Cryptococcosis: Difference between revisions

Cryptococcosis
Cryptococcosis
Other names	Busse-Buschke disease, cryptococcic meningitis, cryptococcosis lung, cryptococcosis skin, European Blastomycosis, torular meningitis, torulosis
	Micrograph of cryptococcosis showing the characteristically thick capsule of cryptococcus. Field stain.
Pronunciation	/ˌkrɪptəkəˈkoʊsɪs, -toʊ-, -kɒ-/ ;
Specialty	Infectious disease
Symptoms	Lung: Cough, difficulty breathing, chest pain and fever.; Brain: Headache, fever, neck pain, nausea, vomiting, light sensitivity, confusion, change in behaviour.; Skin: Nodules with dead tissue.;
Causes	Cryptococcus neoformans, Cryptococcus gattii
Risk factors	HIV/AIDS, Aviculture
Diagnostic method	Biopsy, culture
Treatment	Antifungal medication
Medication	Fluconazole; Amphotericin B; Flucytosine;

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Cryptococcosis is a potentially fatal fungal infection of mainly the lungs, presenting as a pneumonia, and in the brain, where it appears as a meningitis.^[4]^[9] Coughing, difficulty breathing, chest pain and fever are seen when the lungs are infected.^[5] When the brain is infected, symptoms include headache, fever, neck pain, nausea and vomiting, light sensitivity and confusion or changes in behavior.^[5] It can also affect other parts of the body including skin, where it may appear as several fluid-filled nodules with dead tissue.^[6]

It is caused by the fungi Cryptococcus neoformans or less commonly Cryptococcus gattii, and is acquired by breathing in the spores from the air.^[4] These fungi are found around the world in soil, decaying wood, pigeon droppings, and in the hollows of some species of trees.^[9]^[12] Whereas C. neoformans generally infects people with HIV/AIDS and those on immunosuppressant drugs and does not usually affect fit and healthy people, C. gattii (found in some parts of Canada and the US) does.^[9]^[12] Once breathed in, the dried yeast cells colonize the lungs, where they are either cleared by immune cells, lie dormant, or cause infection and spread.^[13]

Diagnosis is by isolating Cryptococcus from a sample of affected tissue or direct observation of the fungus by using staining of body fluids.^[9] It can be cultured from a cerebrospinal fluid, sputum, and skin biopsy.^[9] Treatment is with fluconazole or amphotericin B.^[9]^[10]

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.^[14] Cryptococcosis was rare before the 1970s which saw an increase in at-risk groups such as people with organ transplant or on immunosuppressant medications.^[9] The number of cases escalated in the mid-1980s with over 80% occurring in people with HIV/AIDS.^[9] Pigeon breeders (or otherwise people who spend significant time with pigeons) are known to have a high incidence of cryptococcal infections including primary cutaneous cryptococcus due to the fungi's association with pigeon droppings.^[15]^{[better source needed]}

Classification

Cryptococcus is generally classified according to how it is acquired and the site of infection.^[16] It typically begins in the lungs before spreading to other parts of the body, particularly the brain and nervous system.^[1] Skin involvement is less common.^[1]

Signs and symptoms

Cough, shortness of breath, chest pain and fever are seen when the lungs are infected, appearing like a pneumonia.^[5] There may also be feeling of tiredness.^[4] When the brain is infected, symptoms include headache, fever, neck pain, nausea and vomiting, light sensitivity, confusion or changes in behaviour.^[5] It can also affect other parts of the body including skin, eyes, bones and prostate.^[9] In the skin, it may appear as several fluid-filled nodules with dead tissue.^[6] Depending on the site of infection, other features may include loss of vision, blurred vision, inability to move an eye and memory loss.^[9]

Symptom onset is often sudden when lungs are infected and gradual over several weeks when the central nervous system is affected.^[9]

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.^[17]

Cause

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.^[18]

Distribution is worldwide in soil.^[19] 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.^[20]

In humans, C. neoformans chiefly infects the skin, lungs, and central nervous system (causing meningitis).^[20] Less commonly it may affect other organs such as the eye or prostate.^[20]

Primary cutaneous cryptococcosis

Primary cutaneous cryptococcosis (PCC) is a distinct clinical diagnosis separate from the secondary cutaneous cryptococcosis that is spread from 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.^[21] The upper limbs account for a majority of infections. Isolates found in PCC include Cryptococcus neoformans (most common), Cryptococcus gattii, and Cryptococcus laurentii. Prognosis for PCC is generally good outside of disseminated infection.^[22]

Morphologic description of the lesions show 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.^[23]

Pulmonary cryptococcosis

Cryptococcus (both C. neoformans and C. gattii) plays a common role in pulmonary invasive mycosis seen in adults with HIV and other immunocompromised conditions.^[18] It also affects healthy adults at a much lower frequency and severity as healthy hosts may have no or mild symptoms.^[24] Immune-competent hosts may not seek or require treatment, but careful observation may be important.^[25] Cryptococcal pneumonia has a potential to disseminate to the central nervous system (CNS) especially in immunocompromised individuals.^[26]

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, it 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.^[18] Moreover, pulmonary cryptococcosis worsen the prognosis of cryptococcal meningitis.^[18]

Cryptococcal meningitis

Cryptococcal meningitis (infection of the meninges, the tissue covering the brain) is believed to result from 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.^[27]

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.^[28]

Cryptococcus species (both C. neoformans and C. gattii) are responsible for 68% of meningitis cases in those with HIV.^[17] Cryptococcus is considered an "emerging" disease in healthy adults.^[29] 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.^[30] CD4+ T cells have proven roles in the defense against Cryptococcus, but it can also contribute to clinical deterioration due its inflammatory response.^[31]

Diagnosis

Symptom onset is often subacute, progressively worsened over several weeks, and delays in diagnosis are associated with increased mortality.^[20]^[17]

Cerebrospinal fluid (CSF) or blood antigen testing by lateral flow assay for cryptococcal antigens has a sensitivity and specificity greater than 99% for cryptococcosis.^[17] A CSF fungal culture can tell if there is 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.^[17] 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.^[32] Blood cultures may be positive in heavy infections. India ink of the CSF is a traditional microscopic method of diagnosis,^[33] although the sensitivity is poor in early infection, and may miss 15–20% of patients with culture-positive cryptococcal meningitis.^[34] 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.^[17]

Prevention

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 rates of detectable cryptococcal antigen in peripheral blood is often 4–12% in persons with CD4 counts lower than 100 cells/mcL.^[35]^[36] Cryptococcal antigen screen and preemptive treatment with fluconazole is cost saving to the healthcare system by avoiding cryptococcal meningitis.^[37] The World Health Organization recommends cryptococcal antigen screening in HIV-infected persons entering care with CD4<100 cells/μL.^[38] This undetected subclinical cryptococcal (if not preemptively treated with anti-fungal therapy) will often go on to develop cryptococcal meningitis, despite receiving HIV therapy.^[36]^[39] 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.^[40]^[41]

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.^[42]

Treatment

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).^[43]

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.^[17] Where flucytosine is not available, fluconazole should be used with amphotericin.^[38] Amphotericin-based induction therapy has much greater microbiologic activity than fluconazole monotherapy with 30% better survival at 10 weeks.^[32]^[44] 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.^[44] 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.^[38]

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.^[45] A 2018 Cochrane review also supports the delayed starting of treatment until cryptococcosis starts improving with antifungal treatment.^[46]

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).^[17]^[47]^[11] 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 prior to 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.^[17]

IRIS

Immune reconstitution inflammatory syndrome is possible in those with cryptococcal infection, especially those with concurrent HIV starting anti-retroviral therapy. With anti-retroviral therapy for the HIV, the CD4+ T-cell counts recover and the restored immune system mounts an exaggerated, hyperinflammatory response against cryptococcal infection in the body.^[17]

IRIS has a 5% incidence in those with HIV and cryptococcosis starting anti-retroviral therapy. It usually occurs within 4 weeks of starting anti-retroviral therapy.^[17] The risk of IRIS is increased in those with a high fungal burden, lower CD4+ T-cell count, and lower inflammatory marker levels.^[17]

Epidemiology

Cryptococcosis is usually associated with immunosuppressed people, such as those with AIDs, corticosteroid use, diabetes, and organ transplant.^[48] Cryptococcus comprizes two clinically relevant species, Cryptococcus neoformans and Cryptococcus gattii.^[49] 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.^[50]

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.^[14] 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.^[51] 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%.^[51] 19% of all AIDS related deaths are due to cryptococcal disease.^[52] 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.^[53] In sub-Saharan Africa approximately a third of HIV patients will develop cryptococcosis.^[54]

In the United States

In the United States 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 fell by 90% due to the proliferation of antiretroviral therapy.^[55]^[56] The estimated prevalence of cryptococcosis cases amongst HIV patients in the U.S. is 2.8%.^[57] In immunocompetent patients cryptococcus typically presents itself as Cryptococcus gattii.^[56] Despite its rarity cryptococcus has been more commonly seen, with upwards of 20% of cases in immunocompetent people.^[58] 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.^[59] C. gattii has been found in over 90 people in the United States, most of these cases originating in Washington or Oregon.^[60]

In sub-Saharan Africa

Sub-Saharan Africa is the main hub for HIV/AIDS worldwide. HIV/AIDS accounts for about 0.5% of the world's population.^[61] Remarkably, sub-Saharan Africa holds 71% of HIV/AIDs cases.^[62] Cryptococcal meningitis is a primary contributor to mortality among individuals with HIV/AIDS in sub-Saharan Africa.^[63] Approximately 160,000 cases of cryptococcal meningitis are reported in West Africa, resulting in 130,000 deaths in sub-Saharan Africa.^[64] Uganda is reported to have the highest occurrence of cryptococcus meningitis.^[54] Reflecting that, Ethiopia has the least occurrence.^[54] 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, amphotericin-B is not considered a treatment, as it showed not a significant reduction in the mortality rate.^[65]

Other animals

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.^[66]^[67]

