CryptococcosisB45.9

Buses 1894; Buschke 1895; Sanfelice 1894

Worldwide spread, partly fatal systemic mycosis of humans caused by the very virulent, diploid yeast fungus Cryptococcus neoformans.

The infection occurs mainly in immunocompromised persons (e.g. organ transplant patients, malignant primary diseases, HIV infection: cryptococcosis is an AIDS-defining infection) by inhalation of contaminated dust.

The most important infection caused by Cryptococcus neoformans worldwide is menigoencephalitis. This is almost always the result of a mostly bland pulmonary cryptococcosis.

The following organs are most commonly affected: lungs, kidneys, meninges and, less frequently (10% of cases) skin (cutaneous cryptococcosis).

Cutaneous cryptococcosis is also mainly secondary to haematogenic spread. Only rarely does the infection develop through inoculation of the pathogen from the environment.

The two yeast fungi Cryptococcus neoformans (capsule serotype A,D and AD) and Cryptococcus gattii (serotypes A and C) are the cause of cryptococcosis. Characteristic are the slimy, shiny colonies in culture. Cryptococcus neoformans occurs in 2 variants:

• Cryptococcus neoformans variatio neoformans is preferably isolated in patients with AIDS.
• Cryptococcus neoformans variatio grubii causes cutaneous cryptococcosis.

Cryptococcus gattii also infects immunocompetent people.

The pathogen occurs in the environment in soil and dust. The yeast fungus has its natural habitat in decaying tree trunks. Also in bird droppings, especially from pigeons and parrots. By inhalation, the pathogen reaches the lungs, where it causes asymptomatic infections in immunocompetent people, which heal without any problems. In immunocompetent people the fungus spreads hematogenically and causes different organ manifestations.

Worldwide spread. Common among HIV-infected persons (80-90% of all infections worldwide; 6-30% of all HIV-infected persons, in Africa up to 80%, suffer from cryptococcosis) The occurrence of Cryptococcus gattii together with eucalyptus trees is known.

Incidence (general population): 0.2-1/100.000 inhabitants/year.

Incidence (HIV-infected people in Europe): 200-500/100.000 inhabitants/year.

Infection occurs through inhalation of dust containing the pathogen. C. neoformans is particularly common in bird dung, especially pigeon dung, and in the ground.

Mainly men between 30 and 60 years of age.

The entry point is the lung; haematogenic or lymphogenic pathogen sowing with infestation of the CNS, skeleton, heart, eyes, testes and skin (10-15% of cases)

The entry point is the lung parenchyma. Almost all organs can be involved due to hematogenic scattering.

Systemic phenomena:

• Lung infestation (by inhalation of fungal spores): pneumonia; tumor-like nodules (cryptococomas) in the lung parenchyma are less frequent.
• Hematogenic spread leads to disseminated organ infestation.
• Cryptococcal meningitis: the pathogen exhibits a strong neurotropism. Signs of a manifestation of the CNS can be headaches and other neurological abnormalities as well as psychological alterations. In addition to subacute meningoencephalitis, chronic meningitis can also occur. CNS involvement is one of the most important opportunistic infections occurring worldwide and especially in AIDS patients.

Skin symptoms:

• Acne-like red-brown or red-blueish papules, plaques and nodules. The raised areas are usually smooth at first, but can also be scaly and crusty. Melting and ulcerating nodules and plaques in the skin and subcutis are possible. Lymphadenitis is to be expected concomitantly.
• Especially in immunocompromised patients, generalised papular or small-node clinical pictures may also occur with non-itching, painless red-livid elevations. Papulo vesicles are rarer.

• Histology: Histological detection of budding 5-15um PAS-positive cells surrounded by a capsule from a sample excision
• Microscopy: direct microscopic detection of encapsulated yeast in an ink preparation from liquor sediment, urine, biopsy or BAL. Liquor ink preparation according to Burri
• Cultivation in culture (Sabouraud glucose agar; no growth with cyclohexemide addition); detection usually possible within 3-5 days Special media are necessary for differentiation against other yeasts: e.g. Guizotia abyssinica creatinine agar, also called "Staib Agar". A cultural detection of Cryptococcus neoformans should always be performed. Quantitative cultures before and 2 weeks after the start of antimycotic therapy can be helpful to document a response to therapy.
• Serology: Antigen detection. This is primarily performed in serum and CSF. Conventional commercial antigen detection tests have a high specificity and sensitivity (>95%) in HIV infected patients with a high bacterial count. Caution: a cytologically and serologically inconspicuous CSF result does not exclude cryptococcosis and should be supplemented by serum antigen screening if there is a well-founded suspicion. In case of localized infections (e.g. pneumonia) not immunosuppressed, the sensitivity is lower.

Crypotococcal meningitis:

Amphotericin B (day 1: 0.1 mg/kg bw, day 2: 0.2 mg/kg bw, day 3: 0.3 mg/kg bw, then 0.5-0.7 mg/kg bw/day i.v.) combined with 5-flucytosine (e.g. Ancotil) 100-150mg/kg bw/day distributed over 4 ED. Thereafter, the treatment is continued for at least 12 weeks with Fluconazole (400mg/day). The elimination of fungi from the CSF often requires a lifelong treatment with Fluconazole. Remark: In vitro resistance of the pathogens against antimycotics (especially Fluconazole, 5-flucytosine) is rare in Germany. However, it can be associated with recurrence and progressive infections with persistence of cultural evidence under therapy.

Alternative: Fluconazole (e.g. Diflucan) in a dosage of 400-600 mg/day.

Alternative: voriconazole (e.g. Vfend®) in a dosage of 400-600 mg/day; in patients > 40 kg kg KG: 2x200mg p.o.; or in patients < 40 kg KG2mal/day 100 mg p.o.

Therapy over several weeks depending on clinical symptoms. Afterwards Fluconazole (e.g. Diflucan), 200 mg/day, as a recurrence prophylaxis. S.u. HIV infection.

It is estimated that around 1.0 million people die annually from systemic cryptococcosis. Encephalitis caused by cryptococci is fatal if left untreated.

Specific primary prophylaxis is rarely indicated. However, patients with HIV infection are recommended to avoid known risks (see above).

In HIV-infected patients from countries with a high incidence of cryptococcosis (Africa, Southeast Asia), a latent infection can be excluded by means of a GM assay before starting antiretroviral therapy.

For persons with immunosuppression, lifelong secondary prophylaxis must be discussed.

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