II. Definitions

  1. Cryptococcus
    1. Fungal organisms, primarily of 2 species important to humans
      1. Cryptococcus neoformans
      2. Cryptococcus gatti
    2. Cryptococcus is most commonly found in soil, decaying wood, tree hollows, bird droppings
  2. Cryptococcosis
    1. Fungal infection acquired via spore inhalation
    2. Invasive fungal infection (esp. Meningitis) in Immunocompromised patients (esp. AIDS)
    3. Infection may occur in immunocompetent patients, but is contained without hematogenous spread
      1. However, should that patient become Immunocompromised later, reactivation may occur

III. Pathophysiology

  1. Invasive fungal infection in Immunocompromised patients
  2. Facultative intracellular organisms
  3. Most commonly caused by Cryptococcus neoformans
    1. Cryptococcus gatti is less common, and may affect immunocompetent patients

IV. Epidemiology

  1. Incidence
    1. United States: 2-7 cases per 1000 AIDS patients (90% are Meningitis cases, 12% case fatality rate)
    2. Worldwide: 1 Million cases annually (especially sub-Sahara Africa)
      1. Worldwide Deaths per year >600,000
      2. Responsible for 15% of AIDS related dealths worldwide

V. Risk Factors

  1. Consider in all at risk and known HIV patients with Headache
  2. Advanced HIV (AIDS)
    1. CD4 < 50 to 100 cells per mm3 or
    2. AIDS-Defining Illness
  3. Other Immunocompromised patients
    1. Diabetes Mellitus
    2. Chonic liver disease
    3. Chronic Kidney Disease
    4. Immunosuppression (e.g. longterm Corticosteroids, status-post organ transplant)

VI. Symptoms

  1. Insidious onset
    1. Typically starts as occult, asymptomatic infection in 50% of cases, or non-specific symptoms
    2. Inhalation of spores results in asymptomatic lung infection, and then spreads hematogenously
    3. Typically develops over a 2 week period, ultimately manifesting as meningoencephalitis
  2. Headache (91%)
  3. Weight Loss (90%)
  4. Fever (52%)
  5. Malaise
  6. Altered Level of Consciousness or confusion

VII. Signs

  1. Fever (91%)
  2. Muscle wasting (90%)
  3. Motor weakness (40%)
  4. Cranial Nerve palsy (29%)
    1. Hearing Loss
    2. Vision Loss (Optic Neuritis related)
      1. May progress within 12 hours following onset of Optic Neuritis
  5. Organ Involvement
    1. Neurologic involvement (Meningitis) (85-90%)
    2. Lung or skin involvement (25%)

VIII. Precautions

  1. Do not rely on lack of meningismus (meningeal signs) to exclude Cryptococcal Meningitis
    1. Meningeal signs are only present in one quarter of Cryptococcal Meninigitis
  2. Best outcomes are for early diagnosis and treatment (including lowering of Intracranial Pressure)

IX. Differential Diagnosis

X. Imaging

  1. CT Head
    1. Typically performed prior to Lumbar Puncture to exclude Brain Mass
    2. Lumbar Puncture is considered safe when there is no brain shift or significant space occupying lesion