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^ Boulware, DR; Meya, DB; Muzoora, Conrad; Rolfes, MA; Huppler Hullsiek, K; Musubire, Abdu; Taseera, Kabanda; Nabeta, HW; Schutz, C; Williams, DA A.; Rajasingham, R; Rhein, J; Thienemann, F; Lo, MW; Nielsen, K; Bergemann, T L.; Kambugu, A; Manabe, YC; Janoff, EN; Bohjanen, PR; Meintjes, G (26 June 2014). "Timing of Antiretroviral Therapy after Diagnosis of Cryptococcal Meningitis". New England Journal of Medicine. 370 (26): 2487–98. doi:10.1056/NEJMoa1312884. PMC 4127879. PMID 24963568.
^ Eshun-Wilson, Ingrid; Okwen, Mbah P.; Richardson, Marty; Bicanic, Tihana (24 July 2018). "Early versus delayed antiretroviral treatment in HIV-positive people with cryptococcal meningitis". The Cochrane Database of Systematic Reviews. 2018 (7): CD009012. doi:10.1002/14651858.CD009012.pub3. PMC 6513637. PMID 30039850.
^ Rolfes, et al. (1 December 2014). "The Effect of Therapeutic Lumbar Punctures on Acute Mortality From Cryptococcal Meningitis". Clinical Infectious Diseases. 59 (11): 1607–1614. doi:10.1093/cid/ciu596.
^ Mada, Pradeep Kumar; Jamil, Radia T.; Alam, Mohammed U. (2023), "Cryptococcus", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID 28613714, retrieved 2023-11-15
^ 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 (September 2010). "Prevalence of the VNIc genotype of Cryptococcus neoformans in non-HIV-associated cryptococcosis in the Republic of Korea". FEMS Yeast Res. 10 (6): 769–78. doi:10.1111/j.1567-1364.2010.00648.x. PMC 2920376. PMID 20561059.
^ Harris, Julie; Lockhart, Shawn; Chiller, Tom (February 2012). "Cryptococcus gattii: where do we go from here?". Medical Mycology. 50 (2): 113–129. doi:10.3109/13693786.2011.607854. PMID 21939343. S2CID 21577621.
^ ^a ^b Rajasingham, Radha; Smith, Rachel M; Park, Benjamin J; Jarvis, Joseph N; Govender, Nelesh P; Chiller, Tom M; Denning, David W; Loyse, Angela; Boulware, David R (August 2017). "Global burden of disease of HIV-associated cryptococcal meningitis: an updated analysis". The Lancet Infectious Diseases. 17 (8): 873–881. doi:10.1016/S1473-3099(17)30243-8. PMC 5818156. PMID 28483415.
^ Rajasingham, Radha; Govender, Nelesh P; Jordan, Alexander; Loyse, Angela; Shroufi, Amir; Denning, David W; Meya, David B; Chiller, Tom M; Boulware, David R (December 2022). "The global burden of HIV-associated cryptococcal infection in adults in 2020: a modelling analysis". The Lancet Infectious Diseases. 22 (12): 1748–1755. doi:10.1016/S1473-3099(22)00499-6. PMC 9701154. PMID 36049486.
^ Meintjes, Graeme; Maartens, Gary (25 July 2024). "HIV-Associated Tuberculosis". New England Journal of Medicine. 391 (4): 343–355. doi:10.1056/NEJMra2308181.
^ ^a ^b ^c Alemayehu, Tsegaye; Ayalew, Sosina; Buzayehu, Temesgen; Daka, Deresse (2020-04-20). "Magnitude of Cryptococcosis among HIV patients in sub-Saharan Africa countries: a systematic review and meta-analysis". African Health Sciences. 20 (1): 114–121. doi:10.4314/ahs.v20i1.16. PMC 7750036. PMID 33402899.
^ "C. neoformans Infection Statistics". Fungal Diseases. Centers for Disease Control and Prevention. 2022-11-02. Retrieved 2023-11-15.
^ ^a ^b Mada, Pradeep Kumar; Jamil, Radia T.; Alam, Mohammed U. (2023), "Cryptococcus", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID 28613714, NBK431060, retrieved 2023-11-15
^ Alemayehu, Tsegaye; Ayalew, Sosina; Buzayehu, Temesgen; Daka, Deresse (2020-04-20). "Magnitude of Cryptococcosis among HIV patients in sub-Saharan Africa countries: a systematic review and meta-analysis". African Health Sciences. 20 (1): 114–121. doi:10.4314/ahs.v20i1.16. PMC 7750036. PMID 33402899.
^ Stack M, Hiles J, Valinetz E, Gupta SK, Butt S, Schneider JG (August 2023). "Cryptococcal Meningitis in Young, Immunocompetent Patients: A Single-Center Retrospective Case Series and Review of the Literature". Open Forum Infect Dis. 10 (8): ofad420. doi:10.1093/ofid/ofad420. PMC 10456216. PMID 37636518.
^ Howard-Jones, Annaleise R.; Sparks, Rebecca; Pham, David; Halliday, Catriona; Beardsley, Justin; Chen, Sharon C.-A. (November 2022). "Pulmonary Cryptococcosis". Journal of Fungi. 8 (11): 1156. doi:10.3390/jof8111156. PMC 9696922. PMID 36354923.
^ Harris, Julie; Lockhart, Shawn; Chiller, Tom (February 2012). "Cryptococcus gattii: where do we go from here?". Medical Mycology. 50 (2): 113–129. doi:10.3109/13693786.2011.607854. PMID 21939343. S2CID 21577621.
^ "HIV and AIDS Epidemic Global Statistics". HIV.gov. Retrieved 2023-12-12.
^ Kharsany, Ayesha B.M.; Karim, Quarraisha A. (2016-04-08). "HIV Infection and AIDS in Sub-Saharan Africa: Current Status, Challenges and Opportunities". The Open AIDS Journal. 10: 34–48. doi:10.2174/1874613601610010034. PMC 4893541. PMID 27347270.
^ "C. neoformans Infection Statistics". Fungal Diseases. Centers for Disease Control and Prevention. 2022-11-02. Retrieved 2023-11-26.
^ Akaihe, Chidinma Lynda; Nweze, Emeka Innocent (January 2021). "Epidemiology of Cryptococcus and cryptococcosis in Western Africa". Mycoses. 64 (1): 4–17. doi:10.1111/myc.13188. PMID 32969547. S2CID 221884476.
^ Patel, Raju K K; Leeme, Tshepo; Azzo, Caitlin; Tlhako, Nametso; Tsholo, Katlego; Tawanana, Ephraim O; Molefi, Mooketsi; Mosepele, Mosepele; Lawrence, David S; Mokomane, Margaret; Tenforde, Mark W; Jarvis, Joseph N (2018-11-01). "High Mortality in HIV-Associated Cryptococcal Meningitis Patients Treated With Amphotericin B–Based Therapy Under Routine Care Conditions in Africa". Open Forum Infectious Diseases. 5 (11): ofy267. doi:10.1093/ofid/ofy267. PMC 6251350. PMID 30488038.
^ "Deep Fungal Infections". Archived from the original on 2010-04-13.
^ Akira Takeuchi, D. V. M. (July 2014). "Feline Cryptococcosis – WSAVA 2003 Congress – VIN". Vin.com.

External links

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[35] "FIGURE 1. Prevalence of asymptomatic antigenemia with corresponding cost per life saved based on LFA cost of $2.50 per test".

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[39] Jarvis, JN; Harrison, TS; Govender, N; Lawn, SD; Longley, N; Bicanic, T; Maartens, G; Venter, F; Bekker, LG; Wood, R; Meintjes, G (2011). "Routine cryptococcal antigen screening for HIV-infected patients with low CD4+ T-lymphocyte counts—time to implement in South Africa?" (PDF). South African Medical Journal. 101 (4): 232–4. doi:10.7196/samj.4752 (inactive 2024-11-10). PMID 21786721.{{cite journal}}: CS1 maint: DOI inactive as of November 2024 (link)

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[43] "Practice Guidelines for the Management of Cryptococcal Disease". Infectious Disease Society of America. 2010. Archived from the original on 2018-07-25. Retrieved 2013-09-14.

[Rajasingham-44] Rajasingham, Radha; Rolfes, M.A.; Birkenkamp, K.E.; Meya, D.B.; Boulware, D.R. (2012). Farrar, Jeremy (ed.). "Cryptococcal Meningitis Treatment Strategies in Resource-Limited Settings: A Cost-Effectiveness Analysis". PLOS Medicine. 9 (9): e1001316. doi:10.1371/journal.pmed.1001316. PMC 3463510. PMID 23055838.

[45] Boulware, DR; Meya, DB; Muzoora, Conrad; Rolfes, MA; Huppler Hullsiek, K; Musubire, Abdu; Taseera, Kabanda; Nabeta, HW; Schutz, C; Williams, DA A.; Rajasingham, R; Rhein, J; Thienemann, F; Lo, MW; Nielsen, K; Bergemann, T L.; Kambugu, A; Manabe, YC; Janoff, EN; Bohjanen, PR; Meintjes, G (26 June 2014). "Timing of Antiretroviral Therapy after Diagnosis of Cryptococcal Meningitis". New England Journal of Medicine. 370 (26): 2487–98. doi:10.1056/NEJMoa1312884. PMC 4127879. PMID 24963568.

[46] Eshun-Wilson, Ingrid; Okwen, Mbah P.; Richardson, Marty; Bicanic, Tihana (24 July 2018). "Early versus delayed antiretroviral treatment in HIV-positive people with cryptococcal meningitis". The Cochrane Database of Systematic Reviews. 2018 (7): CD009012. doi:10.1002/14651858.CD009012.pub3. PMC 6513637. PMID 30039850.

[Rolfes_2014-47] Rolfes, et al. (1 December 2014). "The Effect of Therapeutic Lumbar Punctures on Acute Mortality From Cryptococcal Meningitis". Clinical Infectious Diseases. 59 (11): 1607–1614. doi:10.1093/cid/ciu596.

[48] Mada, Pradeep Kumar; Jamil, Radia T.; Alam, Mohammed U. (2023), "Cryptococcus", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID 28613714, retrieved 2023-11-15

[49] 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 (September 2010). "Prevalence of the VNIc genotype of Cryptococcus neoformans in non-HIV-associated cryptococcosis in the Republic of Korea". FEMS Yeast Res. 10 (6): 769–78. doi:10.1111/j.1567-1364.2010.00648.x. PMC 2920376. PMID 20561059.

[50] Harris, Julie; Lockhart, Shawn; Chiller, Tom (February 2012). "Cryptococcus gattii: where do we go from here?". Medical Mycology. 50 (2): 113–129. doi:10.3109/13693786.2011.607854. PMID 21939343. S2CID 21577621.

[Rajasingham-2017-51] Rajasingham, Radha; Smith, Rachel M; Park, Benjamin J; Jarvis, Joseph N; Govender, Nelesh P; Chiller, Tom M; Denning, David W; Loyse, Angela; Boulware, David R (August 2017). "Global burden of disease of HIV-associated cryptococcal meningitis: an updated analysis". The Lancet Infectious Diseases. 17 (8): 873–881. doi:10.1016/S1473-3099(17)30243-8. PMC 5818156. PMID 28483415.

[Rajasingham_2022-52] Rajasingham, Radha; Govender, Nelesh P; Jordan, Alexander; Loyse, Angela; Shroufi, Amir; Denning, David W; Meya, David B; Chiller, Tom M; Boulware, David R (December 2022). "The global burden of HIV-associated cryptococcal infection in adults in 2020: a modelling analysis". The Lancet Infectious Diseases. 22 (12): 1748–1755. doi:10.1016/S1473-3099(22)00499-6. PMC 9701154. PMID 36049486.

[Meintjes_2024-53] Meintjes, Graeme; Maartens, Gary (25 July 2024). "HIV-Associated Tuberculosis". New England Journal of Medicine. 391 (4): 343–355. doi:10.1056/NEJMra2308181.

[Alemayehu-2020-54] Alemayehu, Tsegaye; Ayalew, Sosina; Buzayehu, Temesgen; Daka, Deresse (2020-04-20). "Magnitude of Cryptococcosis among HIV patients in sub-Saharan Africa countries: a systematic review and meta-analysis". African Health Sciences. 20 (1): 114–121. doi:10.4314/ahs.v20i1.16. PMC 7750036. PMID 33402899.

[55] "C. neoformans Infection Statistics". Fungal Diseases. Centers for Disease Control and Prevention. 2022-11-02. Retrieved 2023-11-15.

