:Cryptococcosis

Cryptococcus is generally classified according to how it is acquired and the site of infection.{{cite journal | vauthors = Alanazi AH, Adil MS, Lin X, Chastain DB, Henao-Martínez AF, Franco-Paredes C, Somanath PR | title = Elevated Intracranial Pressure in Cryptococcal Meningoencephalitis: Examining Old, New, and Promising Drug Therapies | journal = Pathogens | volume = 11 | issue = 7 | page = 783 | date = July 2022 | pmid = 35890028 | pmc = 9321092 | doi = 10.3390/pathogens11070783 | doi-access = free }} It typically begins in the lungs before spreading to other parts of the body, particularly the brain and nervous system. Skin involvement is less common.

Cough, shortness of breath, chest pain, and fever are seen when the lungs are infected, appearing like a pneumonia. There may also be feeling of tiredness. When the brain is infected, symptoms include headache, fever, neck pain, nausea and vomiting, light sensitivity, confusion, or changes in behaviour. It can also affect other parts of the body including skin, eyes, bones, and prostate. In the skin, it may appear as several fluid-filled nodules with dead tissue. Depending on the site of infection, other features may include loss of vision, blurred vision, inability to move an eye, and memory loss.

Symptom onset is often sudden when lungs are infected and gradual over several weeks when the central nervous system is affected.

Signs and symptoms of cryptococcal infection may be delayed in those with HIV or AIDS. A positive cryptococcal antigen test may precede symptoms by 3 weeks in those with HIV/AIDS. Others may have re-activation of latent cryptococcal disease years later. In those with HIV, approximately 50% of people have a fever, but fever is rare in previously healthy and immunocompetent people with cryptococcosis.

Cryptococcosis is a common opportunistic infection for AIDS and is particularly common among people living with AIDS in Africa. Other conditions that pose an increased risk include certain malignancies (such as lymphoma), liver cirrhosis, organ transplants, and long-term corticosteroid therapy.{{cite journal | vauthors = Setianingrum F, Rautemaa-Richardson R, Denning DW | title = Pulmonary cryptococcosis: A review of pathobiology and clinical aspects | journal = Medical Mycology | volume = 57 | issue = 2 | pages = 133–150 | date = February 2019 | pmid = 30329097 | doi = 10.1093/mmy/myy086 | doi-access = free }}

Distribution is worldwide in soil.{{cite encyclopedia |title=Meningitis: cryptococcal: Overview |date=September 2010 |encyclopedia=Medical Reference: Encyclopedia |publisher=University of Maryland Medical Center |url=http://www.umm.edu/ency/article/000642.htm |access-date=2011-04-26 |archive-date=2013-05-23 |archive-url=https://web.archive.org/web/20130523235445/http://www.umm.edu/ency/article/000642.htm |url-status=dead }} The prevalence of cryptococcosis has been increasing over the past 50 years for many reasons, including the increase in incidence of AIDS and the expanded use of immunosuppressive drugs.{{cite journal | vauthors = Gushiken AC, Saharia KK, Baddley JW | title = Cryptococcosis | journal = Infectious Disease Clinics of North America | volume = 35 | issue = 2 | pages = 493–514 | date = June 2021 | pmid = 34016288 | doi = 10.1016/j.idc.2021.03.012 | s2cid = 235074157 }}

In humans, C. neoformans chiefly infects the skin, lungs, and central nervous system (causing meningitis). Less commonly it may affect other organs such as the eye or prostate.

Primary cutaneous cryptococcosis (PCC) is a distinct clinical diagnosis separate from the secondary cutaneous cryptococcosis that is spread by systematic infection. Males are more likely to develop the infection and a 2020 study showed that the sex bias may be due to a growth hormone, produced by C. neoformans called gibberellic acid (GA) that is upregulated by testosterone.{{cite journal | vauthors = Tucker JS, Guess TE, McClelland EE | title = The Role of Testosterone and Gibberellic Acid in the Melanization of Cryptococcus neoformans | journal = Frontiers in Microbiology | volume = 11 | issue = | pages = 1921 | date = 2020 | pmid = 32922377 | pmc = 7456850 | doi = 10.3389/fmicb.2020.01921 | doi-access = free }} The upper limbs account for a majority of infections. Isolates found in PCC include Cryptococcus neoformans (most common), Cryptococcus gattii, and Cryptococcus laurentii. The prognosis for PCC is generally good outside of disseminated infection.{{cite journal | vauthors = Du L, Yang Y, Gu J, Chen J, Liao W, Zhu Y | title = Systemic Review of Published Reports on Primary Cutaneous Cryptococcosis in Immunocompetent Patients | journal = Mycopathologia | volume = 180 | issue = 1–2 | pages = 19–25 | date = August 2015 | pmid = 25736173 | doi = 10.1007/s11046-015-9880-7 }}

