Cryptococcal Meningitis: A Guide to Infection

Cryptococcal meningitis is a potentially deadly infection of the protective lining of the brain and spinal cord (the meninges) caused by the fungus Cryptococcus neoformans (C. neoformans). It is mainly seen in immunocompromised people, especially those with human immunodeficiency virus (HIV) and/or AIDS (HIV/AIDS). Symptoms range from fever, nausea, and stiff neck to vision changes, seizures, and even death.

The diagnosis of cryptococcal meningitis involves a spinal tap to examine cerebrospinal fluid (CSF) extracted from between the bones of the lower spine. Treatment involves the aggressive use of antifungal drugs to clear the infection and alleviate symptoms.

This article explains cryptococcal meningitis, who is vulnerable to infection, and how to recognize the signs of the disease. It also describes how the infection is diagnosed, treated, and prevented, as well as the consequences of untreated cryptococcosis.

Cryptococcal Meningitis Contagiousness and Fungus Sources 

Cryptococcal meningitis is primarily caused by C. neoformans. In its yeast state—when the fungus is actively growing and producing buds—C. neoformans is found mainly in soil and bird droppings (such as from pigeons or chickens). The buds, in turn, produce tiny spores that can become airborne and be inhaled.

Although the spores are generally harmless to people with normal immune systems, they can bypass the weakened defenses of immunocompromised people and embed themselves in the lungs.

Without the means to stem the infection, the fungus can rapidly grow and spread, causing a potentially serious lung infection called pulmonary cryptococcosis. Symptoms include coughing, shortness of breath, chest pain, and fever.

If not recognized and treated, C. neoformans can disseminate (spread) into the bloodstream and establish an infection in the meninges, causing inflammation referred to as meningitis. At this stage, the risk of death is significantly increased even with treatment.

Less Common Causes

Cryptococcus gattii (C. gattii) is a less common cause of cryptococcal meningitis, mainly isolated to tropical and subtropical regions of the planet. In sub-Saharan Africa, C. gattii is the primary cause of cryptococcosis.

That said, C. gattii infections have been diagnosed in recent years in North America's west coast, in the Pacific Northwest and British Columbia. Theories of how it got there include transport in contaminated ship ballasts, dissemination by the 1964 Alaskan earthquake and tsunami, and changes in global ocean weather patterns.

Although the rate of infection remains low, the fungus's appearance in North America concerns public health officials. C. gattii is known to cause disease in people with intact immune systems, not just in immunocompromised people.

Isolated cases of C. gattii have been seen as far south as Southern California, primarily among people with HIV/AIDS.

Who Is More Likely to Acquire Cryptococcal Meningitis?

Cryptococcal meningitis, whether by C. neoformans or C. gattii, predominantly affects immunocompromised people. Because of this, it is commonly referred to as an opportunistic infection, meaning one that only causes disease when the body's defenses are down.

During the height of the AIDS crisis in the 1980s and 1990s, cryptococcal meningitis was a leading cause of death among people living with HIV, not only in the United States but around the world.

With the introduction of effective antiretroviral therapy in the mid-1990s (which works by suppressing HIV and restoring immune function), the rate of cryptococcal infections and deaths plummeted.

Even so, around 152,000 cases of cryptococcal meningitis are diagnosed in people with HIV each year, mainly in sub-Saharan Africa, resulting in around 112,000 deaths annually.

All told, around 90% of cryptococcal infections are in people with HIV, typically those who are untreated and diagnosed with AIDS (the most advanced stage of HIV infection).

Other people with severely weakened immune systems are also at risk of cryptococcal meningitis, including:

• Organ transplant recipients
• People with cancer
• People with advanced liver cirrhosis
• People with uncontrolled type 2 diabetes
• People with end-stage kidney disease
• People with certain autoimmune diseases

First Symptoms of Cryptococcal Meningitis

Although cryptococcal meningitis is often preceded by pulmonary cryptococcosis, between 25% and 55% of cryptococcal lung infections are entirely asymptomatic, meaning there are no signs or symptoms.

In those who develop symptoms, the infection is generally subacute. This means that the symptoms are less profound and, therefore, more easily dismissed or ignored.

For this reason, many people with HIV will only experience illness when C. neoformans has disseminated and causes meningitis or meningoencephalitis (inflammation of the meninges and brain).

Most cases start relatively mildly, usually around two weeks after an infection has been established, causing generalized and nonspecific symptoms (those that could be attributed to a number of conditions) like:

• Low-grade fever
• Headache
• Malaise (a general feeling of unwellness)

These symptoms can develop over many weeks before the so-called classic signs of meningitis appear.

Other Symptoms Over the Course of Infection 

The classic signs of cryptococcal meningitis develop in between one-quarter and one-third of people with cryptococcosis. The people most likely to experience this are those with a severely suppressed immune system. In those with HIV, this is defined as having a CD4 lymphocyte count (a measurement of a type of white blood cell) of under 100.

Classic signs and symptoms of cryptococcal meningitis include:

• Fever
• Severe, persistent headache
• Photophobia (sensitivity to light)
• Neck stiffness
• Nausea and vomiting
• An altered mental state (confusion)
  

If meningoencephalitis develops, a person may also experience lethargy (tiredness), personality changes, memory loss, hallucinations, and reduced consciousness due to increased pressure inside the brain.

As a disseminated infection, additional symptoms can develop if other organ systems are affected. The skin and lungs are most commonly affected, causing skin ulcers or a pox-like rash or breathing problems like acute respiratory distress.