[Mada-2023-56] Mada, Pradeep Kumar; Jamil, Radia T.; Alam, Mohammed U. (2023), "Cryptococcus", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID 28613714, NBK431060, retrieved 2023-11-15

[57] Alemayehu, Tsegaye; Ayalew, Sosina; Buzayehu, Temesgen; Daka, Deresse (2020-04-20). "Magnitude of Cryptococcosis among HIV patients in sub-Saharan Africa countries: a systematic review and meta-analysis". African Health Sciences. 20 (1): 114–121. doi:10.4314/ahs.v20i1.16. PMC 7750036. PMID 33402899.

[58] Stack M, Hiles J, Valinetz E, Gupta SK, Butt S, Schneider JG (August 2023). "Cryptococcal Meningitis in Young, Immunocompetent Patients: A Single-Center Retrospective Case Series and Review of the Literature". Open Forum Infect Dis. 10 (8): ofad420. doi:10.1093/ofid/ofad420. PMC 10456216. PMID 37636518.

[59] Howard-Jones, Annaleise R.; Sparks, Rebecca; Pham, David; Halliday, Catriona; Beardsley, Justin; Chen, Sharon C.-A. (November 2022). "Pulmonary Cryptococcosis". Journal of Fungi. 8 (11): 1156. doi:10.3390/jof8111156. PMC 9696922. PMID 36354923.

[60] Harris, Julie; Lockhart, Shawn; Chiller, Tom (February 2012). "Cryptococcus gattii: where do we go from here?". Medical Mycology. 50 (2): 113–129. doi:10.3109/13693786.2011.607854. PMID 21939343. S2CID 21577621.

[61] "HIV and AIDS Epidemic Global Statistics". HIV.gov. Retrieved 2023-12-12.

[62] Kharsany, Ayesha B.M.; Karim, Quarraisha A. (2016-04-08). "HIV Infection and AIDS in Sub-Saharan Africa: Current Status, Challenges and Opportunities". The Open AIDS Journal. 10: 34–48. doi:10.2174/1874613601610010034. PMC 4893541. PMID 27347270.

[63] "C. neoformans Infection Statistics". Fungal Diseases. Centers for Disease Control and Prevention. 2022-11-02. Retrieved 2023-11-26.

[64] Akaihe, Chidinma Lynda; Nweze, Emeka Innocent (January 2021). "Epidemiology of Cryptococcus and cryptococcosis in Western Africa". Mycoses. 64 (1): 4–17. doi:10.1111/myc.13188. PMID 32969547. S2CID 221884476.

[65] Patel, Raju K K; Leeme, Tshepo; Azzo, Caitlin; Tlhako, Nametso; Tsholo, Katlego; Tawanana, Ephraim O; Molefi, Mooketsi; Mosepele, Mosepele; Lawrence, David S; Mokomane, Margaret; Tenforde, Mark W; Jarvis, Joseph N (2018-11-01). "High Mortality in HIV-Associated Cryptococcal Meningitis Patients Treated With Amphotericin B–Based Therapy Under Routine Care Conditions in Africa". Open Forum Infectious Diseases. 5 (11): ofy267. doi:10.1093/ofid/ofy267. PMC 6251350. PMID 30488038.

[66] "Deep Fungal Infections". Archived from the original on 2010-04-13.

[67] Akira Takeuchi, D. V. M. (July 2014). "Feline Cryptococcosis – WSAVA 2003 Congress – VIN". Vin.com.