Morphologic description of the lesions shows umbilicated papules, nodules, and violaceous plaques that can mimic other cutaneous diseases like molluscum contagiosum and Kaposi's sarcoma. These lesions may be present months before other signs of system infection in patients with AIDS.{{cite journal | vauthors = Murakawa GJ, Kerschmann R, Berger T | title = Cutaneous Cryptococcus infection and AIDS. Report of 12 cases and review of the literature | journal = Archives of Dermatology | volume = 132 | issue = 5 | pages = 545–548 | date = May 1996 | pmid = 8624151 | doi = 10.1001/archderm.1996.03890290079010 }}

Cryptococcus (both C. neoformans and C. gattii) plays a common role in pulmonary invasive mycosis seen in adults with HIV and other immunocompromised conditions. It also affects healthy adults at a much lower frequency and severity as healthy hosts may have no or mild symptoms.{{cite journal | vauthors = Choi KH, Park SJ, Min KH, Kim SR, Lee MH, Chung CR, Han HJ, Lee YC | title = Treatment of asymptomatic pulmonary cryptococcosis in immunocompetent hosts with oral fluconazole | journal = Scandinavian Journal of Infectious Diseases | volume = 43 | issue = 5 | pages = 380–385 | date = May 2011 | pmid = 21271944 | doi = 10.3109/00365548.2011.552521 }} Immune-competent hosts may not seek or require treatment, but careful observation may be important.{{cite journal | vauthors = Saag MS, Graybill RJ, Larsen RA, Pappas PG, Perfect JR, Powderly WG, Sobel JD, Dismukes WE | title = Practice guidelines for the management of cryptococcal disease. Infectious Diseases Society of America | journal = Clinical Infectious Diseases | volume = 30 | issue = 4 | pages = 710–718 | date = April 2000 | pmid = 10770733 | doi = 10.1086/313757 }} Cryptococcal pneumonia has the potential to disseminate to the central nervous system (CNS), especially in immunocompromised individuals.{{cite journal | vauthors = Brizendine KD, Baddley JW, Pappas PG | title = Pulmonary cryptococcosis | journal = Seminars in Respiratory and Critical Care Medicine | volume = 32 | issue = 6 | pages = 727–734 | date = December 2011 | pmid = 22167400 | doi = 10.1055/s-0031-1295720 }}

Pulmonary cryptococcosis has a worldwide distribution and is commonly underdiagnosed due to limitations in diagnostic capabilities. Since pulmonary nodules are its most common radiological feature, they can clinically and radiologically mimic lung cancer, TB, and other pulmonary mycoses. The sensitivity of cultures and the Cryptococcal (CrAg) antigen with lateral flow device on serum are rarely positive in the absence of disseminated disease. Moreover, pulmonary cryptococcosis worsens the prognosis of cryptococcal meningitis.

Image:Meningitis criptocócica diseminada.png

{{See also|Chronic meningitis}}

Cryptococcal meningitis (infection of the meninges, the tissue covering the brain) is believed to result from the dissemination of the fungus from either an observed or undetected pulmonary infection. Often there is also silent dissemination throughout the brain when meningitis is present. People with defects in their cell-mediated immunity, for example, people with AIDS, are especially susceptible to disseminated cryptococcosis. Cryptococcosis is often fatal, even if treated. It is estimated that the three-month case-fatality rate is 9% in high-income regions, 55% in low/middle-income regions, and 70% in sub-Saharan Africa. As of 2009 there were globally approximately 958,000 annual cases and 625,000 deaths within three months after infection.{{cite journal | vauthors = Park BJ, Wannemuehler KA, Marston BJ, Govender N, Pappas PG, Chiller TM | title = Estimation of the current global burden of cryptococcal meningitis among persons living with HIV/AIDS | journal = AIDS | volume = 23 | issue = 4 | pages = 525–530 | date = February 2009 | pmid = 19182676 | doi = 10.1097/QAD.0b013e328322ffac | s2cid = 5735550 | doi-access = free }}

Although C. neoformans infection most commonly occurs as an opportunistic infection in immunocompromised people (such as those living with AIDS), C. gattii often infects immunocompetent people as well.{{cite journal | vauthors = D'Souza CA, Kronstad JW, Taylor G, Warren R, Yuen M, Hu G, Jung WH, Sham A, Kidd SE, Tangen K, Lee N, Zeilmaker T, Sawkins J, McVicker G, Shah S, Gnerre S, Griggs A, Zeng Q, Bartlett K, Li W, Wang X, Heitman J, Stajich JE, Fraser JA, Meyer W, Carter D, Schein J, Krzywinski M, Kwon-Chung KJ, Varma A, Wang J, Brunham R, Fyfe M, Ouellette BF, Siddiqui A, Marra M, Jones S, Holt R, Birren BW, Galagan JE, Cuomo CA | title = Genome variation in Cryptococcus gattii, an emerging pathogen of immunocompetent hosts | journal = mBio | volume = 2 | issue = 1 | pages = e00342–e00310 | date = 2011-02-08 | pmid = 21304167 | pmc = 3037005 | doi = 10.1128/mBio.00342-10 | publisher = American Society for Microbiology }}

