/nature04220 [^14]: Bruner KT, Franco-Paredes C, Henao-Martínez AF, et al. Cryptococcus gattii Complex Infections in HIV-Infected Patients, Southeastern United States. _Emerging Infectious Diseases_. 2018;24(11):1998-2002. doi:10.3201/eid2411.180787. [^15]: Hagen F, Colom M, Swinne D, et al. Autochthonous and Dormant Cryptococcus gattii Infections in Europe. _Emerging Infectious Diseases_. 2012;18(10):1618-1624. doi:10.3201/eid1810.120068. [^16]: Bruner KT, Franco-Paredes C, Henao-Martínez AF, et al. Cryptococcus gattii Complex Infections in HIV-Infected Patients, Southeastern United States. _Emerging Infectious Diseases_. 2018;24(11):1998-2002. doi:10.3201/eid2411.180787. [^17]: Castrodale LJ, Gerlach RF, Preziosi DE, Frederickson P, Lockhart SR. Prolonged incubation period for Cryptococcus gattii infection in cat, Alaska, USA. Emerg Infect Dis. 2013 Jun;19(6):1034-5. doi: 10.3201/eid1906.130006. PMID: 23735429; PMCID: PMC3713837. [^18]: Chamilos G, Lionakis MS, Kontoyiannis DP. Call for Action: Invasive Fungal Infections Associated With Ibrutinib and Other Small Molecule Kinase Inhibitors Targeting Immune Signaling Pathways. Clin Infect Dis. 2018 Jan 6;66(1):140-148. doi: 10.1093/cid/cix687. PMID: 29029010; PMCID: PMC5850040. [^19]: Browne SK, Burbelo PD, Chetchotisakd P, Suputtamongkol Y, Kiertiburanakul S, Shaw PA, Kirk JL, Jutivorakool K, Zaman R, Ding L, Hsu AP, Patel SY, Olivier KN, Lulitanond V, Mootsikapun P, Anunnatsiri S, Angkasekwinai N, Sathapatayavongs B, Hsueh PR, Shieh CC, Brown MR, Thongnoppakhun W, Claypool R, Sampaio EP, Thepthai C, Waywa D, Dacombe C, Reizes Y, Zelazny AM, Saleeb P, Rosen LB, Mo A, Iadarola M, Holland SM. Adult-onset immunodeficiency in Thailand and Taiwan. N Engl J Med. 2012 Aug 23;367(8):725-34. doi: 10.1056/NEJMoa1111160. PMID: 22913682; PMCID: PMC4190026. [^20]: Wen Zeng and others, Characterization of Anti–Interferon-γ Antibodies in HIV-Negative Patients Infected With Disseminated _Talaromyces marneffei_ and Cryptococcosis, _Open Forum Infectious Diseases_, Volume 6, Issue 10, October 2019, ofz208, [https://doi.org/10.1093/ofid/ofz208](https://doi.org/10.1093/ofid/ofz208) [^21]: Rosen LB, Freeman AF, Yang LM, Jutivorakool K, Olivier KN, Angkasekwinai N, Suputtamongkol Y, Bennett JE, Pyrgos V, Williamson PR, Ding L, Holland SM, Browne SK. Anti-GM-CSF autoantibodies in patients with cryptococcal meningitis. J Immunol. 2013 Apr 15;190(8):3959-66. doi: 10.4049/jimmunol.1202526. Epub 2013 Mar 18. PMID: 23509356; PMCID: PMC3675663. [^22]: Saijo T, Chen J, Chen SC, Rosen LB, Yi J, Sorrell TC, Bennett JE, Holland SM, Browne SK, Kwon-Chung KJ. Anti-granulocyte-macrophage colony-stimulating factor autoantibodies are a risk factor for central nervous system infection by Cryptococcus gattii in otherwise immunocompetent patients. mBio. 2014 Mar 18;5(2):e00912-14. doi: 10.1128/mBio.00912-14. PMID: 24643864; PMCID: PMC3967522. [^23]: Panackal AA, Rosen LB, Uzel G, Davis MJ, Hu G, Adeyemo A, Tekola-Ayele F, Lisco A, Diachok C, Kim JD, Shaw D, Sereti I, Stoddard J, Niemela J, Rosenzweig SD, Bennett JE, Williamson PR. Susceptibility to Cryptococcal Meningoencephalitis Associated With Idiopathic CD4+ Lymphopenia and Secondary Germline or Acquired Defects. Open Forum Infect Dis. 2017 Jun 7;4(2):ofx082. doi: 10.1093/ofid/ofx082. PMID: 28638843; PMCID: PMC5461987. [^24]: Choe YH, Moon H, Park SJ, Kim SR, Han HJ, Lee KS, Lee YC. Pulmonary cryptococcosis in asymptomatic immunocompetent hosts. Scand J Infect Dis. 2009;41(8):602-7. doi: 10.1080/00365540903036212. PMID: 19513938. [^25]: Ssebambulidde K, Bangdiwala AS, Kwizera R, Kandole TK, Tugume L, Kiggundu R, Mpoza E, Nuwagira E, Williams DA, Lofgren SM, Abassi M, Musubire AK, Cresswell FV, Rhein J, Muzoora C, Hullsiek KH, Boulware DR, Meya DB; Adjunctive Sertraline for Treatment of HIV-associated Cryptococcal Meningitis Team. Symptomatic Cryptococcal Antigenemia Presenting as Early Cryptococcal Meningitis With Negative Cerebral Spinal Fluid Analysis. Clin Infect Dis. 2019 May 30;68(12):2094-2098. doi: 10.1093/cid/ciy817. PMID: 30256903; PMCID: PMC6541705. [^26]: Bicanic T, Muzoora C, Brouwer AE, Meintjes G, Longley N, Taseera K, Rebe K, Loyse A, Jarvis J, Bekker LG, Wood R, Limmathurotsakul D, Chierakul W, Stepniewska K, White NJ, Jaffar S, Harrison TS. Independent association between rate of clearance of infection and clinical outcome of HIV-associated cryptococcal meningitis: analysis of a combined cohort of 262 patients. Clin Infect Dis. 2009 Sep 1;49(5):702-9. doi: 10.1086/604716. PMID: 19613840; PMCID: PMC2965403. [^27]: Wake RM, Britz E, Sriruttan C, Rukasha I, Omar T, Spencer DC, Nel JS, Mashamaite S, Adelekan A, Chiller TM, Jarvis JN, Harrison TS, Govender NP. High Cryptococcal Antigen Titers in Blood Are Predictive of Subclinical Cryptococcal Meningitis Among Human Immunodeficiency Virus-Infected Patients. Clin Infect Dis. 2018 Feb 10;66(5):686-692. doi: 10.1093/cid/cix872. PMID: 29028998; PMCID: PMC6220350. 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