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@@ Line 7: / Line 7: @@
 | caption       = [[Micrograph]] of cryptococcosis showing the characteristically thick capsule of cryptococcus. [[Field stain]].
 | field         = [[Infectious disease (medical specialty)|Infectious disease]]<ref name=ICD-11/>
-| pronounce     = {{IPAc-en|ˌ|k|r|ɪ|p|t|ə|k|ə|ˈ|k|oʊ|s|ɪ|s|,_|-|t|oʊ|-|,_|-|k|ɒ|-}}{{refn|{{Cite dictionary |url=http://www.lexico.com/definition/Cryptococcosis |archive-url=https://web.archive.org/web/20210507044344/https://www.lexico.com/definition/cryptococcosis |url-status=dead |archive-date=2021-05-07 |title=Cryptococcosis |dictionary=[[Lexico]] UK English Dictionary |publisher=[[Oxford University Press]]}} }}{{refn|{{MerriamWebsterDictionary|accessdate=2016-01-21|Cryptococcosis}}}}|
+| pronounce     = {{IPAc-en|ˌ|k|r|ɪ|p|t|ə|k|ə|ˈ|k|oʊ|s|ɪ|s|,_|-|t|oʊ|-|,_|-|k|ɒ|-}}{{refn|{{Cite encyclopedia |url=http://www.lexico.com/definition/Cryptococcosis |archive-url=https://web.archive.org/web/20210507044344/https://www.lexico.com/definition/cryptococcosis |url-status=dead |archive-date=2021-05-07 |title=Cryptococcosis |dictionary=[[Lexico]] UK English Dictionary |publisher=[[Oxford University Press]]}} }}{{refn|{{MerriamWebsterDictionary|accessdate=2016-01-21|Cryptococcosis}}}}|
 | symptoms      = *Lung: [[Cough]], [[shortness of breath|difficulty breathing]], [[chest pain]] and [[fever]].<ref name=CDCSymp/>
 * Brain: [[Headache]], fever, [[meningism|neck pain]], [[nausea]], [[vomiting]], [[Photophobia|light sensitivity]], [[cognitive impairment|confusion]], change in behaviour.<ref name=CDCSymp/>
@@ Line 15: / Line 15: @@
 | duration      =
 | types         =
-| causes        = ''[[Cryptococcus neoformans]]'',<ref name=CDC>{{cite web |title=C. neoformans Infection {{!}} Fungal Diseases {{!}} CDC |url=https://www.cdc.gov/fungal/diseases/cryptococcosis-neoformans/index.html |website=www.cdc.gov |access-date=5 June 2021 |language=en-us |date=29 December 2020}}</ref> ''[[Cryptococcus gattii]]''<ref name=CDCGatti>{{cite web |title=Where C. gattii Infection Comes From {{!}} Fungal Disease {{!}} CDC |url=https://www.cdc.gov/fungal/diseases/cryptococcosis-gattii/causes.html |website=www.cdc.gov |access-date=5 June 2021 |language=en-us |date=29 January 2021}}</ref>
+| causes        = ''[[Cryptococcus neoformans]]'',<ref name=CDC>{{cite web |title=C. neoformans Infection |work=Fungal Diseases |url=https://www.cdc.gov/fungal/diseases/cryptococcosis-neoformans/index.html |publisher=Centers for Disease Control and Prevention |access-date=5 June 2021 |language=en-us |date=29 December 2020}}</ref> ''[[Cryptococcus gattii]]''<ref name=CDCGatti>{{cite web |title=Where C. gattii Infection Comes From |work=Fungal Disease |url=https://www.cdc.gov/fungal/diseases/cryptococcosis-gattii/causes.html |publisher=Centers for Disease Control and Prevention |access-date=5 June 2021 |language=en-us |date=29 January 2021}}</ref>
 | risks         = [[HIV/AIDS]],<ref name=Maziarz2016/> [[Aviculture]]
 | diagnosis     = [[Biopsy]], [[microbiological culture|culture]]<ref name=Maziarz2016/>
@@ Line 21: / Line 21: @@
 | prevention    =
 | treatment     = [[Antifungal drug|Antifungal medication]]
-| medication    = *[[Fluconazole]]<ref name=CDCTreat>{{cite web |title=Treatment for C. neoformans Infection {{!}} Fungal Diseases {{!}} CDC |url=https://www.cdc.gov/fungal/diseases/cryptococcosis-neoformans/treatment.html |website=www.cdc.gov |access-date=6 June 2021 |language=en-us |date=14 January 2021}}</ref>
+| medication    = *[[Fluconazole]]<ref name=CDCTreat>{{cite web |title=Treatment for C. neoformans Infection |work=Fungal Diseases |url=https://www.cdc.gov/fungal/diseases/cryptococcosis-neoformans/treatment.html |publisher=Centers for Disease Control and Prevention |access-date=6 June 2021 |language=en-us |date=14 January 2021}}</ref>
 * [[Amphotericin B]]<ref name=Maziarz2016/>
+* [[Flucytosine]]<ref name="Perfect 2010" />
 | prognosis     =
 | frequency     =
 | deaths        =
 }}
-<!-- Definition and symptoms -->
-'''Cryptococcosis''' is a potentially fatal [[mycosis|fungal infection]] of mainly the [[lungs]], presenting as a [[pneumonia]], and [[brain]], where it appears as a [[meningitis]].<ref name=ICD-11>{{cite web |title=ICD-11 - ICD-11 for Mortality and Morbidity Statistics |url=https://icd.who.int/browse11/l-m/en#/http%3a%2f%2fid.who.int%2ficd%2fentity%2f390527954 |website=icd.who.int |access-date=5 June 2021}}</ref><ref name=Maziarz2016>{{cite journal |last1=Maziarz |first1=Eileen K. |last2=Perfect |first2=John R. |title=Cryptococcosis |journal=Infectious Disease Clinics of North America |date=2016 |volume=30 |issue=1 |pages=179–206 |doi=10.1016/j.idc.2015.10.006 |pmid=26897067 |pmc=5808417 |issn=0891-5520}}</ref> [[Cough]], [[shortness of breath|difficulty breathing]], [[chest pain]] and [[fever]] are seen when the lungs are infected.<ref name=CDCSymp>{{cite web |title=Symptoms of C. neoformans Infection {{!}} Fungal Diseases {{!}} CDC |url=https://www.cdc.gov/fungal/diseases/cryptococcosis-neoformans/symptoms.html |website=www.cdc.gov |access-date=6 June 2021 |language=en-us |date=14 January 2021}}</ref> When the brain is infected, symptoms include [[headache]], fever, [[meningism|neck pain]], [[nausea]] and [[vomiting]], [[Photophobia|light sensitivity]] and [[cognitive impairment|confusion]] or changes in behavior.<ref name=CDCSymp/> It can also affect other parts of the body including [[skin]], where it may appear as several fluid-filled [[nodule (medicine)|nodules]] with [[necrosis|dead tissue]].<ref name=John2017>{{cite book|last=Johnstone |first=Ronald B.|title=Weedon's Skin Pathology Essentials |url=https://books.google.com/books?id=NTE_DAAAQBAJ|year=2017|publisher=Elsevier |edition=2nd|isbn=978-0-7020-6830-0|page=446|chapter=25. Mycoses and Algal infections}}</ref>
+'''Cryptococcosis''' is a potentially fatal [[mycosis|fungal infection]] of mainly the [[lungs]], presenting as a [[pneumonia]], and in the [[brain]], where it appears as a [[meningitis]].<ref name=ICD-11>{{cite web |title=ICD-11 — ICD-11 for Mortality and Morbidity Statistics |url=https://icd.who.int/browse11/l-m/en#/http%3a%2f%2fid.who.int%2ficd%2fentity%2f390527954 |website=icd.who.int |access-date=5 June 2021}}</ref><ref name=Maziarz2016>{{cite journal |last1=Maziarz |first1=Eileen K. |last2=Perfect |first2=John R. |title=Cryptococcosis |journal=Infectious Disease Clinics of North America |date=2016 |volume=30 |issue=1 |pages=179–206 |doi=10.1016/j.idc.2015.10.006 |pmid=26897067 |pmc=5808417 }}</ref> [[Coughing]], [[shortness of breath|difficulty breathing]], [[chest pain]] and [[fever]] are seen when the lungs are infected.<ref name=CDCSymp>{{cite web |title=Symptoms of C. neoformans Infection |work=Fungal Diseases |url=https://www.cdc.gov/fungal/diseases/cryptococcosis-neoformans/symptoms.html |publisher=Centers for Disease Control and Prevention |access-date=6 June 2021 |date=14 January 2021}}</ref> When the brain is infected, symptoms include [[headache]], fever, [[meningism|neck pain]], [[nausea]] and [[vomiting]], [[Photophobia|light sensitivity]] and [[cognitive impairment|confusion]] or changes in behavior.<ref name=CDCSymp/> It can also affect other parts of the body including [[skin]], where it may appear as several fluid-filled [[nodule (medicine)|nodules]] with [[necrosis|dead tissue]].<ref name=John2017>{{cite book|last=Johnstone |first=Ronald B.|title=Weedon's Skin Pathology Essentials |url=https://books.google.com/books?id=NTE_DAAAQBAJ|year=2017|publisher=Elsevier |edition=2nd|isbn=978-0-7020-6830-0|page=446|chapter=25. Mycoses and Algal infections}}</ref>
 <!-- Cause and mechanism -->
-It is caused by the [[pathogenic fungi|fungi]] ''[[Cryptococcus neoformans]]'' or less commonly ''[[Cryptococcus gattii]]'', and is acquired by [[inhalation|breathing in]] the [[propagule|spores]] from the air.<ref name=ICD-11/> These fungi are found around the world in soil, decaying wood, pigeon droppings, and in the hollows of some species of trees.<ref name=Maziarz2016/><ref name=CDCWhere>{{cite web |title=Where C. neoformans Infection Comes From {{!}} Fungal Diseases {{!}} CDC |url=https://www.cdc.gov/fungal/diseases/cryptococcosis-neoformans/causes.html |website=www.cdc.gov |access-date=5 June 2021 |language=en-us |date=2 February 2021}}</ref> Whereas ''C. neoformans'' infects generally people with HIV/AIDS and those on [[immunosuppressant drugs]] and does not usually affect fit and healthy people, ''C. gattii'' (found in some parts of Canada and the US) does.<ref name=Maziarz2016/><ref name=CDCWhere/> Once breathed in, the dried yeast cells colonize the lungs, where they are either cleared by [[phagocytes|immune cells]], lie dormant, or cause infection and spread.<ref name=Sabiiti2012>{{cite journal |last1=Sabiiti |first1=Wilber |last2=May |first2=Robin C. |title=Mechanisms of infection by the human fungal pathogen Cryptococcus neoformans |journal=Future Microbiology |date=November 2012 |volume=7 |issue=11 |pages=1297–1313 |doi=10.2217/fmb.12.102 |pmid=23075448 |url=https://pubmed.ncbi.nlm.nih.gov/23075448/ |issn=1746-0921|url-access=subscription}}</ref>
+It is caused by the [[pathogenic fungi|fungi]] ''[[Cryptococcus neoformans]]'' or less commonly ''[[Cryptococcus gattii]]'', and is acquired by [[inhalation|breathing in]] the [[propagule|spores]] from the air.<ref name=ICD-11/> These fungi are found around the world in soil, decaying wood, pigeon droppings, and in the hollows of some species of trees.<ref name=Maziarz2016/><ref name=CDCWhere>{{cite web |title=Where C. neoformans Infection Comes From |work=Fungal Diseases |url=https://www.cdc.gov/fungal/diseases/cryptococcosis-neoformans/causes.html |publisher=Centers for Disease Control and Prevention |access-date=5 June 2021 |language=en-us |date=2 February 2021}}</ref> Whereas ''C.&nbsp;neoformans'' generally infects people with HIV/AIDS and those on [[immunosuppressant drugs]] and does not usually affect fit and healthy people, ''C.&nbsp;gattii'' (found in some parts of Canada and the US) does.<ref name=Maziarz2016/><ref name=CDCWhere/> Once breathed in, the dried yeast cells colonize the lungs, where they are either cleared by [[phagocytes|immune cells]], lie dormant, or cause infection and spread.<ref name=Sabiiti2012>{{cite journal |last1=Sabiiti |first1=Wilber |last2=May |first2=Robin C. |title=Mechanisms of infection by the human fungal pathogen ''Cryptococcus neoformans'' |journal=Future Microbiology |date=November 2012 |volume=7 |issue=11 |pages=1297–1313 |doi=10.2217/fmb.12.102 |pmid=23075448 }}</ref>
 <!-- Diagnosis and treatment -->
-Diagnosis is by isolating Cryptococcus from a sample of affected tissue or direct observation of the fungus by using staining of body fluids.<ref name=Maziarz2016/> It can be cultured from a [[cerebrospinal fluid]], sputum, and [[skin biopsy]].<ref name=Maziarz2016/> Treatment is with [[fluconazole]] or [[amphotericin B]].<ref name=Maziarz2016/><ref name=CDCTreat/>
+Diagnosis is by isolating ''Cryptococcus'' from a sample of affected tissue or direct observation of the fungus by using staining of body fluids.<ref name=Maziarz2016/> It can be cultured from a [[cerebrospinal fluid]], sputum, and [[skin biopsy]].<ref name=Maziarz2016/> Treatment is with [[fluconazole]] or [[amphotericin B]].<ref name=Maziarz2016/><ref name=CDCTreat/>
 <!-- Epidemiology and history -->
