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School of Biological Sciences
The University of Adelaide
AUSTRALIA 5005

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Dr David Ellis
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Cryptococcosis

Description:

Cryptococcosis is a chronic, subacute to acute pulmonary, systemic or meningitic disease, initiated by the inhalation of basidiospores and/or desiccated yeast cells of Cryptococcus neoformans. Primary pulmonary infections have no diagnostic symptoms and are usually subclinical. On dissemination, the fungus usually shows a predilection for the central nervous system, however skin, bones and other visceral organs may also become involved. Although C. neoformans is regarded as the principle pathogenic species, C. albidus and C. laurentii have on occasion also been implicated in human infection.

Clinical manifestations:

Cryptococcus is an encapsulated basidiomycete yeast-like fungus with a predilection for the respiratory and nervous system of humans and animals. Two species, C. neoformans and C. gattii are distinguishable biochemically and by molecular techniques.

In humans, C. neoformans affects immunocompromised hosts predominantly and is the commonest cause of fungal meningitis; worldwide, 7-10% of patients with AIDS are affected. AIDS associated cryptococcosis accounts for 50% of all cryptococcal infections reported annually and usually occurs in HIV patients when their CD4 lymphocyte count is below 200/mm3. Meningitis is the predominant clinical presentation with fever and headache as the most common symptoms. Secondary cutaneous infections occur in up to 15% of patients with disseminated cryptococcosis and often indicate a poor prognosis. Lesions usually begin as small papules that subsequently ulcerate, but may also present as abscesses, erythematous nodules, or cellulitis. This variety is found worldwide.

In contrast, the distribution of cryptococcosis due to Cryptococcus gattii is geographically restricted, non-immunocompromised hosts are usually affected, large mass lesions in lung and/or brain (cryptococcomas) are characteristic and morbidity from neurological disease is high. Human disease is endemic in Australia, Papua New Guinea, parts of Africa, the Mediterranean region, India, south-east Asia, Mexico, Brazil, Paraguay and Southern California.

1. Pulmonary Cryptococcosis:

Asymptomatic carriage of Cryptococcus has been reported from the respiratory tract, especially sputum and from skin in healthy people as a result of normal environmental exposure. In addition, patients with chronic lung disease, such as bronchitis and bronchiectasis, may also have asymptomatic colonization, with Cryptococcus being isolated from their sputum over many years.

Subclinical cryptococcosis may result of environmental exposure, normal individuals may experience a self-limiting pneumonia with accompanying sensitization. Most primary infections of this type have no diagnostic symptoms and are usually discovered only by routine chest x-ray. When present, symptoms include cough, low-grade fever and pleuritic pain.

x-ray
X-ray showing pulmonary cryptococcal infection [right upper lobe].

Invasive pulmonary cryptococcosis may occur in some patients when primary infections may not readily resolve in some patients, leading to a more chronic pneumonia progressing slowly over several years. Patients may become pyrexic and have an accompanying cough, however many pulmonary lesions are often asymptomatic, especially when chronic granulomas are formed. Chronic pulmonary cryptococcosis also increases the risk of dissemination to the central nervous system.

2. Central Nervous System:

Dissemination to the brain and meninges is the most common clinical manifestation of cryptococcosis and includes meningitis, meningoencephalitis or expanding cryptococcoma.

Meningitis is the most common clinical form, accounting for up to 85% of the total number of cases, however the clinical signs are rarely dramatic. Symptoms usually develop slowly over several months, and initially include headache, followed by drowsiness, dizziness, irritability, confusion, nausea, vomiting, neck stiffness and focal neurological defects, such as ataxia. Diminishing visual acuity and coma may also occur in later stages of the infection. Acute onset cases may also occur, especially in patients with widespread disease, and these patients may deteriorate rapidly and die in a matter of weeks.

Meningoencephalitis due to invasion of the cerebral cortex, brain stem and cerebellum is an uncommon, rapid fulminate infection, often leading to coma and death within a short time. Symptoms include slow response to treatment and signs of cerebral edema or hydrocephalitis, especially papilledema.

MRI scan
MRI scan showing multiple cryptococcomas [white masses] in the brain.

Cryptococcoma is a rare entity, characterized by localized, solid, tumor-like masses, usually found in the cerebral hemispheres or cerebellum, or more rarely in the spinal cord. Symptoms are consistent with an expanding intracranial mass and include headache, drowsiness, nausea, vomiting, mental changes, slurred speech, double vision, unsteadiness of gait, coma, paralysis and hemiparesis. These symptoms may mimic cerebral neoplasm which may delay a true diagnosis.

3. Cutaneous Cryptococcosis:

Primary cutaneous cryptococcosis in the form of ulcerated lesions or cellulitis occasionally occurs, especially in immunosuppressed patients. These lesions may resolve spontaneously or with systemic antifungal treatment. However, all patients with skin lesions should be monitored carefully for possible dissemination to the central nervous system.

Secondary cutaneous infections occur in up to 15% of patients with disseminated cryptococcosis and often indicate a poor prognosis. Lesions usually begin as small papules that subsequently ulcerate, but may also present as abscesses, erythematous nodules, or cellulitis.

In patients with AIDS, skin manifestations represent the second most common site of disseminated cryptococcosis. Lesions often occur on the head and neck and may present as papules, nodules, plaques, ulcers, abscesses, cutaneous ulcerated plaques, herpetiform lesions, lesions simulating both molluscum contagiosum and Kaposi's sarcoma. Anal ulceration may also occur.

Nodular skin lesion
Nodular skin lesion caused by C. neoformans.

Ulcerated skin lesion in an HIV+ patient
Ulcerated skin lesion in an HIV+ patient.