XI. Labs

  1. Blood Cultures positive (>75%)
  2. Serum cryptococcal Antigen
    1. Test Sensitivity: 98 to 99%
    2. Test Specificity: 94%
    3. High titer (>1024:1)
  3. CSF Exam
    1. General Findings
      1. CSF Glucose usually normal
      2. CSF Protein mildly elevated
      3. CSF White Blood Cell Count usually less than 20
    2. Definitive Diagnosis
      1. India Ink stain usually shows organism (Test Sensitivity 60 to 80%)
        1. Cream-colored fungal colonies develop within 3-7 days on culture
        2. Indicated when CSF Cryptococcal Antigen test is unavailable
      2. CSF Cryptococcal Antigen test (>95% Test sensitive, specific)
    3. Increased CSF Opening Pressure
      1. Typically CSF Opening Pressure >350 mm H2O in Crytococcal Meningitis
        1. Increased pressure results from high fungal burden in CNS interfering with CSF reabsorption
      2. Differential diagnosis (other causes of increased CSF Opening Pressure in HIV)
        1. Toxoplasma Encephalitis
        2. CNS Lymphoma
        3. Tuberculous Meningitis
      3. Risk of obstructrive Hydrocephalus presenting as cognitive deficit and ataxic gait
        1. High pressure responsible for adverse sequelae
      4. Therapeutic CSF removal is indicated when opening pressure >30 mm H2O
        1. Treat with serial LPs, lumbar drain or VP Shunt
        2. Goal CSF Pressure reduction by 50% or to <20 mm H2O (normal pressure)

XII. Management: Acute (CNS and extraneural involvement)

  1. Precautions
    1. Start empiric therapy while awaiting definitive diagnosis when Cryptococcal Meningitis is suspected
    2. Lower Intracranial Pressure as soon as possible (initially via Lumbar Puncture)
      1. Critical factor in best neurologic outcomes
      2. Goal CSF Pressure reduction by 50% or to <20 mm H2O (normal pressure)
  2. Step 1: Initial Induction Phase - Combination Antimicrobial Therapy for 2 to 8 weeks
    1. Amphotericin B (High dose) 0.7 mg/kg/day AND
    2. Flucytosine (100 mg/kg/day)
  3. Step 2: Repeat CSF with opening pressure at 2 weeks (or sooner depending on status)
    1. Obtain repeat CSF Culture
      1. If positive, then continue combination therapy (as in step 1)
      2. If negative, then may transition to Fluconazole (see step 3 below)
    2. Lower Intracranial Pressure as needed
      1. Serial Lumbar Puncture
      2. Lumbar drain
      3. VP Shunt
  4. Step 3: Maintenance Antifungal after initial induction (in step 1)
    1. Fluconazole (200 to 400 mg/day) for up to 1 year
  5. Step 4: Prophylaxis after maintenance (if indicated)
    1. Start after maintenance completed (step 3) if CD4 <100 cells/uL
    2. Relapse occurs in >80% if no suppression given (if CD4 <100 cells/uL)
    3. Fluconazole 200 mg/day

XIII. Management: Other

  1. Immunocompetent Patients with Suspected Pulmonary Crytopococcus
    1. Exclude Crytopococcal Meningitis with Lumbar Puncture first
    2. Fluconazole 400 mg daily for 6 to 12 months
  2. Avoid harmful measures
    1. Avoid Dexamethasone
      1. Associated with increased mortality
      2. Beardsley (2016) N Engl J Med 374(6): 542-4 +PMID: 26863355 [PubMed]

XIV. Prognosis

  1. Uniformly fatal if left untreated
  2. Overall Mortality: 12%
    1. One year mortality in U.S. approaches 20 to 30%

XV. Resources

  1. Mada (2023) Cryptococcus, StatPearls, Treasure Island, FL
    1. https://www.ncbi.nlm.nih.gov/books/NBK431060/

XVI. References

  1. Parker and Bond (2023) Crit Dec Emerg Med 37(10): 4-9
  2. Perkins (2013) Crit Dec Emerg Med 27(3): 2-9
  3. Friedmann (1995) Arch Intern Med 155(20): 2231-7 [PubMed]
  4. Mwaba (2001) Postgrad Med J 77(814): 769-73 [PubMed]

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Related Studies

Ontology: Infection by Cryptococcus neoformans (C0010414)