Cryptococcus species (both C. neoformans and C. gattii) are responsible for 68% of meningitis cases in those with HIV.{{cite journal | vauthors = Meya DB, Williamson PR | title = Cryptococcal Disease in Diverse Hosts | journal = The New England Journal of Medicine | volume = 390 | issue = 17 | pages = 1597–1610 | date = May 2024 | pmid = 38692293 | doi = 10.1056/NEJMra2311057 }} Cryptococcus is considered an "emerging" disease in healthy adults.{{cite journal | vauthors = Pasquier E, Kunda J, De Beaudrap P, Loyse A, Temfack E, Molloy SF, Harrison TS, Lortholary O | title = Long-term Mortality and Disability in Cryptococcal Meningitis: A Systematic Literature Review | journal = Clinical Infectious Diseases | volume = 66 | issue = 7 | pages = 1122–1132 | date = March 2018 | pmid = 29028957 | doi = 10.1093/cid/cix870 }} Though the rate of infection is clearly higher with immunocompromised individuals, some studies suggest a higher mortality rate in patients with non-HIV cryptococcal meningitis secondary to the role of T-cell mediated reaction and injury.{{cite journal | vauthors = Anjum S, Williamson PR | title = Clinical Aspects of Immune Damage in Cryptococcosis | journal = Current Fungal Infection Reports | volume = 13 | issue = 3 | pages = 99–108 | date = September 2019 | pmid = 33101578 | pmc = 7580832 | doi = 10.1007/s12281-019-00345-7 }} CD4+ T cells have proven roles in the defense against Cryptococcus, but it can also contribute to clinical deterioration due its inflammatory response.{{cite journal | vauthors = Neal LM, Xing E, Xu J, Kolbe JL, Osterholzer JJ, Segal BM, Williamson PR, Olszewski MA | title = CD4⁺ T Cells Orchestrate Lethal Immune Pathology despite Fungal Clearance during Cryptococcus neoformans Meningoencephalitis | journal = mBio | volume = 8 | issue = 6 | pages = e01415–17 | date = November 2017 | pmid = 29162707 | pmc = 5698549 | doi = 10.1128/mBio.01415-17 }}

Symptom onset is often subacute, progressively worsened over several weeks, and delays in diagnosis are associated with increased mortality.

Cerebrospinal fluid (CSF) or blood antigen testing by lateral flow assay for cryptococcal antigens has a sensitivity and specificity greater than 99% for cryptococcosis. A CSF fungal culture can tell if there is a microbiological failure (failure of the fungal infections to treat the infection). CSF fungal culture has a 90% sensitivity and 100% specificity for the diagnosis of cryptococcal meningitis. CSF cell analysis is characterized by increased lymphocytes, reduced protein, and reduced glucose. For any person who has cryptococcosis at a site outside of the central nervous system (e.g., pulmonary cryptococcosis), a lumbar puncture is indicated to evaluate the cerebrospinal fluid (CSF) for evidence of cryptococcal meningitis, even if they do not have signs or symptoms of CNS disease. Detection of cryptococcal antigen (capsular material) by culture of CSF, sputum and urine provides definitive diagnosis. Blood cultures may be positive in heavy infections. India ink of the CSF is a traditional microscopic method of diagnosis,{{cite journal | vauthors = Zerpa R, Huicho L, Guillén A | title = Modified India ink preparation for Cryptococcus neoformans in cerebrospinal fluid specimens | journal = Journal of Clinical Microbiology | volume = 34 | issue = 9 | pages = 2290–2291 | date = September 1996 | pmid = 8862601 | pmc = 229234 | doi = 10.1128/JCM.34.9.2290-2291.1996 }} although the sensitivity is poor in early infection, and may miss 15–20% of patients with culture-positive cryptococcal meningitis.{{cite journal | vauthors = Boulware DR, Rolfes MA, Rajasingham R, von Hohenberg M, Qin Z, Taseera K, Schutz C, Kwizera R, Butler EK, Meintjes G, Muzoora C, Bischof JC, Meya DB | title = Multisite validation of cryptococcal antigen lateral flow assay and quantification by laser thermal contrast | journal = Emerging Infectious Diseases | volume = 20 | issue = 1 | pages = 45–53 | date = January 2014 | pmid = 24378231 | pmc = 3884728 | doi = 10.3201/eid2001.130906 }} Rapid diagnostic methods to detect cryptococcal antigen include latex agglutination testing, lateral flow immunochromatographic assay (LFA), or enzyme immunoassay (EIA). Polymerase chain reaction (PCR) has been used on tissue specimens, with PCR having a sensitivity of 82% and a specificity of 98% for cryptococcal infection.