-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.<ref name=Vallab2016/> Cryptococcosis was rare before the 1970s which saw an increase in at-risk groups such as people with [[organ transplant]] or on [[Immunosuppressive drug|immunosuppressant medications]].<ref name=Maziarz2016/> The number of cases escalated in the mid-1980s with over 80% occurring in people with [[HIV/AIDS]].<ref name=Maziarz2016/> Pigeon breeders (or otherwise people who spend significant time with pigeons, known as “pigeon fanciers”) are known to have a high incidence of cryptococcal infections including PCC due to Cryptococcus' association with pigeon droppings.<ref>Walter JE, Atchison RW. Epidemiological and immunological studies of Cryptococcus neoformans. J Bacteriol. 1966 Jul;92(1):82-7. doi: 10.1128/JB.92.1.82-87.1966. PMID 5328755; PMCID: PMC276199.</ref><ref>Beatson M, Harwood M, Reese V, Robinson-Bostom L. Primary cutaneous cryptococcosis in an elderly pigeon breeder. JAAD Case Rep. 2019 May 7;5(5):433-435. doi: 10.1016/j.jdcr.2019.03.006. PMID 31192987; PMCID: PMC6510938.</ref>
+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.<ref name="Vallab2016">{{cite book |last1=Vallabhaneni |first1=Snigdha |title=Fungal Infections, An Issue of Infectious Disease Clinics of North America |last2=Mody |first2=Rajal K. |last3=Walker |first3=Tiffany |last4=Chiller |first4=Tom |date=2016 |publisher=Elsevier |isbn=978-0-323-41649-8 |editor1-last=Sobel |editor1-first=Jack |location=Philadelphia |pages=3–4 |chapter=1. The global burden of fungal disease |editor2-last=Ostrosky-Zeichner |editor2-first=Luis |chapter-url=https://books.google.com/books?id=uwndCwAAQBAJ&pg=PA3}}</ref> Cryptococcosis was rare before the 1970s which saw an increase in at-risk groups such as people with [[organ transplant]] or on [[Immunosuppressive drug|immunosuppressant medications]].<ref name=Maziarz2016/> The number of cases escalated in the mid-1980s with over 80% occurring in people with [[HIV/AIDS]].<ref name=Maziarz2016/> Pigeon breeders (or otherwise people who spend significant time with pigeons) are known to have a high incidence of cryptococcal infections including primary cutaneous cryptococcus due to the fungi's association with pigeon droppings.<ref>{{cite journal |vauthors=Walter JE, Atchison RW |title=Epidemiological and immunological studies of ''Cryptococcus neoformans'' |journal=J Bacteriol |volume=92 |issue=1 |pages=82–7 |date=July 1966 |pmid=5328755 |pmc=276199 |doi=10.1128/jb.92.1.82-87.1966 }}</ref>{{Better source needed|date=October 2024}}
 == Classification ==
-Cryptococcus is generally classified according to how it is acquired and its site.<ref>{{cite journal |journal=Pathogens|doi=10.3390/pathogens11070783 |doi-access=free |title=Elevated Intracranial Pressure in Cryptococcal Meningoencephalitis: Examining Old, New, and Promising Drug Therapies |date=July 2022 |volume=11 |issue=7 |page=783 |last1=Alanazi |first1=Abdulaziz H. |last2=Adil |first2=Mir S. |last3=Lin |first3=Xiaorong |last4=Chastain |first4=Daniel B. |last5=Henao-Martínez |first5=Andrés F. |last6=Franco-Paredes |first6=Carlos |last7=Somanath |first7=Payaningal R. |pmid=35890028 |pmc=9321092 }}</ref> It typically begins in the lungs before spreading to other parts of the body, particularly the brain and nervous system.<ref name=NORD/> The skin type is less common.<ref name=NORD/>
+Cryptococcus is generally classified according to how it is acquired and the site of infection.<ref>{{cite journal |journal=Pathogens|doi=10.3390/pathogens11070783 |doi-access=free |title=Elevated Intracranial Pressure in Cryptococcal Meningoencephalitis: Examining Old, New, and Promising Drug Therapies |date=July 2022 |volume=11 |issue=7 |page=783 |last1=Alanazi |first1=Abdulaziz H. |last2=Adil |first2=Mir S. |last3=Lin |first3=Xiaorong |last4=Chastain |first4=Daniel B. |last5=Henao-Martínez |first5=Andrés F. |last6=Franco-Paredes |first6=Carlos |last7=Somanath |first7=Payaningal R. |pmid=35890028 |pmc=9321092 }}</ref> It typically begins in the lungs before spreading to other parts of the body, particularly the brain and nervous system.<ref name=NORD/> Skin involvement is less common.<ref name=NORD/>
 ==Signs and symptoms==
@@ Line 46: / Line 47: @@
 Symptom onset is often sudden when lungs are infected and gradual over several weeks when the central nervous system is affected.<ref name=Maziarz2016/>
+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.<ref name="Meya 2024" />
 == Cause ==
-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 [[malignancy|malignancies]] (such as [[lymphoma]]), liver [[cirrhosis]], [[organ transplant]]s, and long-term [[corticosteroid]] therapy.<ref name="setianingrum-2019">{{cite journal
+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 [[malignancy|malignancies]] (such as [[lymphoma]]), liver [[cirrhosis]], [[organ transplant]]s, and long-term [[corticosteroid]] therapy.<ref name=Setianingrum19>{{cite journal
   | author1-first = Findra
   | author1-last = Setianingrum
@@ Line 65: / Line 68: @@
  | url = https://academic.oup.com/mmy/article/57/2/133/5133472
   | access-date = 2022-08-18
+| doi-access = free
-}}</ref>
+  }}</ref>
-Distribution is worldwide in soil.<ref>{{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}}</ref> 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.<ref name="gushiken-2021">{{Cite journal
+Distribution is worldwide in soil.<ref>{{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 }}</ref> 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.<ref name="gushiken-2021">{{Cite journal
   | author1-first = Alexis C.
   | author1-last = Gushiken
@@ Line 85: / Line 89: @@
  }}</ref>
-In humans, ''C. neoformans'' chiefly infects the skin, lungs, and central nervous system (causing [[meningitis]]).<ref name="gushiken-2021"/> Less commonly it may affect other organs such as the eye or prostate.<ref name="gushiken-2021"/>
+In humans, ''C.&nbsp;neoformans'' chiefly infects the skin, lungs, and central nervous system (causing [[meningitis]]).<ref name="gushiken-2021"/> Less commonly it may affect other organs such as the eye or prostate.<ref name="gushiken-2021"/>
-== Primary Cutaneous Cryptococcosis ==
+== Primary cutaneous cryptococcosis ==
-Primary Cutaneous Cryptococcosis (PCC) is a distinct clinical diagnosis separate from the secondary cutaneous cryptococcosis that is spread from 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.<ref>Tucker JS, Guess TE, McClelland EE. The Role of Testosterone and Gibberellic Acid in the Melanization of ''Cryptococcus neoformans''. Front. Microbiol. 2020 Aug 13;11:1921. doi: 10.3389/fmicb.2020.01921. PMID 32922377; PMCID: PMC7456850.</ref>  The upper limbs account for a majority of infections. Isolates found in PCC include ''[[Cryptococcus neoformans]]'' (most common), ''[[Cryptococcus gattii]]'', and ''[[Cryptococcus laurentii]]''. Prognosis for PCC is generally good outside of disseminated infection.<ref>Du L, Yang Y, Gu J, Chen J, Liao W, Zhu Y. Systemic Review of Published Reports on Primary Cutaneous Cryptococcosis in Immunocompetent Patients. Mycopathologia. 2015 Aug;180(1-2):19-25. doi: 10.1007/s11046-015-9880-7. Epub 2015 Mar 4. PMID 25736173.</ref>
+Primary cutaneous cryptococcosis (PCC) is a distinct clinical diagnosis separate from the secondary cutaneous cryptococcosis that is spread from 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.&nbsp;neoformans'' called gibberellic acid (GA) that is upregulated by testosterone.<ref>{{cite journal |vauthors=Tucker JS, Guess TE, McClelland EE |title=The Role of Testosterone and Gibberellic Acid in the Melanization of ''Cryptococcus neoformans'' |journal=Front Microbiol |volume=11 |issue= |pages=1921 |date=2020 |pmid=32922377 |pmc=7456850 |doi=10.3389/fmicb.2020.01921 |doi-access=free }}</ref>  The upper limbs account for a majority of infections. Isolates found in PCC include ''[[Cryptococcus neoformans]]'' (most common), ''[[Cryptococcus gattii]]'', and ''[[Cryptococcus laurentii]]''. Prognosis for PCC is generally good outside of disseminated infection.<ref>{{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 }}</ref>
-Morphologic description of the lesions show 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.<ref>Murakawa GJ, Kerschmann R, Berger T. Cutaneous Cryptococcus infection and AIDS. Report of 12 cases and review of the literature. Arch Dermatol. 1996 May;132(5):545-8. PMID 8624151.</ref>
+Morphologic description of the lesions show 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.<ref>{{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=Arch Dermatol |volume=132 |issue=5 |pages=545–8 |date=May 1996 |doi=10.1001/archderm.1996.03890290079010 |pmid=8624151 }}</ref>
-== Pulmonary Cryptococcosis ==
+== Pulmonary cryptococcosis ==
-Cryptococcus (both ''C. neoformans'' and ''C. gattii'') plays a common role in pulmonary invasive mycosis seen in adults with HIV and other immunocompromised conditions.<ref name=":0">Setianingrum F, Rautemaa-Richardson R, Denning DW. Pulmonary cryptococcosis: A review of pathobiology and clinical aspects. Med Mycol. 2019 Feb 1;57(2):133-150. doi: 10.1093/mmy/myy086. PMID 30329097.</ref> It also affects healthy adults at a much lower frequency and severity as healthy hosts may have no or mild symptoms.<ref>Choi KH, Park SJ, Min KH, Kim SR, Lee MH, Chung CR, Han HJ, Lee YC. Treatment of asymptomatic pulmonary cryptococcosis in immunocompetent hosts with oral fluconazole. Scand J Infect Dis. 2011 May;43(5):380-5. doi: 10.3109/00365548.2011.552521. Epub 2011 Jan 28. PMID 21271944.</ref> Immune-competent hosts may not seek or require treatment, but careful observation may be important.<ref>Saag MS, Graybill RJ, Larsen RA, Pappas PG, Perfect JR, Powderly WG, Sobel JD, Dismukes WE. Practice guidelines for the management of cryptococcal disease. Infectious Diseases Society of America. Clin Infect Dis. 2000 Apr;30(4):710-8. doi: 10.1086/313757. Epub 2000 Apr 20. PMID 10770733.</ref>  Cryptococcal pneumonia has a potential to disseminate to the central nervous system (CNS) especially in immunocompromised individuals.<ref>Brizendine KD, Baddley JW, Pappas PG. Pulmonary cryptococcosis. Semin Respir Crit Care Med. 2011 Dec;32(6):727-34. doi: 10.1055/s-0031-1295720. Epub 2011 Dec 13. PMID 22167400.</ref>
+''Cryptococcus'' (both ''C.&nbsp;neoformans'' and ''C.&nbsp;gattii'') plays a common role in pulmonary invasive mycosis seen in adults with HIV and other immunocompromised conditions.<ref name=Setianingrum19/> It also affects healthy adults at a much lower frequency and severity as healthy hosts may have no or mild symptoms.<ref>{{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=Scand J Infect Dis |volume=43 |issue=5 |pages=380–5 |date=May 2011 |pmid=21271944 |doi=10.3109/00365548.2011.552521 }}</ref> Immune-competent hosts may not seek or require treatment, but careful observation may be important.<ref>{{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=Clin Infect Dis |volume=30 |issue=4 |pages=710–8 |date=April 2000 |pmid=10770733 |doi=10.1086/313757 }}</ref>  Cryptococcal pneumonia has a potential to disseminate to the central nervous system (CNS) especially in immunocompromised individuals.<ref>{{cite journal |vauthors=Brizendine KD, Baddley JW, Pappas PG |title=Pulmonary cryptococcosis |journal=Semin Respir Crit Care Med |volume=32 |issue=6 |pages=727–34 |date=December 2011 |pmid=22167400 |doi=10.1055/s-0031-1295720 }}</ref>
-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, it 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.<ref name=":0" /> Moreover, pulmonary cryptococcosis worsen the prognosis of cryptococcal meningitis.<ref name=":0" />