Definition (NCI) An acute or chronic, localized or disseminated infection by Cryptococcus neoformans. Sites of involvement include the lungs, central nervous system and meninges, skin, and visceral organs.--2004
Definition (CSP) infection with a fungus of the species Cryptococcus neoformans.
Definition (MSH) Infection with a fungus of the species CRYPTOCOCCUS NEOFORMANS.
Concepts Disease or Syndrome (T047)
MSH D003453
ICD9 117.5
ICD10 B45 , B45.9
SnomedCT 42386007, 187090005, 187494009, 187097008, 20850004
LNC LA10446-5
English Cryptococcoses, Cryptococcosis, Cryptococcus neoformans, Toruloses, Torulosis, Infection by Cryptococcus neoformans, Cryptococcosis NOS, Cryptococcosis, unspecified, [X]Cryptococcosis, unspecified, cryptococcosis (diagnosis), cryptococcosis, C.neoformans infection, Cryptococcus neoformans infection, Cryptococcosis, NOS, Cryptococcosis [Disease/Finding], torula, cryptococcus infection neoformans, cryptococcoses, cryptococcus neoformans, Busse - Buschke's disease, [X]Cryptococcosis, unspecified (disorder), Cryptococcosis NOS (disorder), (Cryptococcosis [& European]) or (torula) or (Busse Buschkes disease) (disorder), (Cryptococcosis [& European]) or (torula) or (Busse Buschkes disease), Infection due to Cryptococcus, Torula, Busse-Buschke's disease, European Blastomycosis, European blastomycosis, European cryptococcosis, Busse-Buschke disease, Cryptococcosis (disorder), torulosis, Torula histolytica; infection, infection; Blastomyces, blastomycotic, European, infection; Cryptococcus neoformans, infection; Torula histolytica, Busse-Buschke (etiology), Busse-Buschke (manifestation), Cryptococcus neoformans; infection
Dutch Cryptococcus neoformans, torulosis, C. neoformans-infectie, Cryptococcus neoformans-infectie, Cryptococcus neoformans; infectie, Torula histolytica; infectie, infectie; Blastomyces, blastomycotisch, Europees, infectie; Cryptococcus neoformans, infectie; Torula histolytica, Cryptokokkose, niet gespecificeerd, cryptococcose, Cryptococcosis, Cryptokokkose, Torulosis
French Infection à C.neoformans, Infection à Cryptococcus neoformans, Cryptococcus neoformans, Cryptococcose, Torulose, Blastomycose européenne
German C. neoformans Infektion, Cryptococcus neoformans Infektion, Torulopse, Cryptococcus neoformans, Kryptokokkose, nicht naeher bezeichnet, Cryptococcus-Mykose, Kryptokokkose, Torulosis, Torulose
Italian Infezione da Clostridium neoformans, Criptococcus neoformans, Iinfezione da Criptococcus neoformans, Torulosi, Criptococcosi
Portuguese Cryptococcus neoformans, Infecção por C. neoformans, Infecção por Cryptococcus neoformans, Criptococose, Torulose
Spanish Infección por C. neoformans, Cryptococcus neoformans, Infección por Cryptococcus neoformans, toruloma, criptococosis, SAI, [X]criptococosis, no especificada (trastorno), criptococosis, SAI (trastorno), [X]criptococosis, no especificada, enfermedad de Busse - de Buschke, blastomicosis europea, criptococosis (trastorno), criptococosis europea, criptococosis, enfermedad de Busse-Buschke, infección por Cryptococcus neoformans, torulosis, Criptococosis, Torulosis
Japanese クリプトコッカス・ネオフォルマンス, クリプトコッカス・ネオフォルマンス感染, クリプトコッカスショウ, クリプトコッカスネオフォルマンスカンセン, クリプトコッカスネオフォルマンス, ブッセ・ブシュケ病, Busse-Buschke病, クリプトコッカス症, クリプトコックス症, ブッセ-ブシュケ病
Swedish Kryptokockos
Czech kryptokokóza, Toluróza, Infekce kvasinkou Cryptococcus neoformans, Kryptokokóza, Cryptococcus neoformans, Infekce C.neoformans, evropská blastomykóza, torulóza
Finnish Kryptokokkoosi
Russian SAKHAROMIKOZ, TORULEZ, KRIPTOKOKKOZ, BLASTOMIKOZ EVROPEISKII, БЛАСТОМИКОЗ ЕВРОПЕЙСКИЙ, КРИПТОКОККОЗ, САХАРОМИКОЗ, ТОРУЛЕЗ
Korean 상세불명의 크립토콕쿠스증, 크립토콕쿠스증
Croatian KRIPTOKOKOZA
Polish Kryptokokoza, Zakażenie Cryptococcus, Toruloza, Drożdżyca głęboka Busse-Buschkego, Drożdżyca europejska
Hungarian Cryptococcus neoformans, Torulosis, Cryptococcus neoformans fertőzés, cryptococcosis, C. neoformans fertőzés
Norwegian Kryptokokkose