Image:Cryptococcosis of lung in patient with AIDS. Mucicarmine stain 962 lores.jpg

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Image:Pulmonary cryptococcosis (3) Alcian blue-PAS.jpg

Image:Cryptococcus smear MGG 2010-01-26.JPG

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Image:Cryptococcus smear PAS 2010-01-26.JPG

Cryptococcosis is a very subacute infection with a prolonged subclinical phase lasting weeks to months in persons with HIV/AIDS before the onset of symptomatic meningitis. In Sub-Saharan Africa, the prevalence rate of detectable cryptococcal antigen in peripheral blood is often 4–12% in persons with CD4 counts lower than 100 cells/mcL.{{cite web|title=FIGURE 1. Prevalence of asymptomatic antigenemia with corresponding cost per life saved based on LFA cost of $2.50 per test.|url=http://journals.lww.com/jaids/_layouts/oaks.journals/ImageView.aspx?k=jaids:2012:04150:00011&i=FF1&year=2012&issue=04150&article=00011}}{{cite journal | vauthors = Meya DB, Manabe YC, Castelnuovo B, Cook BA, Elbireer AM, Kambugu A, Kamya MR, Bohjanen PR, Boulware DR | title = Cost-effectiveness of serum cryptococcal antigen screening to prevent deaths among HIV-infected persons with a CD4+ cell count < or = 100 cells/microL who start HIV therapy in resource-limited settings | journal = Clinical Infectious Diseases | volume = 51 | issue = 4 | pages = 448–455 | date = August 2010 | pmid = 20597693 | pmc = 2946373 | doi = 10.1086/655143 }}

Cryptococcal antigen screen and preemptive treatment with fluconazole is cost-saving to the healthcare system by avoiding cryptococcal meningitis.{{cite journal | vauthors = Rajasingham R, Meya DB, Boulware DR | title = Integrating cryptococcal antigen screening and pre-emptive treatment into routine HIV care | journal = Journal of Acquired Immune Deficiency Syndromes | volume = 59 | issue = 5 | pages = e85–e91 | date = April 2012 | pmid = 22410867 | pmc = 3311156 | doi = 10.1097/QAI.0b013e31824c837e }} The World Health Organization recommends cryptococcal antigen screening in HIV-infected persons entering care with CD4<100 cells/μL. This undetected subclinical cryptococcal (if not preemptively treated with anti-fungal therapy) will often go on to develop cryptococcal meningitis, despite receiving HIV therapy.{{cite journal | vauthors = Jarvis JN, Harrison TS, Govender N, Lawn SD, Longley N, Bicanic T, Maartens G, Venter F, Bekker LG, Wood R, Meintjes G | title = Routine cryptococcal antigen screening for HIV-infected patients with low CD4+ T-lymphocyte counts--time to implement in South Africa? | journal = South African Medical Journal = Suid-Afrikaanse Tydskrif vir Geneeskunde | volume = 101 | issue = 4 | pages = 232–234 | date = April 2011 | pmid = 21786721 | doi = 10.7196/samj.4752 | doi-broken-date = 2024-11-10 | doi-access = free }} Cryptococcosis accounts for 20–25% of the mortality after initiating HIV therapy in Africa. What is effective preemptive treatment is unknown, with the current recommendations on dose and duration based on expert opinion. Screening in the United States is controversial, with official guidelines not recommending screening, despite cost-effectiveness and a 3% U.S. cryptococcal antigen prevalence in CD4<100 cells/μL.{{cite journal | vauthors = Rajasingham R, Boulware DR | title = Reconsidering cryptococcal antigen screening in the U.S. among persons with CD4 <100 cells/mcL | journal = Clinical Infectious Diseases | volume = 55 | issue = 12 | pages = 1742–1744 | date = December 2012 | pmid = 22918997 | pmc = 3501329 | doi = 10.1093/cid/cis725 }}{{cite journal | vauthors = McKenney J, Smith RM, Chiller TM, Detels R, French A, Margolick J, Klausner JD | title = Prevalence and correlates of cryptococcal antigen positivity among AIDS patients--United States, 1986-2012 | journal = MMWR. Morbidity and Mortality Weekly Report | volume = 63 | issue = 27 | pages = 585–587 | date = July 2014 | pmid = 25006824 | pmc = 4584711 }}

Antifungal prophylaxis such as fluconazole and itraconazole reduces the risk of contracting cryptococcosis in those with low CD4 cell count and high risk of developing such disease in a setting of cryptococcal antigen screening tests are not available.{{cite journal | vauthors = Awotiwon AA, Johnson S, Rutherford GW, Meintjes G, Eshun-Wilson I | title = Primary antifungal prophylaxis for cryptococcal disease in HIV-positive people | journal = The Cochrane Database of Systematic Reviews | volume = 2018 | issue = 8 | pages = CD004773 | date = August 2018 | pmid = 30156270 | pmc = 6513489 | doi = 10.1002/14651858.CD004773.pub3 | collaboration = Cochrane Infectious Diseases Group }}