+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, it 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.<ref name=Setianingrum19 /> Moreover, pulmonary cryptococcosis worsen the prognosis of cryptococcal meningitis.<ref name=Setianingrum19 />
 == Cryptococcal meningitis ==
 [[Image:Meningitis criptocócica diseminada.png|thumb|250px|Disseminated cryptococcal meningitis]]
+{{See also|Chronic meningitis}}
-Cryptococcal meningitis (infection of the [[meninges]], the tissue covering the brain) is believed to result from dissemination of the fungus from either an observed or unappreciated 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.<ref>{{cite journal|title=Estimation of the current global burden of cryptococcal meningitis among persons living with HIV/AIDS|journal=AIDS|date=2009-02-20|volume=23|issue=4|pages=525–30|doi=10.1097/QAD.0b013e328322ffac|vauthors=Park BJ, Wannemuehler KA, Marston BJ, Govender N, Pappas PG, Chiller TM |pmid=19182676|s2cid=5735550}}</ref>
+Cryptococcal meningitis (infection of the [[meninges]], the tissue covering the brain) is believed to result from 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.<ref>{{cite journal|title=Estimation of the current global burden of cryptococcal meningitis among persons living with HIV/AIDS|journal=AIDS|date=2009-02-20|volume=23|issue=4|pages=525–30|doi=10.1097/QAD.0b013e328322ffac|vauthors=Park BJ, Wannemuehler KA, Marston BJ, Govender N, Pappas PG, Chiller TM |pmid=19182676|s2cid=5735550|doi-access=free}}</ref>
-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.<ref>{{Cite journal
+Although ''C.&nbsp;neoformans'' infection most commonly occurs as an opportunistic infection in immunocompromised people (such as those living with AIDS), ''C.&nbsp;gattii'' often infects immunocompetent people as well.<ref>{{Cite journal
   | author1-first = C. A.
   | author1-last = D’Souza
@@ Line 117: / Line 122: @@
  }}</ref>
-[[Cryptococcus]] (both ''[[Cryptococcus neoformans|C. neoformans]]'' and ''[[Cryptococcus gattii|C. gattii]]'') is the dominant and leading<ref>Traoré FA, Cissoko Y, Tounkara TM, Sako FB, Mouelle AD, Kpami DO, Traoré M, Doumbouya M. Étiologies des méningites lymphocytaires chez les personnes vivant avec le VIH suivies dans le service des maladies infectieuses de Conakry [Causes of lymphocytic meningitis in people with HIV admitted to the Infectious Disease department of Conakry]. Med Sante Trop. 2015 Jan-Mar;25(1):52-5. French. doi: 10.1684/mst.2014.0391. PMID 25466555.</ref> etiologic agent of meningitis in adults with HIV and is considered an "emerging" disease in healthy adults.<ref>Pasquier E, Kunda J, De Beaudrap P, Loyse A, Temfack E, Molloy SF, Harrison TS, Lortholary O. Long-term Mortality and Disability in Cryptococcal Meningitis: A Systematic Literature Review. Clin Infect Dis. 2018 Mar 19;66(7):1122-1132. doi: 10.1093/cid/cix870. PMID 29028957.</ref> 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.<ref>Anjum S, Williamson PR. Clinical Aspects of Immune Damage in Cryptococcosis. Curr Fungal Infect Rep. 2019 Sep;13(3):99-108. doi: 10.1007/s12281-019-00345-7. Epub 2019 Jul 22. PMID 33101578; PMCID: PMC7580832.</ref> CD4+ T cells have proven roles in the defense against Cryptococcus, but it can also contribute to clinical deterioration due its inflammatory response.<ref>Neal LM, Xing E, Xu J, Kolbe JL, Osterholzer JJ, Segal BM, Williamson PR, Olszewski MA. CD4+ T Cells Orchestrate Lethal Immune Pathology despite Fungal Clearance during ''Cryptococcus neoformans'' Meningoencephalitis. mBio. 2017 Nov 21;8(6):e01415-17. doi: 10.1128/mBio.01415-17. PMID 29162707; PMCID: PMC5698549.</ref>
+''[[Cryptococcus]]'' species (both ''[[Cryptococcus neoformans|C. neoformans]]'' and ''[[Cryptococcus gattii|C. gattii]]'') are responsible for 68% of meningitis cases in those with HIV.<ref name="Meya 2024">{{cite journal |last1=Meya |first1=David B. |last2=Williamson |first2=Peter R. |title=Cryptococcal Disease in Diverse Hosts |journal=New England Journal of Medicine |date=2 May 2024 |volume=390 |issue=17 |pages=1597–1610 |doi=10.1056/NEJMra2311057|pmid=38692293 }}</ref> Cryptococcus is considered an "emerging" disease in healthy adults.<ref>{{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=Clin Infect Dis |volume=66 |issue=7 |pages=1122–32 |date=March 2018 |pmid=29028957 |doi=10.1093/cid/cix870 }}</ref> 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.<ref>{{cite journal |vauthors=Anjum S, Williamson PR |title=Clinical Aspects of Immune Damage in Cryptococcosis |journal=Curr Fungal Infect Rep |volume=13 |issue=3 |pages=99–108 |date=September 2019 |pmid=33101578 |pmc=7580832 |doi=10.1007/s12281-019-00345-7 }}</ref> CD4+ T cells have proven roles in the defense against ''Cryptococcus'', but it can also contribute to clinical deterioration due its inflammatory response.<ref>{{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 }}</ref>
 == Diagnosis ==
+Symptom onset is often subacute, progressively worsened over several weeks, and delays in diagnosis are associated with increased mortality.<ref name="gushiken-2021"/><ref name="Meya 2024" />
-Dependent on the infectious syndrome, symptoms include fever, fatigue, dry cough, headache, blurred vision, and confusion.<ref name="Barron">{{cite journal |vauthors=Barron MA, Madinger NE|title=Opportunistic Fungal Infections, Part 3: Cryptococcosis, Histoplasmosis, Coccidioidomycosis, and Emerging Mould Infections |journal=Infections in Medicine|date=November 18, 2008 |url=http://www.consultantlive.com/infection/article/1145625/1404367?pageNumber=1}}</ref> Symptom onset is often subacute, progressively worsened over several weeks. The two most common presentations are meningitis (an infection in and around the brain) and pulmonary (lung) infection.<ref name="gushiken-2021"/>
-Any person who is found to have 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 [[Microbiological culture|culture]] of CSF, [[sputum]] and [[urine]] provides definitive diagnosis.<ref name=Rhein />  Blood cultures may be positive in heavy infections. [[India ink]] of the CSF is a traditional microscopic method of diagnosis,<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|pmc=229234|doi=10.1128/JCM.34.9.2290-2291.1996}}</ref> although the sensitivity is poor in early infection, and may miss 15–20% of patients with culture-positive cryptococcal meningitis.<ref name="Boulware 45–53">{{cite journal|last=Boulware|first=DR|author2=Rolfes, MA |author3=Rajasingham, R |author4=von Hohenberg, M |author5=Qin, Z |author6=Taseera, K |author7=Schutz, C |author8=Kwizera, R |author9=Butler, EK |author10=Meintjes, G |author11=Muzoora, C |author12=Bischof, JC |author13=Meya, DB |title=Multisite validation of cryptococcal antigen lateral flow assay and quantification by laser thermal contrast.|journal=Emerging Infectious Diseases|date=Jan 2014|volume=20|issue=1|pages=45–53|pmid=24378231|doi=10.3201/eid2001.130906|pmc=3884728}}</ref>   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|doi=10.1016/S0255-0857(21)02835-8 |pmid=17642731|url=http://www.ijmm.org/article.asp?issn=0255-0857;year=2004;volume=22;issue=3;spage=188;epage=190;aulast=Shashikala|doi-access=free}}</ref> Cryptococcal antigen from [[cerebrospinal fluid]] is the best test for diagnosis of cryptococcal meningitis in terms of sensitivity.<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|url=https://air.unimi.it/bitstream/2434/6221/2/Antinori.pdf}}</ref> Apart from conventional methods of detection like direct microscopy and culture, rapid diagnostic methods to detect cryptococcal antigen by latex agglutination test, lateral flow [[immunochromatographic]] assay (LFA), or enzyme immunoassay (EIA). A new cryptococcal antigen LFA was FDA approved in July 2011.<ref name="Boulware 45–53"/><ref>{{cite journal  |vauthors=Jarvis JN, Percival A, Bauman S, Pelfrey J, Meintjes G, Williams GN, etal | year = 2011 | title = Evaluation of a novelpoint-of-care cryptococcal antigen test on serum, plasma, and urine frompatients with HIV-associated cryptococcal meningitis | journal = Clin Infect Dis | volume = 53 | issue = 10| pages = 1019–23 | doi = 10.1093/cid/cir613 | pmid = 21940419 | pmc = 3193830 }}</ref>   Polymerase chain reaction (PCR) has been used on tissue specimens.
+Cerebrospinal fluid (CSF) or blood antigen testing by [[lateral flow assay]] for cryptococcal antigens has a sensitivity and specificity greater than 99% for cryptococcosis.<ref name="Meya 2024" /> A CSF [[Microbiological culture|fungal culture]] can tell if there is 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.<ref name="Meya 2024" /> 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 [[Microbiological culture|culture]] of CSF, [[sputum]] and [[urine]] provides definitive diagnosis.<ref name=Rhein /> Blood cultures may be positive in heavy infections. [[India ink]] of the CSF is a traditional microscopic method of diagnosis,<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|pmc=229234|doi=10.1128/JCM.34.9.2290-2291.1996}}</ref> although the sensitivity is poor in early infection, and may miss 15–20% of patients with culture-positive cryptococcal meningitis.<ref name="Boulware 45–53">{{cite journal|last=Boulware|first=DR|author2=Rolfes, MA |author3=Rajasingham, R |author4=von Hohenberg, M |author5=Qin, Z |author6=Taseera, K |author7=Schutz, C |author8=Kwizera, R |author9=Butler, EK |author10=Meintjes, G |author11=Muzoora, C |author12=Bischof, JC |author13=Meya, DB |title=Multisite validation of cryptococcal antigen lateral flow assay and quantification by laser thermal contrast.|journal=Emerging Infectious Diseases|date=Jan 2014|volume=20|issue=1|pages=45–53|pmid=24378231|doi=10.3201/eid2001.130906|pmc=3884728}}</ref> 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.<ref name="Meya 2024" />
+<gallery>
-Cryptococcosis can rarely occur in the non-immunosuppressed people, particularly with ''[[Cryptococcus gattii]]''.
-<gallery>Image:Cryptococcosis of lung in patient with AIDS. Mucicarmine stain 962 lores.jpg
+Image:Cryptococcosis of lung in patient with AIDS. Mucicarmine stain 962 lores.jpg
 Image:Pulmonary cryptococcosis (1) histiocytic penumonia.jpg
 Image:Pulmonary cryptococcosis (3) Alcian blue-PAS.jpg
@@ Line 135: / Line 140: @@
 == Prevention ==
 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 rates of detectable cryptococcal antigen in peripheral blood is often 4–12% in persons with CD4 counts lower than 100 cells/mcL.<ref>{{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}}</ref><ref name="pmid20597693">{{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 = Clin. Infect. Dis. | volume = 51 | issue = 4 | pages = 448–55 | date = August 2010 | pmid = 20597693 | pmc = 2946373 | doi = 10.1086/655143 }}</ref>