Ontology: Cryptococcus (C0010415)

Definition (NCI) A genus of fungi in the phylum Basidiomycota that grows in culture as an encapsulated yeast. Its sexual form is called Filobasidiella and its asexual form is called Cryptococcus.
Definition (MSH) A mitosporic Tremellales fungal genus whose species usually have a capsule and do not form pseudomycellium. Teleomorphs include Filobasidiella and Fidobasidium.
Definition (CSP) mitosporic Tremellales fungal genus whose species usually have a capsule and do not form pseudomycellium.
Concepts Fungus (T004)
MSH D003454
SnomedCT 89912005, 17579001
LNC LP20005-2
English Cryptococcus, Torula, Genus Torula, Torula (organism), Genus Torula (organism), Torula Pers., Torulas, cryptococcal, cryptococcus, torula, Cryptococcus (organism), Cryptococcus, NOS, Torula, NOS
Swedish Cryptococcus
Czech Cryptococcus
Spanish género Torula, género Torula (organismo), Torula (organismo), Cryptococcus (organismo), criptococo, Cryptococcus, Torula
Finnish Cryptococcus
Russian KRIPTOKOKKI, GLENOSPORELLA, KRIPTOKOKKOZA VOZBUDITELI, ГЛЕНОСПОРЕЛЛА, КРИПТОКОККИ, КРИПТОКОККОЗА ВОЗБУДИТЕЛИ
Italian Torula, Cryptococcus
Polish Cryptococcus
Japanese クリプトコッカス, Cryptococcus属, クリプトコッカス属, クリプトコックス属, トルラ属, クリプトコックス
Norwegian Cryptococcus, Torula
French Cryptococcus, Torula
German Cryptococcus, Torula
Dutch Cryptococcus, Torula
Portuguese Cryptococcus, Torula

Ontology: Cryptococcus neoformans (C0010416)

Definition (MSH) A species of the fungus CRYPTOCOCCUS. Its teleomorph is Filobasidiella neoformans.
Definition (NCI_CDISC) Any fungal organism that can be assigned to the species Cryptococcus neoformans.
Definition (NCI) A species of the fungus cryptococcus, the causative agent of cryptococcosis.
Definition (CSP) species of the fungus Cryptococcus, which causes cryptococcosis; its teleomorph is Filobasidiella neoformans.
Concepts Fungus (T004)
MSH D003455
SnomedCT 67168003
LNC LP14810-3, MTHU017442
English Cryptococcus neoformans, neoformans, Cryptococcus, neoforman, Cryptococcus, Cryptococcus neoforman, cryptococcus neoformans, Cryptococcus neoformans (San Felice) Vuill. 1901, Lipomyces neoformans, T. neoformans, Torula neoformans, Debaryomyces neoformans, C. neoformans, S. neoformans, CRYPTOCOCCUS NEOFORMANS, D. neoformans, B. neoformans, L. neoformans, Torulopsis neoformans, Saccharomyces neoformans, Blastomyces neoformans, Torula histolytica, Leucosporidium neoformans, Cryptococcus hominis, Cryptococcus neoformans (organism), Crypto
Swedish Cryptococcus neoformans
Czech Cryptococcus neoformans
Finnish Kryptokokki
Japanese クリプトコッカス・ネオフォルマンス, クリプトコックス・ネオフォルマンス
Polish Cryptococcus neoformans
Norwegian Cryptococcus neoformans
Spanish Cryptococcus neoformans (organismo), Cryptococcus neoformans
French Cryptococcus neoformans
German Cryptococcus neoformans
Italian Cryptococcus neoformans
Russian CRYPTOCOCCUS NEOFORMANS
Dutch Cryptococcus neoformans
Portuguese Cryptococcus neoformans

