Cryptococcosis (Cryptococcal Infection)

What cryptococcosis is

Cryptococcus is a yeast-like fungus that lives in the environment. Its spores are small enough to reach deep into the lungs when inhaled. Two species cause almost all human disease:

After inhalation, a healthy immune system usually contains the fungus in the lungs, sometimes for life, without symptoms. If immunity later drops, dormant fungus can reactivate. The fungus has a thick sugar capsule that helps it hide from immune cells and gives it a strong tendency to spread through the blood to the brain and spinal cord.

Cryptococcal meningitis remains one of the leading causes of death in people with advanced HIV worldwide, especially in sub-Saharan Africa. It is much rarer in the US because of effective HIV treatment.

Risk factors

• Advanced HIV infection, especially a CD4 count below 100 cells/µL
• Solid organ transplant and anti-rejection drugs
• Long-term corticosteroids or other immune-suppressing medicines
• Blood cancers, cirrhosis, sarcoidosis and chronic kidney disease
• For C. gattii: living in or traveling to areas where it is found, even with normal immunity

Symptoms

Lung infection

Lung cryptococcosis may cause no symptoms and be found as a nodule on a chest scan. When it does cause symptoms, they look like pneumonia or tuberculosis: cough, fever, chest pain, shortness of breath, tiredness and weight loss.

Cryptococcal meningitis

This is the most serious form. It usually develops slowly over 1 to 2 weeks, sometimes longer, which can delay diagnosis:

• persistent, worsening headache
• fever, nausea and vomiting
• confusion, memory problems or personality change
• blurred or double vision, sensitivity to light, and sometimes sudden blindness from high pressure around the brain
• a stiff neck (often milder than in bacterial meningitis)
• seizures and drowsiness in advanced cases

Much of the harm comes from high pressure in the fluid around the brain, which damages the optic nerves and brain.

Skin and other sites

Spread through the blood can cause skin bumps or ulcers that sometimes look like molluscum, and infection of bones, the prostate or the eyes.

Diagnosis

1. Cryptococcal antigen (CrAg) test: a blood or spinal fluid test that detects the fungus capsule. It is highly accurate and is also used to screen people with advanced HIV before symptoms start.
2. Lumbar puncture (spinal tap): measures opening pressure and tests the fluid for CrAg, fungal culture and India ink stain.
3. Blood cultures.
4. Chest X-ray or CT for lung disease, and brain MRI or CT for masses or swelling.
5. Biopsy of a lung nodule or skin lesion when needed.
6. HIV test and CD4 count if not already known.

Treatment

Treatment depends on where the infection is and how strong the immune system is.

Meningitis and severe disease

Treatment comes in three phases:

• Induction (about 2 weeks): IV amphotericin B (usually the liposomal form) plus oral flucytosine to kill the fungus quickly. The WHO also recommends a single high dose of liposomal amphotericin B with flucytosine and fluconazole where resources are limited.
• Consolidation (about 8 weeks): high-dose oral fluconazole.
• Maintenance (at least 1 year): lower-dose fluconazole to stop relapse. In people with HIV it can be stopped once the CD4 count has stayed above 100 on HIV treatment and the viral load is suppressed.

Pressure control matters as much as the drugs. Repeated lumbar punctures drain fluid when opening pressure is high. A shunt is occasionally needed.

Timing of HIV treatment

Starting antiretroviral therapy too soon can trigger a dangerous inflammatory reaction (immune reconstitution inflammatory syndrome). Guidelines advise starting HIV treatment about 4 to 6 weeks after antifungal treatment begins in people with meningitis.

Lung or mild disease

Fluconazole by mouth for 6 to 12 months is usual for mild to moderate lung infection. Large C. gattii masses may need longer treatment or surgery.

Outlook

Untreated cryptococcal meningitis is almost always fatal. With prompt treatment and pressure control, most people in well-resourced settings survive, though some are left with vision loss, hearing loss or memory problems. Outcomes are worse when diagnosis is delayed, consciousness is reduced at presentation or the fungal load is very high.

Prevention

There is no vaccine. The most effective prevention is early HIV diagnosis and treatment. People with advanced HIV are screened with a blood CrAg test, and those who test positive without symptoms get preemptive fluconazole, which prevents many cases of meningitis. People with weak immunity should avoid areas heavy with bird droppings and wear a mask when cleaning them.

Frequently asked questions

Is cryptococcosis contagious?

No. Cryptococcosis is caught from spores in the environment. It does not spread from person to person, and although pigeons and other birds carry it in their droppings, it is not passed directly from pets or birds to people.

Can healthy people get cryptococcosis?

Rarely with C. neoformans, which mostly affects people with weakened immunity. C. gattii is different: it can infect healthy people, which was seen during an outbreak in British Columbia and the US Pacific Northwest that began in 1999.

How is cryptococcal meningitis different from bacterial meningitis?

Bacterial meningitis usually comes on over hours with high fever and a very stiff neck. Cryptococcal meningitis typically develops over 1 to 2 weeks with a gradually worsening headache, fever and confusion. It needs different tests and months of antifungal treatment.

How long is treatment for cryptococcosis?

For meningitis, about 2 weeks of intensive IV treatment, 8 weeks of high-dose fluconazole, then at least a year of maintenance fluconazole. Lung infections in otherwise healthy people are usually treated with fluconazole for 6 to 12 months.

Can cryptococcosis come back?

Yes, if the immune system stays weak and maintenance treatment stops too early. That is why fluconazole is continued until immunity recovers, for example a CD4 count above 100 on HIV treatment for several months.