-Cryptococcal antigen screen and preemptive treatment with fluconazole is cost saving to the healthcare system by avoiding cryptococcal meningitis.<ref>{{cite journal|last=Rajasingham|first=R|author2=Meya, DB |author3=Boulware, DR |title=Integrating cryptococcal antigen screening and pre-emptive treatment into routine HIV care|journal=Journal of Acquired Immune Deficiency Syndromes|date=Apr 15, 2012|volume=59|issue=5|pages=e85–91|pmid=22410867|doi=10.1097/QAI.0b013e31824c837e|pmc=3311156}}</ref>   The World Health Organization recommends cryptococcal antigen screening in HIV-infected persons entering care with CD4<100 cells/μL.<ref name="WHO Recs" /> This undetected subclinical cryptococcal (if not preemptively treated with anti-fungal therapy) will often go on to develop cryptococcal meningitis, despite receiving HIV therapy.<ref name="pmid20597693"/><ref>{{cite journal|last=Jarvis|first=JN |author2=Harrison, TS |author3=Govender, N |author4=Lawn, SD |author5=Longley, N |author6=Bicanic, T |author7=Maartens, G |author8=Venter, F |author9=Bekker, LG |author10=Wood, R |author11=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|year=2011|volume=101|issue=4|pages=232–4|pmid=21786721|doi=10.7196/samj.4752|url=https://open.uct.ac.za/bitstream/11427/24418/1/Jarvis_Article_2011.pdf|doi-access=free}}</ref>  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.<ref>{{cite journal|last=Rajasingham|first=R|author2=Boulware, DR|title=Reconsidering cryptococcal antigen screening in the U.S. among persons with CD4 &lt;100 cells/mcL.|journal=Clinical Infectious Diseases|date=Dec 2012|volume=55|issue=12|pages=1742–4|pmid=22918997|doi=10.1093/cid/cis725|pmc=3501329}}</ref><ref name="pmid25006824">{{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 Morb. Mortal. Wkly. Rep. | volume = 63 | issue = 27 | pages = 585–7 | date = July 2014 | pmid = 25006824 | pmc = 4584711 }}</ref>
+Cryptococcal antigen screen and preemptive treatment with fluconazole is cost saving to the healthcare system by avoiding cryptococcal meningitis.<ref>{{cite journal|last=Rajasingham|first=R|author2=Meya, DB |author3=Boulware, DR |title=Integrating cryptococcal antigen screening and pre-emptive treatment into routine HIV care|journal=Journal of Acquired Immune Deficiency Syndromes|date=Apr 15, 2012|volume=59|issue=5|pages=e85–91|pmid=22410867|doi=10.1097/QAI.0b013e31824c837e|pmc=3311156}}</ref>   The World Health Organization recommends cryptococcal antigen screening in HIV-infected persons entering care with CD4<100 cells/μL.<ref name="WHO Recs" /> This undetected subclinical cryptococcal (if not preemptively treated with anti-fungal therapy) will often go on to develop cryptococcal meningitis, despite receiving HIV therapy.<ref name="pmid20597693"/><ref>{{cite journal|last=Jarvis|first=JN |author2=Harrison, TS |author3=Govender, N |author4=Lawn, SD |author5=Longley, N |author6=Bicanic, T |author7=Maartens, G |author8=Venter, F |author9=Bekker, LG |author10=Wood, R |author11=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|year=2011|volume=101|issue=4|pages=232–4|pmid=21786721|doi=10.7196/samj.4752|doi-broken-date=2024-11-10 |url=https://open.uct.ac.za/bitstream/11427/24418/1/Jarvis_Article_2011.pdf|doi-access=free}}</ref>  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.<ref>{{cite journal|last=Rajasingham|first=R|author2=Boulware, DR|title=Reconsidering cryptococcal antigen screening in the U.S. among persons with CD4 &lt;100 cells/mcL.|journal=Clinical Infectious Diseases|date=Dec 2012|volume=55|issue=12|pages=1742–4|pmid=22918997|doi=10.1093/cid/cis725|pmc=3501329}}</ref><ref name="pmid25006824">{{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 Morb. Mortal. Wkly. Rep. | volume = 63 | issue = 27 | pages = 585–7 | date = July 2014 | pmid = 25006824 | pmc = 4584711 }}</ref>
-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.<ref>{{Cite journal |last1=Awotiwon |first1=Ajibola A |last2=Johnson |first2=Samuel |last3=Rutherford |first3=George W |last4=Meintjes |first4=Graeme |last5=Eshun-Wilson |first5=Ingrid |date=2018-08-29 |editor-last=Cochrane Infectious Diseases Group |title=Primary antifungal prophylaxis for cryptococcal disease in HIV-positive people |journal=Cochrane Database of Systematic Reviews |volume=2018 |issue=8 |pages=CD004773 |language=en |doi=10.1002/14651858.CD004773.pub3 |pmc=6513489 |pmid=30156270}}</ref>
+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.<ref>{{Cite journal |last1=Awotiwon |first1=Ajibola A |last2=Johnson |first2=Samuel |last3=Rutherford |first3=George W |last4=Meintjes |first4=Graeme |last5=Eshun-Wilson |first5=Ingrid |date=2018-08-29 |editor-last=Cochrane Infectious Diseases Group |title=Primary antifungal prophylaxis for cryptococcal disease in HIV-positive people |journal=Cochrane Database of Systematic Reviews |volume=2018 |issue=8 |pages=CD004773 |doi=10.1002/14651858.CD004773.pub3 |pmc=6513489 |pmid=30156270}}</ref>
 == Treatment ==
-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).<ref>{{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}}</ref>
+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).<ref>{{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 }}</ref>
-People living with AIDS often have a greater burden of disease and higher mortality (30–70% at 10-weeks), but recommended therapy is with [[amphotericin B]] and [[flucytosine]]. Where [[flucytosine]] is not available (many low and middle income countries), [[fluconazole]] should be used with amphotericin.<ref name="WHO Recs">{{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}}</ref> [[Amphotericin]]-based induction therapy has much greater microbiologic activity than [[fluconazole]] monotherapy with 30% better survival at 10-weeks.<ref name="Rhein">{{cite journal|last=Rhein|first=J|author2=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}}</ref><ref name=Rajasingham>{{cite journal|last=Rajasingham|first=Radha|author2=Rolfes, M.A. |author3=Birkenkamp, K.E. |author4=Meya, D.B. |author5= Boulware, D.R. |title=Cryptococcal Meningitis Treatment Strategies in Resource-Limited Settings: A Cost-Effectiveness Analysis|journal=PLOS Medicine|year=2012|volume=9|issue=9|pages=e1001316|doi=10.1371/journal.pmed.1001316|editor1-last=Farrar|editor1-first=Jeremy|pmid=23055838|pmc=3463510}}</ref>  Based on a systematic review of existing data, the most cost-effective induction treatment in resource-limited settings appears to be one week of amphotericin B coupled with high-dose [[fluconazole]].<ref name=Rajasingham />   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.<ref name="WHO Recs" />
+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.<ref name="Meya 2024" /> Where flucytosine is not available, [[fluconazole]] should be used with amphotericin.<ref name="WHO Recs">{{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}}</ref> [[Amphotericin]]-based induction therapy has much greater microbiologic activity than fluconazole monotherapy with 30% better survival at 10 weeks.<ref name="Rhein">{{cite journal|last=Rhein|first=J|author2=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}}</ref><ref name=Rajasingham>{{cite journal|last=Rajasingham|first=Radha|author2=Rolfes, M.A. |author3=Birkenkamp, K.E. |author4=Meya, D.B. |author5= Boulware, D.R. |title=Cryptococcal Meningitis Treatment Strategies in Resource-Limited Settings: A Cost-Effectiveness Analysis|journal=PLOS Medicine|year=2012|volume=9|issue=9|pages=e1001316|doi=10.1371/journal.pmed.1001316|editor1-last=Farrar|editor1-first=Jeremy|pmid=23055838|pmc=3463510 |doi-access=free }}</ref>  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.<ref name=Rajasingham />   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.<ref name="WHO Recs" />
-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.<ref>{{cite journal|last1=Boulware|first1=DR|last2=Meya|first2=DB|last3=Muzoora|first3=Conrad|last4=Rolfes|first4=MA|last5=Huppler Hullsiek|first5=K|last6=Musubire|first6=Abdu|last7=Taseera|first7=Kabanda|last8=Nabeta|first8=HW|last9=Schutz|first9=C|last10=Williams|first10=DA A.|last11=Rajasingham|first11=R|last12=Rhein|first12=J|last13=Thienemann|first13=F|last14=Lo|first14=MW|last15=Nielsen|first15=K|last16=Bergemann|first16=T L.|last17=Kambugu|first17=A|last18=Manabe|first18=YC|last19=Janoff|first19=EN|last20=Bohjanen|first20=PR|last21=Meintjes|first21=G|title=Timing of Antiretroviral Therapy after Diagnosis of Cryptococcal Meningitis|journal=New England Journal of Medicine|date=26 June 2014|volume=370|issue=26|pages=2487–2498|doi=10.1056/NEJMoa1312884|pmid=24963568|pmc=4127879}}</ref> A 2018 Cochrane review also supports the delayed starting of treatment until cryptococcosis starts improving with antifungal treatment.<ref>{{Cite journal|last1=Eshun-Wilson|first1=Ingrid|last2=Okwen|first2=Mbah P.|last3=Richardson|first3=Marty|last4=Bicanic|first4=Tihana|date=24 July 2018|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|doi=10.1002/14651858.CD009012.pub3|issn=1469-493X|pmc=6513637|pmid=30039850}}</ref>
+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.<ref>{{cite journal|last1=Boulware|first1=DR|last2=Meya|first2=DB|last3=Muzoora|first3=Conrad|last4=Rolfes|first4=MA|last5=Huppler Hullsiek|first5=K|last6=Musubire|first6=Abdu|last7=Taseera|first7=Kabanda|last8=Nabeta|first8=HW|last9=Schutz|first9=C|last10=Williams|first10=DA A.|last11=Rajasingham|first11=R|last12=Rhein|first12=J|last13=Thienemann|first13=F|last14=Lo|first14=MW|last15=Nielsen|first15=K|last16=Bergemann|first16=T L.|last17=Kambugu|first17=A|last18=Manabe|first18=YC|last19=Janoff|first19=EN|last20=Bohjanen|first20=PR|last21=Meintjes|first21=G|title=Timing of Antiretroviral Therapy after Diagnosis of Cryptococcal Meningitis|journal=New England Journal of Medicine|date=26 June 2014|volume=370|issue=26|pages=2487–98|doi=10.1056/NEJMoa1312884|pmid=24963568|pmc=4127879}}</ref> A 2018 Cochrane review also supports the delayed starting of treatment until cryptococcosis starts improving with antifungal treatment.<ref>{{Cite journal|last1=Eshun-Wilson|first1=Ingrid|last2=Okwen|first2=Mbah P.|last3=Richardson|first3=Marty|last4=Bicanic|first4=Tihana|date=24 July 2018|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|doi=10.1002/14651858.CD009012.pub3|pmc=6513637|pmid=30039850}}</ref>
+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 puncture]]s to lower the intracranial pressure by draining CSF are associated with reduced mortality in those with cryptococcal meningitis (with or without HIV).<ref name="Meya 2024" /><ref name="Rolfes 2014">{{cite journal |vauthors = Rolfes et al. |title=The Effect of Therapeutic Lumbar Punctures on Acute Mortality From Cryptococcal Meningitis |journal=Clinical Infectious Diseases |date=1 December 2014 |volume=59 |issue=11 |pages=1607–1614 |doi=10.1093/cid/ciu596}}</ref><ref name="Perfect 2010">{{cite journal |vauthors = Perfect JR et al. |title=Clinical Practice Guidelines for the Management of Cryptococcal Disease: 2010 Update by the Infectious Diseases Society of America |journal=Clinical Infectious Diseases |date=1 February 2010 |volume=50 |issue=3 |pages=291–322 |doi=10.1086/649858|pmid=20047480 |pmc=5826644 }}</ref> 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 prior to 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.<ref name="Meya 2024" />
 === IRIS ===
+[[Immune reconstitution inflammatory syndrome]] is possible in those with cryptococcal infection, especially those with concurrent HIV starting [[Management of HIV/AIDS|anti-retroviral therapy]]. With anti-retroviral therapy for the HIV, the CD4+ T-cell counts recover and the restored immune system mounts an exaggerated, hyperinflammatory response against cryptococcal infection in the body.<ref name="Meya 2024" />
+IRIS has a 5% incidence in those with HIV and cryptococcosis starting anti-retroviral therapy. It usually occurs within 4 weeks of starting anti-retroviral therapy.<ref name="Meya 2024" /> The risk of IRIS is increased in those with a high fungal burden, lower CD4+ T-cell count, and lower inflammatory marker levels.<ref name="Meya 2024" />