Ontology: Meningitis, Cryptococcal (C0085436)

Definition (MSH) Meningeal inflammation produced by CRYPTOCOCCUS NEOFORMANS, an encapsulated yeast that tends to infect individuals with ACQUIRED IMMUNODEFICIENCY SYNDROME and other immunocompromised states. The organism enters the body through the respiratory tract, but symptomatic infections are usually limited to the lungs and nervous system. The organism may also produce parenchymal brain lesions (torulomas). Clinically, the course is subacute and may feature HEADACHE; NAUSEA; PHOTOPHOBIA; focal neurologic deficits; SEIZURES; cranial neuropathies; and HYDROCEPHALUS. (From Adams et al., Principles of Neurology, 6th ed, pp721-2)
Concepts Disease or Syndrome (T047)
MSH D016919
ICD9 321.0
ICD10 B45.1
SnomedCT 187092002, 14232007
English Cryptococcal Meningitides, Meningitides, Cryptococcal, Meningitis, Cryptococcal, Cryptococcal Meningitis, CRYPTOCOCCAL MENINGITIS, cryptococcal meningitis, cryptococcal meningitis (diagnosis), Meningitis cryptococcal, Cryptococcal neoformans meningitis, Meningitis torula, Meningitis, Cryptococcal [Disease/Finding], crypto meningitis, meningitis cryptococcal, Cryptococcal meningitis, Meningitis due to cryptococcus, Cryptococcal meningitis (disorder), Meningitis due to Cryptococcus
Italian Meningite criptococcica, Meningite da Criptococcus neoformans, Meningite torula, Meningite da criptococco, Meningite da Cryptococcus neoformans
Dutch Cryptococcus neoformans meningitis, cryptokokkenmeningitis, Torula-meningitis, cryptokokkenhersenvliesontsteking, Cryptokokkenmeningitis, Meningitis, cryptokokken-
French Méningite à Cryptococcus, Méningite à Cryptococcus neoformans, Méningite à torula, Méningite à cryptocoque, Méningite cryptococcique, Méningite à cryptocoques
German Cryptococcus neoformans Meninigitis, Torulameningitis, Meningitis durch Kryptokokken, Meningitis, Kryptokokken-, Kryptokokkenmeningitis
Portuguese Meningite por Cryptococcus neoformans, Meningite a torula, Meningite por criptococo, Meningite criptocócica, Meningite Criptocócica
Spanish Meningitis torula, Meningitis por Cryptococcus neoformans, meningitis criptocócica, meningitis por Cryptococcus, meningitis por criptococos (trastorno), meningitis por criptococos, Meningitis criptocócica, Meningitis Criptocócica
Japanese クリプトコッカス・ネオフォルマンス性髄膜炎, 酵母菌性髄膜炎, クリプトコッカスセイズイマクエン, クリプトコッカスネオフォルマンスセイズイマクエン, コウボキンセイズイマクエン, クリプトコッカス性髄膜炎, 髄膜炎-クリプトコッカス, クリプトコッカス髄膜炎
Swedish Hjärnhinneinflammation, kryptokock
Finnish Kryptokokin aiheuttama aivokalvotulehdus
Russian MENINGIT KRIPTOKOKKOVYI, МЕНИНГИТ КРИПТОКОККОВЫЙ
Czech Torulózní meningitida, Kryptokoková meningitida, Meningitida způsobená kvasinkou Cryptococcus neoformans, meningitida kryptokoková, kryptokoková meningitis, kryptokoková meningitida
Polish Zapalenie opon mózgowych kryptokokowe, Zapalenie opon kryptokokowe
Hungarian Cryptococcalis meningitis, Cryptococcus neoformans meningitis, cryptococcus meningitis, Torula meningitis
Norwegian Meningitt ved kryptokokkose, Kryptokokkmeningitt, Cryptococcus-meningitt