Treatment options in persons without HIV infection have not been well studied. Intravenous Amphotericin B combined with flucytosine by mouth is recommended for initial treatment (induction therapy).{{cite web |title=Practice Guidelines for the Management of Cryptococcal Disease |publisher=Infectious Disease Society of America |year=2010 |url=http://www.idsociety.org/Organism/#CryptococcalDisease |access-date=2013-09-14 |archive-date=2018-07-25 |archive-url=https://web.archive.org/web/20180725230335/http://www.idsociety.org/organism/#CryptococcalDisease |url-status=dead }}

People living with AIDS often have a greater burden of disease and higher mortality (30–70% at 10 weeks), recommended therapy is with amphotericin B and flucytosine. Adding flucytosine to amphotericin B is associated with earlier fungal clearance and increased survival, however, it is not readily available in many lower-income regions. Where flucytosine is not available, fluconazole should be used with amphotericin.{{cite web|last=World Health Organization|title=Rapid advice: Diagnosis, prevention and management of cryptococcal disease in HIV-infected adults, adolescents, and children|url=https://www.who.int/hiv/pub/cryptococcal_disease2011/en/|archive-url=https://web.archive.org/web/20140221174558/http://www.who.int/hiv/pub/cryptococcal_disease2011/en/|url-status=dead|archive-date=February 21, 2014|access-date=1 August 2012}} Amphotericin-based induction therapy has much greater microbiologic activity than fluconazole monotherapy with 30% better survival at 10 weeks.{{cite journal| vauthors = Rhein J, Boulware DR|title=Prognosis and management of cryptococcal meningitis in patients with HIV infection|journal=Neurobehavioral HIV Medicine |year=2012 |volume=4 |pages=45 |doi=10.2147/NBHIV.S24748 |doi-access=free}}{{cite journal | vauthors = Rajasingham R, Rolfes MA, Birkenkamp KE, Meya DB, Boulware DR | title = Cryptococcal meningitis treatment strategies in resource-limited settings: a cost-effectiveness analysis | journal = PLOS Medicine | volume = 9 | issue = 9 | pages = e1001316 | year = 2012 | pmid = 23055838 | pmc = 3463510 | doi = 10.1371/journal.pmed.1001316 | veditors = Farrar J | doi-access = free }} Based on a systematic review, the most cost-effective induction treatment in resource-limited settings appears to be one week of amphotericin B coupled with high-dose fluconazole. After initial induction treatment as above, typical consolidation therapy is with oral fluconazole for at least 8 weeks used with secondary prophylaxis with fluconazole thereafter.

The decision on when to start treatment for HIV appears to be very different than other opportunistic infections. A large multi-site trial supports deferring ART for 4–6 weeks was overall preferable with 15% better 1-year survival than earlier ART initiation at 1–2 weeks after diagnosis.{{cite journal | vauthors = Boulware DR, Meya DB, Muzoora C, Rolfes MA, Huppler Hullsiek K, Musubire A, Taseera K, Nabeta HW, Schutz C, Williams DA, Rajasingham R, Rhein J, Thienemann F, Lo MW, Nielsen K, Bergemann TL, Kambugu A, Manabe YC, Janoff EN, Bohjanen PR, Meintjes G | title = Timing of antiretroviral therapy after diagnosis of cryptococcal meningitis | journal = The New England Journal of Medicine | volume = 370 | issue = 26 | pages = 2487–2498 | date = June 2014 | pmid = 24963568 | pmc = 4127879 | doi = 10.1056/NEJMoa1312884 }} A 2018 Cochrane review also supports the delayed starting of treatment until cryptococcosis starts improving with antifungal treatment.{{cite journal | vauthors = Eshun-Wilson I, Okwen MP, Richardson M, Bicanic T | title = Early versus delayed antiretroviral treatment in HIV-positive people with cryptococcal meningitis | journal = The Cochrane Database of Systematic Reviews | volume = 2018 | issue = 7 | pages = CD009012 | date = July 2018 | pmid = 30039850 | pmc = 6513637 | doi = 10.1002/14651858.CD009012.pub3 }}

Increased intracranial pressure is seen in about 50% of those with HIV-associated cryptococcal meningitis and is usually associated with a high fungal burden. Regular (often daily) lumbar punctures to lower the intracranial pressure by draining CSF are associated with reduced mortality in those with cryptococcal meningitis (with or without HIV).{{cite journal | vauthors = Rolfes MA, Hullsiek KH, Rhein J, Nabeta HW, Taseera K, Schutz C, Musubire A, Rajasingham R, Williams DA, Thienemann F, Muzoora C, Meintjes G, Meya DB, Boulware DR | title = The effect of therapeutic lumbar punctures on acute mortality from cryptococcal meningitis | journal = Clinical Infectious Diseases | volume = 59 | issue = 11 | pages = 1607–1614 | date = December 2014 | pmid = 25057102 | doi = 10.1093/cid/ciu596 | pmc = 4441057 }}{{cite journal | vauthors = Perfect JR, Dismukes WE, Dromer F, Goldman DL, Graybill JR, Hamill RJ, Harrison TS, Larsen RA, Lortholary O, Nguyen MH, Pappas PG, Powderly WG, Singh N, Sobel JD, Sorrell TC | title = Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the infectious diseases society of america | journal = Clinical Infectious Diseases | volume = 50 | issue = 3 | pages = 291–322 | date = February 2010 | pmid = 20047480 | pmc = 5826644 | doi = 10.1086/649858 }} But in those with suspicion of non-communicating hydrocephalus (which may present as focal neurologic symptoms or impaired mentation), a CT or MRI of the brain is required before lumbar puncture to rule out hydrocephalus, due to the risk of brain herniation with lumbar puncture. Non-communicating hydrocephalus is rare in those with HIV-associated cryptococcal meningitis.