-The [[immune reconstitution inflammatory syndrome]] (IRIS) has been described in those with normal immune function with meningitis caused by ''C. gattii'' and ''C. grubii''. The increasing inflammation can cause brain injury or be fatal.<ref>{{cite journal |vauthors=Lane M, McBride J, Archer J |title=Steroid responsive late deterioration in Cryptococcus neoformans variety gattii meningitis |journal=Neurology |volume=63 |issue=4 |pages=713–4 |date=August 2004 |pmid=15326249 |doi=10.1212/01.WNL.0000134677.29120.62|s2cid=42308361 }}</ref><ref>{{cite journal |vauthors=Einsiedel L, Gordon DL, Dyer JR |title=Paradoxical inflammatory reaction during treatment of Cryptococcus neoformans var. gattii meningitis in an HIV-seronegative woman |journal=Clin. Infect. Dis. |volume=39 |issue=8 |pages=e78–82 |date=October 2004 |pmid=15486830 |doi=10.1086/424746 |doi-access=free }}</ref><ref>{{cite journal |vauthors=Ecevit IZ, Clancy CJ, Schmalfuss IM, Nguyen MH |title=The poor prognosis of central nervous system cryptococcosis among nonimmunosuppressed patients: a call for better disease recognition and evaluation of adjuncts to antifungal therapy |journal=Clin. Infect. Dis. |volume=42 |issue=10 |pages=1443–7 |date=May 2006 |pmid=16619158 |doi=10.1086/503570 |doi-access=free }}</ref>
 ==Epidemiology==
+Cryptococcosis is usually associated with immunosuppressed people, such as those with [[HIV/AIDS|AIDs]], [[corticosteroid]] use, [[diabetes]], and [[Organ transplantation|organ transplant]].<ref>{{Citation |last1=Mada |first1=Pradeep Kumar |title=''Cryptococcus'' |date=2023 |url=http://www.ncbi.nlm.nih.gov/books/NBK431060/ |work=StatPearls |access-date=2023-11-15 |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=28613714 |last2=Jamil |first2=Radia T. |last3=Alam |first3=Mohammed U.}}</ref> ''Cryptococcus'' comprizes two clinically relevant species, ''Cryptococcus neoformans'' and ''Cryptococcus gattii''.<ref>{{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 Res |volume=10 |issue=6 |pages=769–78 |date=September 2010 |pmid=20561059 |pmc=2920376 |doi=10.1111/j.1567-1364.2010.00648.x }}</ref> ''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.<ref>{{Cite journal |last1=Harris |first1=Julie |last2=Lockhart |first2=Shawn |last3=Chiller |first3=Tom |date=February 2012 |title=''Cryptococcus gattii'': where do we go from here? |url=https://academic.oup.com/mmy/article-lookup/doi/10.3109/13693786.2011.607854 |journal=Medical Mycology |volume=50 |issue=2 |pages=113–129 |doi=10.3109/13693786.2011.607854 |pmid=21939343 |s2cid=21577621 }}</ref>
-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.<ref name="Vallab2016">{{cite book |last1=Vallabhaneni |first1=Snigdha |last2=Mody |first2=Rajal K. |last3=Walker |first3=Tiffany |last4=Chiller |first4=Tom |editor1-last=Sobel |editor1-first=Jack |editor2-last=Ostrosky-Zeichner |editor2-first=Luis |title=Fungal Infections, An Issue of Infectious Disease Clinics of North America |date=2016 |publisher=Elsevier |location=Philadelphia |isbn=978-0-323-41649-8 |pages=3–4|chapter-url=https://books.google.com/books?id=uwndCwAAQBAJ&pg=PA3 |language=en |chapter=1. The global burden of fungal disease}}</ref>
+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.<ref name="Vallab2016" /> In 2014, amongst people who had a low [[T helper cell|CD4+ cell]] count, the annual incidence rate was estimated to be 278,000 cases. Of those, 223,100 resulted in cryptococcal meningitis.<ref name="Rajasingham-2017">{{Cite journal |last1=Rajasingham |first1=Radha |last2=Smith |first2=Rachel M |last3=Park |first3=Benjamin J |last4=Jarvis |first4=Joseph N |last5=Govender |first5=Nelesh P |last6=Chiller |first6=Tom M |last7=Denning |first7=David W |last8=Loyse |first8=Angela |last9=Boulware |first9=David R |date=August 2017 |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 |doi=10.1016/S1473-3099(17)30243-8|pmid=28483415 |pmc=5818156 }}</ref> 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%.<ref name="Rajasingham-2017" /> 19% of all AIDS related deaths are due to cryptococcal disease.<ref name="Rajasingham 2022">{{cite journal |last1=Rajasingham |first1=Radha |last2=Govender |first2=Nelesh P |last3=Jordan |first3=Alexander |last4=Loyse |first4=Angela |last5=Shroufi |first5=Amir |last6=Denning |first6=David W |last7=Meya |first7=David B |last8=Chiller |first8=Tom M |last9=Boulware |first9=David R |title=The global burden of HIV-associated cryptococcal infection in adults in 2020: a modelling analysis |journal=The Lancet Infectious Diseases |date=December 2022 |volume=22 |issue=12 |pages=1748–1755 |doi=10.1016/S1473-3099(22)00499-6|pmid=36049486 |pmc=9701154 }}</ref> 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.<ref name="Meintjes 2024">{{cite journal |last1=Meintjes |first1=Graeme |last2=Maartens |first2=Gary |title=HIV-Associated Tuberculosis |journal=New England Journal of Medicine |date=25 July 2024 |volume=391 |issue=4 |pages=343–355 |doi=10.1056/NEJMra2308181}}</ref> In sub-Saharan Africa approximately a third of HIV patients will develop cryptococcosis.<ref name="Alemayehu-2020"/>
+=== In the United States ===
+In the United States 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 fell by 90% due to the proliferation of [[Management of HIV/AIDS|antiretroviral therapy]].<ref>{{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}}</ref><ref name="Mada-2023">{{Citation |last1=Mada |first1=Pradeep Kumar |title=''Cryptococcus'' |date=2023 |url=http://www.ncbi.nlm.nih.gov/books/NBK431060/ |id=NBK431060 |work=StatPearls |access-date=2023-11-15 |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=28613714 |last2=Jamil |first2=Radia T. |last3=Alam |first3=Mohammed U.}}</ref> The estimated prevalence of cryptococcosis cases amongst HIV patients in the U.S. is 2.8%.<ref>{{Cite journal |last1=Alemayehu |first1=Tsegaye |last2=Ayalew |first2=Sosina |last3=Buzayehu |first3=Temesgen |last4=Daka |first4=Deresse |date=2020-04-20 |title=Magnitude of Cryptococcosis among HIV patients in sub-Saharan Africa countries: a systematic review and meta-analysis |url=https://www.ajol.info/index.php/ahs/article/view/194953 |journal=African Health Sciences |language=en |volume=20 |issue=1 |pages=114–121 |doi=10.4314/ahs.v20i1.16 |pmid=33402899 |pmc=7750036 }}</ref> In immunocompetent patients cryptococcus typically presents itself as ''[[Cryptococcus gattii]]''.<ref name="Mada-2023" /> Despite its rarity cryptococcus has been more commonly seen, with upwards of 20% of cases in immunocompetent people.<ref>{{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 Infect Dis |volume=10 |issue=8 |pages=ofad420 |date=August 2023 |pmid=37636518 |pmc=10456216 |doi=10.1093/ofid/ofad420 }}</ref> 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.<ref>{{Cite journal |last1=Howard-Jones |first1=Annaleise R. |last2=Sparks |first2=Rebecca |last3=Pham |first3=David |last4=Halliday |first4=Catriona |last5=Beardsley |first5=Justin |last6=Chen |first6=Sharon C.-A. |date=November 2022 |title=Pulmonary Cryptococcosis |journal=Journal of Fungi |language=en |volume=8 |issue=11 |pages=1156 |doi=10.3390/jof8111156 |pmid=36354923 |pmc=9696922 |doi-access=free }}</ref> ''C. gattii'' has been found in over 90 people in the United States, most of these cases originating in Washington or Oregon.<ref>{{Cite journal |last1=Harris |first1=Julie |last2=Lockhart |first2=Shawn |last3=Chiller |first3=Tom |date=February 2012 |title=''Cryptococcus gattii'': where do we go from here? |url=https://academic.oup.com/mmy/article-lookup/doi/10.3109/13693786.2011.607854 |journal=Medical Mycology |language=en |volume=50 |issue=2 |pages=113–129 |doi=10.3109/13693786.2011.607854 |pmid=21939343 |s2cid=21577621 }}</ref>
+=== In sub-Saharan Africa ===
+Sub-Saharan Africa is the main hub for HIV/AIDS worldwide. HIV/AIDS accounts for about 0.5% of the world's population.<ref>{{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}}</ref> Remarkably, sub-Saharan Africa holds 71% of HIV/AIDs cases.<ref>{{Cite journal |last1=Kharsany |first1=Ayesha B.M. |last2=Karim |first2=Quarraisha A. |date=2016-04-08 |title=HIV Infection and AIDS in Sub-Saharan Africa: Current Status, Challenges and Opportunities |journal=The Open AIDS Journal |volume=10 |pages=34–48 |doi=10.2174/1874613601610010034 |pmc=4893541 |pmid=27347270}}</ref> Cryptococcal meningitis is a primary contributor to mortality among individuals with HIV/AIDS in sub-Saharan Africa.<ref>{{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}}</ref>  Approximately 160,000 cases of cryptococcal meningitis are reported in West Africa, resulting in 130,000 deaths in sub-Saharan Africa.<ref>{{Cite journal |last1=Akaihe |first1=Chidinma Lynda |last2=Nweze |first2=Emeka Innocent |date=January 2021 |title=Epidemiology of ''Cryptococcus'' and cryptococcosis in Western Africa |url=https://onlinelibrary.wiley.com/doi/10.1111/myc.13188 |journal=Mycoses |language=en |volume=64 |issue=1 |pages=4–17 |doi=10.1111/myc.13188 |pmid=32969547 |s2cid=221884476 }}</ref> Uganda is reported to have the highest occurrence of cryptococcus meningitis.<ref name="Alemayehu-2020">{{Cite journal |last1=Alemayehu |first1=Tsegaye |last2=Ayalew |first2=Sosina |last3=Buzayehu |first3=Temesgen |last4=Daka |first4=Deresse |date=2020-04-20 |title=Magnitude of Cryptococcosis among HIV patients in sub-Saharan Africa countries: a systematic review and meta-analysis |url=https://www.ajol.info/index.php/ahs/article/view/194953 |journal=African Health Sciences |volume=20 |issue=1 |pages=114–121 |doi=10.4314/ahs.v20i1.16 |pmid=33402899 |pmc=7750036 }}</ref> Reflecting that, Ethiopia has the least occurrence.<ref name="Alemayehu-2020" /> 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, amphotericin-B is not considered a treatment, as it showed not a significant reduction in the mortality rate.<ref>{{Cite journal |last1=Patel |first1=Raju K K |last2=Leeme |first2=Tshepo |last3=Azzo |first3=Caitlin |last4=Tlhako |first4=Nametso |last5=Tsholo |first5=Katlego |last6=Tawanana |first6=Ephraim O |last7=Molefi |first7=Mooketsi |last8=Mosepele |first8=Mosepele |last9=Lawrence |first9=David S |last10=Mokomane |first10=Margaret |last11=Tenforde |first11=Mark W |last12=Jarvis |first12=Joseph N |date=2018-11-01 |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 |language=en |volume=5 |issue=11 |pages=ofy267 |doi=10.1093/ofid/ofy267 |pmid=30488038 |pmc=6251350 }}</ref>
 == Other animals ==
@@ Line 160: / Line 175: @@
 == Further reading ==
+{{refbegin}}
 * {{cite journal | vauthors = Perfect JR et al. | 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 = 2010 | pmid = 20047480 | pmc = 5826644 | doi = 10.1086/649858 }}
 * {{cite journal | vauthors = Gullo FP et al. | 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 = 2013 | pmid = 24141976 | doi = 10.1007/s10096-013-1915-8 | s2cid = 11317427 }}
-* {{cite journal | vauthors = Perfect JR et al. | title = Cryptococcus neoformans: a sugar-coated killer with designer genes | journal = FEMS Immunology and Medical Microbiology | volume = 45 | issue = 11 | pages = 395–404 | date = 2005 | pmid = 16055314 | doi = 10.1016/j.femsim.2005.06.005 | doi-access = free }} (Review)
+* {{cite journal | vauthors = Perfect JR et al. | title =''Cryptococcus neoformans'': a sugar-coated killer with designer genes | journal = FEMS Immunology and Medical Microbiology | volume = 45 | issue = 11 | pages = 395–404 | date = 2005 | pmid = 16055314 | doi = 10.1016/j.femsim.2005.06.005 | doi-access = free }} (Review)
+{{refend}}
 == External links ==
 * [http://emedicine.medscape.com/article/215354-overview Medscape entry on cryptococcosis]
+{{Mycoses}}
+{{Diseases of meninges}}
 {{Medical resources
 | ICD10           = {{ICD10|B|45||b|35}}
@@ Line 179: / Line 198: @@
 | Orphanet        = 1546
 }}
+{{Authority control}}
-{{Mycoses}}
-{{Diseases of meninges}}
 [[Category:Animal fungal diseases]]

Classification	D ICD-10: B45 ICD-9-CM: 117.5 MeSH: D003453 DiseasesDB: 3213
External resources	MedlinePlus: 001328 eMedicine: med/482 Patient UK: Cryptococcosis Orphanet: 1546