Cryptococcosis

What is cryptococcosis?

Cryptococcosis is a serious, invasive fungal infection caused primarily by two species of encapsulated yeasts: Cryptococcus neoformans and Cryptococcus gattii.

Cryptococcosis poses a significant global health concern due to its high rates of morbidity and mortality, particularly where effective antifungal treatments are not available.

Who gets cryptococcosis?

Cryptococcus neoformans is considered an opportunistic pathogen and mainly affects immunocompromised individuals.

Causes of immunodeficiency commonly associated with cryptococcosis include:

• Human immunodeficiency virus / acquired immunodeficiency syndrome (HIV/AIDS)
• Immunosuppressive therapy eg, prolonged corticosteroid use
• Malignancy
• Chronic liver disease or other organ failure syndromes
• Sarcoidosis.

In contrast, Cryptococcus gattii is known to cause cryptococcosis in individuals who appear to be immunocompetent.

C. neoformans and C. gattii are both distributed worldwide and thrive in warm, humid regions. High rates of infection are seen in regions such as sub-Saharan Africa, Southeast Asia, and parts of the Americas.

Cryptococcal infection of the central nervous system (CNS) is the leading cause of death among patients with advanced HIV/AIDS in sub-Saharan Africa.

What causes cryptococcosis?

C. neoformans

• Responsible for the majority of cryptococcosis (about 80% of cases)
• Frequently found in soil contaminated with bird droppings, especially those of pigeons

C. gattii

• A less common cause of cryptococcosis (20% of cases)
• Tends to occupy certain tree types, such as the Eucalyptus genus, and nearby soil

Other species, such as Cryptococcosus laurentii and Cryptococcosus albidus, have been rarely reported to cause cryptococcosis.

Cryptococcosis is typically acquired by inhaling spores or poorly encapsulated yeast cells from the environment.

• Direct skin inoculation is also possible, albeit infrequent.
• Transmission via organ transplantation from an infected donor organ has also been rarely documented.
• There is no evidence for direct animal-to-human or human-to-human transmission ie, cryptococcosis is not contagious.

What are the clinical features of cryptococcosis?

Initial cryptococcal infection typically occurs in the lungs and may disseminate haematogenously to other organs, including the skin, with a strong tropism for the central nervous system (CNS). Immunocompromised individuals are at high risk of dissemination.

Cutaneous cryptococcal infection

Primary cutaneous cryptococcosis (PCC):

• Refers to isolated cutaneous cryptococcal infection without clinical/mycological evidence of dissemination
• Very rare and a diagnosis of exclusion
• Generally has a good prognosis, even in immunocompromised individuals
• Typically presents as a single skin lesion (eg, cryptococcal whitlow, cellulitis, ulcer) at the site of cryptococcal inoculation, often following skin injury.

Secondary cutaneous cryptococcosis (SCC):

• Results from haematogenous dissemination, most often in immunocompromised hosts
• Occurs in up to 15% of disseminated cases
• Typically presents with multiple skin lesions (eg, papules, nodules, ulcers, petechiae/purpura) that can sometimes resemble molluscum contagiosum.

Pulmonary cryptococcosis

• Presentations range from asymptomatic disease (in immunocompetent hosts) to severe pneumonia and acute respiratory distress syndrome.
• Immunocompetent hosts often recover spontaneously without antifungal treatment.

CNS cryptococcosis

• Typically presents as meningoencephalitis, and symptoms include headache, fever, altered mental status, photophobia, focal neurological deficits, and nausea/vomiting.
• Cryptococcal meningoencephalitis is fatal if left untreated.

A haemorrhagic cellulitis-like eruption due to cryptococcosis (CFI-patient1)

An ulcerated area due to cryptococcosis (CFI-patient1)

Spreading erythema due to disseminated cryptococcosis (CFI-patient1)

Click here for more images

How do clinical features vary in differing types of skin?

Papules, pustules, and purpuric lesions may be less evident on individuals with darker skin tones.

What are the complications of cryptococcosis?

• Intracerebral cryptococcoma (‘cryptococcal granuloma’) — more common with C. gattii
• Hydrocephalus and raised intracranial pressure
• Stroke
• Residual neurological deficits eg, hearing/vision loss, cognitive impairment
• Coma and death

How is cryptococcosis diagnosed?

Cryptococcal antigen (CrAg) testing

• Performed on cerebrospinal fluid (CSF) obtained by lumbar puncture or on serum from a blood test.
• Preferred test for rapid and accurate diagnosis due to its high sensitivity and specificity.

Culture and histopathology

• Cultures from CSF, tissue biopsy, blood, sputum, or other bodily fluids can confirm infection.
• Histopathological examination with stains such as Grocott methenamine silver (GMS) is highly sensitive for detecting Cryptococcus in tissue samples. For more information, see: cryptococcosis pathology.

Molecular techniques

Nucleic acid sequence-based amplification (NASBA) and polymerase chain reaction (PCR) are emerging as reliable diagnostic methods.

Imaging

Chest imaging (eg, X-ray, CT scan) may exhibit characteristic radiographic findings of pulmonary disease (eg, nodules or masses).

What is the differential diagnosis for cryptococcosis?

Differentials for cutaneous cryptococcosis include:

• Molluscum contagiosum
• Cellulitis
• Acne vulgaris
• Kaposi sarcoma
• Cutaneous tuberculosis
• Sarcoidosis.

What is the treatment for cryptococcosis?

Cryptococcosis is treated with systemic antifungal therapy, and the regimen depends on the site of infection and immunological status of the patient. Treatment should be guided by current local or national infectious disease protocols.

CNS disease:

• Induction therapy: amphotericin B deoxycholate (or liposomal amphotericin B) plus flucytosine for at least 2 weeks
• Consolidation therapy: fluconazole for at least 8 weeks
• Maintenance therapy (secondary prophylaxis): fluconazole for 6-12 months.

Pulmonary or disseminated disease (outside of the CNS):

• Mild-to-moderate disease: fluconazole for 6-12 months
• Severe pulmonary or disseminated disease (eg, skin, bone, prostate): same as CNS disease.

How do you prevent cryptococcosis?

There is no vaccine for cryptococcosis. Immunocompromised individuals should be advised to avoid environments in which Cryptococcus is commonly found eg, areas contaminated with bird droppings.

Primary prophylaxis

• Fluconazole decreases the occurrence of cryptococcosis in high-risk groups eg, individuals with advanced HIV disease (CD4+ counts 50 cells/µL).
• Routine primary prophylaxis is generally not recommended due to concerns over drug resistance, cost, and side effects.

Secondary prophylaxis

• Also known as maintenance therapy, continued fluconazole after initial treatment is indicated for HIV-infected patients to prevent recurrence.
• Secondary prophylaxis should be maintained for a minimum of one year until patients remain symptom-free with stable CD4+ counts >100 cells/µL for at least six months.

What is the outcome for cryptococcosis?

Early diagnosis and timely intervention are crucial for improving outcomes for those affected.

Patients with HIV:

• Prognosis is generally favourable if they have completed at least one year of secondary prophylaxis (see above).
• Ongoing follow-up is essential to monitor for potential relapses and long-term complications.

Patients without HIV:

• Treatment success rates are generally high.
• However, individuals over 60 years of age, those with haematologic malignancy, or those with organ failure are at higher risk for morbidity and mortality.

Despite aggressive antifungal treatment, CNS cryptococcosis often results in protracted neurological sequelae and requires extended monitoring to manage potential recrudescence (incomplete clearance of infection) or complications.