Immune reconstitution inflammatory syndrome is possible in those with cryptococcal infection, especially those with concurrent HIV starting anti-retroviral therapy. With anti-retroviral therapies for HIV, the CD4+ T-cell counts recover and the restored immune system mounts an exaggerated, hyperinflammatory response against cryptococcal infection in the body.

IRIS has a 5% incidence in those with HIV and cryptococcosis starting anti-retroviral therapy. It usually occurs within 4 weeks of starting antiretroviral therapy. The risk of IRIS is increased in those with a high fungal burden, lower CD4+ T-cell count, and lower inflammatory marker levels.

Cryptococcosis is usually associated with immunosuppressed people, such as those with AIDs, corticosteroid use, diabetes, and organ transplant.{{cite book | vauthors = Mada PK, Jamil RT, Alam MU | chapter = Cryptococcus |date=2023 | chapter-url = http://www.ncbi.nlm.nih.gov/books/NBK431060/ | title = StatPearls |access-date=2023-11-15 |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=28613714 }} Cryptococcus comprizes two clinically relevant species, Cryptococcus neoformans and Cryptococcus gattii.{{cite journal | vauthors = Choi YH, Ngamskulrungroj P, Varma A, Sionov E, Hwang SM, Carriconde F, Meyer W, Litvintseva AP, Lee WG, Shin JH, Kim EC, Lee KW, Choi TY, Lee YS, Kwon-Chung KJ | title = Prevalence of the VNIc genotype of Cryptococcus neoformans in non-HIV-associated cryptococcosis in the Republic of Korea | journal = FEMS Yeast Research | volume = 10 | issue = 6 | pages = 769–778 | date = September 2010 | pmid = 20561059 | pmc = 2920376 | doi = 10.1111/j.1567-1364.2010.00648.x }} C. gattii was previously thought to only be found in tropical climates and in immunocompetent persons, but recent findings of C. gattii in regions such as Canada and Western regions of North America have challenged this initial presumption of the geographic patterns.{{cite journal | vauthors = Harris J, Lockhart S, Chiller T | title = Cryptococcus gattii: where do we go from here? | journal = Medical Mycology | volume = 50 | issue = 2 | pages = 113–129 | date = February 2012 | pmid = 21939343 | doi = 10.3109/13693786.2011.607854 | s2cid = 21577621 }}

Data from 2009 estimated that of the almost one million cases of cryptococcal meningitis that occurred worldwide annually, 700,000 occurred in sub-Saharan Africa and 600,000 per year died. In 2014, amongst people who had a low CD4+ cell count, the annual incidence rate was estimated to be 278,000 cases. Of those, 223,100 resulted in cryptococcal meningitis.{{cite journal | vauthors = Rajasingham R, Smith RM, Park BJ, Jarvis JN, Govender NP, Chiller TM, Denning DW, Loyse A, Boulware DR | title = Global burden of disease of HIV-associated cryptococcal meningitis: an updated analysis | journal = The Lancet. Infectious Diseases | volume = 17 | issue = 8 | pages = 873–881 | date = August 2017 | pmid = 28483415 | pmc = 5818156 | doi = 10.1016/S1473-3099(17)30243-8 }} About 73% of cryptococcal meningitis cases occurred in Sub-Saharan Africa. More than 180,000 fatalities are attributed to cryptococcal meningitis, 135,000 of which occur in sub-Saharan Africa. Case fatality of cryptococcal meningitis varies widely depending on what country the infection occurs. In low-income countries, the case fatality from cryptococcal meningitis is 70%. This differs from middle-income countries where the case fatality rate is 40%. In wealthy countries the case fatality is 20%. 19% of all AIDS-related deaths are due to cryptococcal disease.{{cite journal | vauthors = Rajasingham R, Govender NP, Jordan A, Loyse A, Shroufi A, Denning DW, Meya DB, Chiller TM, Boulware DR | title = The global burden of HIV-associated cryptococcal infection in adults in 2020: a modelling analysis | journal = The Lancet. Infectious Diseases | volume = 22 | issue = 12 | pages = 1748–1755 | date = December 2022 | pmid = 36049486 | pmc = 9701154 | doi = 10.1016/S1473-3099(22)00499-6 }} Cryptococcal disease is the second leading cause of death in those with HIV/AIDS, second only to tuberculosis, which is responsible for 40% of deaths.{{cite journal | vauthors = Meintjes G, Maartens G | title = HIV-Associated Tuberculosis | journal = The New England Journal of Medicine | volume = 391 | issue = 4 | pages = 343–355 | date = July 2024 | pmid = 39047241 | doi = 10.1056/NEJMra2308181 }} In sub-Saharan Africa approximately a third of HIV patients will develop cryptococcosis.