Cryptococcal rhinitis in an African grey parrot
Cryptococcal rhinitis in an African grey parrot from the Adelaide Zoo.

4. Cryptococcosis of Bone:

Osseous cryptococcosis occurs in up to 10% of disseminated cases and may involve bony prominences, cranial bones and vertebrae. The lesions are lytic without periosteal reaction and symptoms of dull pain on movement are reported. Occasional cases of arthritis have also been reported, mostly involving the knee joint.

5. Ocular Cryptococcosis:

Ocular manifestations of cryptococcosis most commonly include papilledema and optic atrophy, due to raised intracranial pressure. Other ocular signs of cryptococcosis are uncommon and usually occur as a result of dissemination.

6. Other forms of Cryptococcosis:

Cryptococcus neoformans is often isolated from urine of patients with disseminated infection. Occasionally, signs of pyelonephritis or prostatitis may be observed. Other rare forms of cryptococcosis include adrenal cortical lesions, endocarditis, hepatitis, sinusitis, and localized oesophageal lesions.

Laboratory diagnosis:

1. Clinical material: Cerebrospinal fluid (CSF), biopsy tissue, sputum, bronchial washings, pus, blood and urine.

2. Direct Microscopy: (a) For exudates and body fluids make a thin wet film under a coverslip using India ink to demonstrate encapsulated yeast cells. Sputum and pus may need to be digested with 10% KOH prior to India ink staining. (b) For tissue sections use PAS digest, GMS and H&E, mucicarmine stain is also useful to demonstrate the polysaccharide capsule. Examine for globose to ovoid, budding yeast cells surrounded by wide gelatinous capsules. Note, non-encapsulated variants, although rare, may also occur.

Interpretation: The demonstration of encapsulated yeast cells in CSF, biopsy tissue, blood or urine should be considered significant, even in the absence of clinical symptoms. Positive sputum specimens should be considered potentially significant, even though Cryptococcus may also occur in respiratory secretions as a saprophyte. Basically, all patients with a positive microscopy for cryptococci, from any site should be investigated for disseminated disease, especially by culture and antigen detection.

typical yeast cell of C. neoformans
India ink preparation of CSF showing a typical yeast cell of C. neoformans surrounded by a characteristic wide gelatinous capsule.

Tissue section from a skin biopsy
Tissue section showing from a skin biopsy showing typical yeast cells of C. neoformans.

Tissue section of lung
Tissue section of lung showing showing atypical non-encapsulated yeast cells of C. neoformans.

3. Culture: Inoculate specimens onto primary isolation media, like Sabouraud's dextrose agar. Look for translucent, smooth gelatinous colonies, later becoming very mucoid and cream in color.

Mucoid colonies
Mucoid colonies of C. neoformans.

Bird seed agar plate
Bird seed agar plate showing the typical brown colour effect seen with C. neoformans.

Interpretation: The isolation of C. neoformans or C. gattii from any site should be considered significant and patients without clinical symptoms should be thoroughly investigated for disseminated disease. Positive culture of CSF is definitive. However, positive culture of respiratory secretions, especially in patients without clinical symptoms, needs to be interpreted with some caution, until additional supporting evidence is available. Isolation of Cryptococcus albidus or C. laurentii, should also be interpreted with caution as these species are infrequent pathogens and once again, additional supporting clinical and microscopic evidence is necessary.

4. Serology: It should be noted that the detection of cryptococcal capsular polysaccharide antigen in spinal fluid is now the method of choice for diagnosing patients with cryptococcal meningitis. In AIDS patients, cryptococcal antigen can be detected in the serum in nearly 100% of cases. However, in non-AIDS patients antigen detection in serum is less sensitive with only about 60% of patients with cryptococcosis reported as being positive. Note, serum specimens should be pretreated with pronase to enhance detection of antigen and avoid false negative results.

5. Identification: The genus Cryptococcus is characterized by globose to elongate yeast-like cells or blastoconidia that reproduce by multilateral budding. Pseudohyphae are absent or rudimentary. On solid media the cultures are generally mucoid or slimy in appearance. Red, orange or yellow carotenoid pigments may be produced, but young colonies of most species are usually non-pigmented, and are cream in color. Most strains have encapsulated cells with the extent of capsule formation depending on the medium. Under certain conditions of growth the capsule may contain starch-like compounds which are released into the medium by many strains. Within the genus Cryptococcus, fermentation of sugars is negative, assimilation of nitrate is variable and assimilation of inositol is positive. The genus Cryptococcus is similar to the genus Rhodotorula. The distinctive difference between the two is the assimilation of inositol, which is positive in Cryptococcus.

Causative agents:

Cryptococcus albidus, Cryptococcus laurentii, Cryptococcus neoformans, Cryptococcus gattii.

Treatment Guidelines

 

Further reading:

Ajello L and R.J. Hay. 1997. Medical Mycology Vol 4 Topley & Wilson's Microbiology and Infectious Infections. 9th Edition, Arnold London.

Ellis, D.H. and T.J. Pfeiffer. 1992. The ecology of Cryptococcus neoformans. Eur. J. Epidemiol. 8:3

Ellis, D.H., D, Marriott and T. Sorrell. Candidial and Cryptococcal infections. An interactive CD-ROM , Pfizer Australia.

Kwon-Chung KJ and JE Bennett 1992. Medical Mycology Lea & Febiger.

Richardson MD and DW Warnock. 1993. Fungal Infection: Diagnosis and Management. Blackwell Scientific Publications, London.

Rippon JW. 1988. Medical Mycology WB Saunders Co.

Warnock DW and MD Richardson. 1991. Fungal infection in the compromised patient. 2nd edition. John Wiley & Sons.