Ontology: Cryptococcus gattii (C0446010)

Definition (MSH) A species of the fungus CRYPTOCOCCUS. Its teleomorph is Filobasidiella bacillispora.
Definition (NCI_CDISC) Any fungal organism that can be assigned to the species Cryptococcus gattii.
Definition (NCI) An encapsulated yeast in the phylum Basidiomycota. This species is globose to ovoid shaped, urease-positive, pseudohyphae- and nitrate-negative, does not ferment sugars, and assimilates glucose, maltose, sucrose, galactose, trehalose, raffinose, inositol, cellobiose, rhamnose, arabinose, melezitose and xylose. C. gattii is a human opportunistic pathogen and causes pulmonary cryptococcosis, basal meningitis and cerebral cryptococcomas in immunocompromised hosts. It is also associated with skin, soft tissue, lymph node, bone, and joint infections.
Concepts Fungus (T004)
MSH D056285
SnomedCT 450862004, 243467007, 243440001
English Cryptococcus neoformans gattii, Cryptococcus neoformans var gattii, Filobasidiella bacillispora Kwon-Chung 1976, Filobasidiella neoformans var. bacillispora (Kwon-Chung) Kwon-Chung 1982, Filobasidiella neoformans var. bacillispora, Cryptococcus gattii, Cryptococcus gattius, gattius, Cryptococcus, gattii, Cryptococcus, Cryptococcus neoformans var. gattii, Cryptococcus bacillisporus Kwon-Chung & J.E.Benn. 1978, Cryptococcus neoformans var. shanghaiensis, Cryptococcus neoformans var. gatti, Cryptococcus neoformans var. gattii Vanbreus. & Takashio 1970, Cryptococcus gattii (Vanbreus. & Takashio) Kwon-Chung & Boekhout 2002, anamorph of Filobasidiella bacillispora, Cryptococcus gattii (organism), Cryptococcus bacillisporus, Cryptococcus neoformans var gattii (organism), C. bacillisporus, C. gattii, CRYPTOCOCCUS GATTII, Filobasidiella bacillispora, Filobasidiella neoformans var bacillispora, Filobasidiella neoformans var bacillispora (organism)
French Cryptococcus gattii, Cryptococcus neoformans var. gattii
German Cryptococcus neoformans var. gattii, Cryptococcus gattii
Italian Cryptococcus neoformans var. gattii, Cryptococcus gattii
Portuguese Cryptococcus gattii
Russian CRYPTOCOCCUS GATTII
Czech Cryptococcus neoformans var. gattii, Cryptococcus gattii
Swedish Cryptococcus gattii
Polish Cryptococcus gattii
Japanese クリプトコッカス・ネオフォルマンス・バライアティ・ガッティイ, クリプトコックス・ネオフォルマンス・バライアティ・ガッティイ, クリプトコッカス・ガッティイ, クリプトコックス・ガッティイ
Spanish Cryptococcus gattii, Cryptococcus gattii (organismo), Cryptococcus bacillisporus, Cryptococcus neoformans, variedad gattii (organismo), Cryptococcus neoformans, variedad gattii, Filobasidiella neoformans, variedad bacillispora (organismo), Filobasidiella neoformans, variedad bacillispora
Norwegian Cryptococcus gattii, Cryptococcus neoformans var. gattii