In the United States, the incidence of cryptococcosis is estimated to be about 0.4-1.3 cases per 100,000 population and 2-7 cases per 100,000 in people affected with AIDS with a case fatality ratio of about 12%. Since 1990 the incidence of AIDS-associated cryptococcosis has fallen by 90% due to the proliferation of antiretroviral therapy.{{Cite web |date=2022-11-02 |title=C. neoformans Infection Statistics |work=Fungal Diseases |url=https://www.cdc.gov/fungal/diseases/cryptococcosis-neoformans/statistics.html |access-date=2023-11-15 |publisher=Centers for Disease Control and Prevention |language=en-us}} The estimated prevalence of cryptococcosis cases amongst HIV patients in the U.S. is 2.8%.{{cite journal | vauthors = Alemayehu T, Ayalew S, Buzayehu T, Daka D | title = Magnitude of Cryptococcosis among HIV patients in sub-Saharan Africa countries: a systematic review and meta-analysis | journal = African Health Sciences | volume = 20 | issue = 1 | pages = 114–121 | date = March 2020 | pmid = 33402899 | pmc = 7750036 | doi = 10.4314/ahs.v20i1.16 }} In immunocompetent patients cryptococcus typically presents itself as Cryptococcus gattii. Despite its rarity cryptococcus has been more commonly seen, with upwards of 20% of cases in immunocompetent people.{{cite journal | vauthors = Stack M, Hiles J, Valinetz E, Gupta SK, Butt S, Schneider JG | title = Cryptococcal Meningitis in Young, Immunocompetent Patients: A Single-Center Retrospective Case Series and Review of the Literature | journal = Open Forum Infectious Diseases | volume = 10 | issue = 8 | pages = ofad420 | date = August 2023 | pmid = 37636518 | pmc = 10456216 | doi = 10.1093/ofid/ofad420 }} Over 50% of cryptococcosis infections in North America are caused by C. gattii. Though C. gattii was originally thought to be restricted to subtropical and tropical regions it has become more prevalent worldwide.{{cite journal | vauthors = Howard-Jones AR, Sparks R, Pham D, Halliday C, Beardsley J, Chen SC | title = Pulmonary Cryptococcosis | journal = Journal of Fungi | volume = 8 | issue = 11 | pages = 1156 | date = October 2022 | pmid = 36354923 | pmc = 9696922 | doi = 10.3390/jof8111156 | doi-access = free }} C. gattii has been found in over 90 people in the United States, most of these cases originating in Washington or Oregon.{{cite journal | vauthors = Harris J, Lockhart S, Chiller T | title = Cryptococcus gattii: where do we go from here? | journal = Medical Mycology | volume = 50 | issue = 2 | pages = 113–129 | date = February 2012 | pmid = 21939343 | doi = 10.3109/13693786.2011.607854 | s2cid = 21577621 }}

Sub-Saharan Africa is the main hub for HIV/AIDS worldwide. HIV/AIDS accounts for about 0.5% of the world's population.{{Cite web |title=HIV and AIDS Epidemic Global Statistics |url=https://www.hiv.gov/hiv-basics/overview/data-and-trends/global-statistics |access-date=2023-12-12 |website=HIV.gov |language=en}} Remarkably, sub-Saharan Africa holds 71% of HIV/AIDs cases.{{cite journal | vauthors = Kharsany AB, Karim QA | title = HIV Infection and AIDS in Sub-Saharan Africa: Current Status, Challenges and Opportunities | journal = The Open AIDS Journal | volume = 10 | pages = 34–48 | date = 2016-04-08 | pmid = 27347270 | pmc = 4893541 | doi = 10.2174/1874613601610010034 }} Cryptococcal meningitis is a primary contributor to mortality among individuals with HIV/AIDS in sub-Saharan Africa.{{Cite web |date=2022-11-02 |title=C. neoformans Infection Statistics |work=Fungal Diseases |url=https://www.cdc.gov/fungal/diseases/cryptococcosis-neoformans/statistics.html |access-date=2023-11-26 |publisher=Centers for Disease Control and Prevention |language=en-us}} Approximately 160,000 cases of cryptococcal meningitis are reported in West Africa, resulting in 130,000 deaths in sub-Saharan Africa.{{cite journal | vauthors = Akaihe CL, Nweze EI | title = Epidemiology of Cryptococcus and cryptococcosis in Western Africa | journal = Mycoses | volume = 64 | issue = 1 | pages = 4–17 | date = January 2021 | pmid = 32969547 | doi = 10.1111/myc.13188 | s2cid = 221884476 }} Uganda is reported to have the highest occurrence of cryptococcus meningitis.{{cite journal | vauthors = Alemayehu T, Ayalew S, Buzayehu T, Daka D | title = Magnitude of Cryptococcosis among HIV patients in sub-Saharan Africa countries: a systematic review and meta-analysis | journal = African Health Sciences | volume = 20 | issue = 1 | pages = 114–121 | date = March 2020 | pmid = 33402899 | pmc = 7750036 | doi = 10.4314/ahs.v20i1.16 }} Reflecting that, Ethiopia has the least occurrence. Presently, treatment options involve either a 7 or 14-day regimen of amphotericin-B, coupled with oral antifungal tablets or oral fluconazole. It is important to note, that amphotericin-B is not considered a treatment, as it showed not a significant reduction in the mortality rate.{{cite journal | vauthors = Patel RK, Leeme T, Azzo C, Tlhako N, Tsholo K, Tawanana EO, Molefi M, Mosepele M, Lawrence DS, Mokomane M, Tenforde MW, Jarvis JN | title = High Mortality in HIV-Associated Cryptococcal Meningitis Patients Treated With Amphotericin B-Based Therapy Under Routine Care Conditions in Africa | journal = Open Forum Infectious Diseases | volume = 5 | issue = 11 | pages = ofy267 | date = November 2018 | pmid = 30488038 | pmc = 6251350 | doi = 10.1093/ofid/ofy267 }}

Cryptococcosis is also seen in cats and occasionally dogs. It is the most common deep fungal disease in cats, usually leading to chronic infection of the nose and sinuses, and skin ulcers. Cats may develop a bump over the bridge of the nose from local tissue inflammation. It can be associated with FeLV infection in cats. Cryptococcosis is most common in dogs and cats but cattle, sheep, goats, horses, wild animals, and birds can also be infected. Soil, fowl manure, and pigeon droppings are among the sources of infection.{{cite web|url=http://www.cathealth.com/FungalINFXdeep.htm|title=Deep Fungal Infections|url-status=dead|archive-url=https://web.archive.org/web/20100413225853/http://www.cathealth.com/FungalINFXdeep.htm|archive-date=2010-04-13}}{{cite journal|url=http://www.vin.com/proceedings/Proceedings.plx?CID=WSAVA2003&PID=6653&O=Generic|title=Feline Cryptococcosis – WSAVA 2003 Congress – VIN|website=Vin.com|date=July 2014| vauthors = Takeuchi A }}

{{Reflist}}

{{refbegin}}

• {{cite journal | vauthors = Perfect JR, Dismukes WE, Dromer F, Goldman DL, Graybill JR, Hamill RJ, Harrison TS, Larsen RA, Lortholary O, Nguyen MH, Pappas PG, Powderly WG, Singh N, Sobel JD, Sorrell TC | title = Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the infectious diseases society of america | journal = Clinical Infectious Diseases | volume = 50 | issue = 3 | pages = 291–322 | date = February 2010 | pmid = 20047480 | pmc = 5826644 | doi = 10.1086/649858 }}
• {{cite journal | vauthors = Gullo FP, Rossi SA, Sardi J, Teodoro VL, Mendes-Giannini MJ, Fusco-Almeida AM | title = Cryptococcosis: epidemiology, fungal resistance, and new alternatives for treatment | journal = European Journal of Clinical Microbiology & Infectious Diseases | volume = 32 | issue = 11 | pages = 1377–1391 | date = November 2013 | pmid = 24141976 | doi = 10.1007/s10096-013-1915-8 | s2cid = 11317427 }}
• {{cite journal | vauthors = Perfect JR | title = Cryptococcus neoformans: a sugar-coated killer with designer genes | journal = FEMS Immunology and Medical Microbiology | volume = 45 | issue = 3 | pages = 395–404 | date = September 2005 | pmid = 16055314 | doi = 10.1016/j.femsim.2005.06.005 | doi-access = free }} (Review)

{{refend}}

• [http://emedicine.medscape.com/article/215354-overview Medscape entry on cryptococcosis]

{{Mycoses}}

{{Diseases of meninges}}

{{Medical resources

| ICD10 = {{ICD10|B|45||b|35}}

| ICD9 = {{ICD9|117.5}}

| ICDO =

| OMIM =

| DiseasesDB = 3213

| MedlinePlus = 001328

| eMedicineSubj = med

| eMedicineTopic = 482

| MeshID = D003453

| Orphanet = 1546

}}

{{Authority control}}

Category:Animal fungal diseases

Category:Bird diseases

Category:Bovine diseases

Category:Cat diseases

Category:Dog diseases

Category:Fungi and humans

Category:HIV/AIDS

Category:Horse diseases

Category:Mycosis-related cutaneous conditions

Category:Sheep and goat diseases

Category:Tremellomycetes

Category:Zoonoses

Category:Fungal diseases