How to Get a Meningitis Diagnosis

Neck stiffness and photophobia are the two telltale signs of meningitis that lead many people to seek a diagnosis. Because cryptococcal meningitis can sometimes be the first symptom of HIV, the diagnostic process can take time.

If meningitis is suspected, the healthcare provider will obtain a sample of cerebrospinal fluid (CSF) using a lumbar puncture (also known as a spinal tap).

A spinal tap is generally done by laying you on your side in a fetal position (with your knees pulled to your chest). After giving you an injection of a local anesthetic, a needle is inserted between the bones of the lower lumbar spine to draw out a small sample of CSF.

The sample is then sent to the lab to check for signs of C. neoformans using the following tests:

• Histology: A microscopic examination of CSF using special dyes to look for yeast cells
  
• Polymerase chain reaction (PCR): A test that can detect the genetic signature of C. neoformans or C. gattii
• Cryptococcal antigen (CrAg): A test that can detect a protein on the surface of yeast cells specific to C. neoformans or C. gattii
• Fungal culture: A gold standard test used to "grow" the fungus in the lab

If the HIV status of the person is unknown, an HIV test would also be ordered.

Cryptococcal Meningitis Treatment and Infection Time

If you have cryptococcal meningitis, the infection will not clear on its own. You will need immediate, urgent treatment with a combination of antifungal drugs with strong action against C. neoformans and C. gattii.

Because cryptococcal meningitis is a high-risk medical condition, the treatment will involve inpatient care in a hospital followed by outpatient treatment at home. The primary treatment will take several months to complete.

The treatment of cryptococcal meningitis consists of three phases: the induction, consolidation, and maintenance phases.

In Hospital

The induction phase involves a combination of antifungal drugs taken one to four times daily for at least two weeks. Some of the drugs are delivered intravenously (into a vein), while others are taken orally (by mouth). Treatment is done in a hospital.

According to guidelines from the Infectious Diseases Society of America (IDSA) and the World Health Organisation (WHO), recommended drug therapies for the induction phase include:

• Amphotericin B delivered intravenously once daily, with flucytosine taken by mouth four times daily (preferred option)
• Amphotericin B delivered intravenously once daily, with fluconazole taken by mouth once daily (alternative option)

Upon completion of the induction phase, most people can return home to continue treatment.

At Home

The consolidation phase starts immediately upon your release from the hospital. The IDSA and WHO recommend the following treatment:

• Fluconazole 800 milligrams (mg) taken once daily for at least eight weeks

After two weeks of the consolidation phase, another spinal tap is performed. If there is no evidence of fungus in your CSF, the fluconazole dose can be dropped to 400 mg once daily for the remainder of this phase.

After two to four weeks, antiretroviral therapy will be started if you have HIV or test positive for HIV. These drugs, typically taken once daily by mouth, keep the virus suppressed and allow your immune system to gradually rebuild itself.

If fungus is found, fluconazole will continue to be taken at the prescribed dose until sterilization (complete fungal clearance) is achieved. This may take far longer than eight weeks.

Ongoing Maintenance Therapy

Once sterilization is achieved, the maintenance phase begins. This involves taking a daily dose of fluconazole to prevent you from getting C. neoformans or any other opportunistic fungal infection.

The IDSA and WHO recommend the following:

• Fluconazole 200 mg taken by mouth once daily

This strategy, also known as prophylactic therapy, helps prevent fungal opportunistic infections until your immune system is strong enough to defend itself.

Maintenance therapy with daily low-dose fluconazole would continue until your immune system reaches a "safe zone" (typically a CD4 count of over 100) and a viral load test shows that HIV levels are undetectable in your blood for at least three months.

Once these goals are met, maintenance therapy can be stopped. However, some people may need ongoing and even permanent fluconazole treatment if their immune systems cannot be adequately restored.

Secondary Complications From Cryptococcal Meningitis

Cryptococcal meningitis rarely occurs in the absence of a severe breakdown of your immune system. Without the means to stop the disease from spreading, cryptococcus meningitis is invariably fatal if left untreated.

Regardless of your immune status, cryptococcal meningitis can lead to cerebral infarctions (obstruction of blood flow to the brain) and permanent brain damage if not treated appropriately.

This can lead to irreversible and potentially devastating complications like:

• Hearing loss and deafness
• Epilepsy
• Vision loss or blindness
• Limb weakness and a loss of mobility
• Memory loss
• Difficulty with speech, language, or communication
• Incontinence

IRIS and Risks of Delayed HIV Therapy

In people with cryptococcal meningitis who delay HIV treatment, antiretroviral therapy can sometimes cause harm by triggering a severe condition known as immune reactivation inflammatory syndrome, or IRIS.

IRIS occurs in people with very low CD4 counts who suddenly start antiretroviral therapy. Freed of the burden of HIV, the immune system can sometimes overreact to an organism like C. neoformans and launch a potentially deadly, whole-body inflammatory assault.

Studies suggest that 1 in 4 people co-infected with HIV with cryptococcal meningitis will experience IRIS within four months of starting HIV therapy. Of these, 1 out of 10 will die as a result of respiratory failure and damage to the central nervous system.

To reduce the risk, health experts recommend starting antiretroviral therapy four to six weeks after antifungal therapy. Your immune system is less likely to overreact if there are fewer fungi in your blood.

How to Lower the Infection Risk

As 9 out of 10 cases of cryptococcal meningitis involve HIV, the first and most effective way to avoid cryptococcosis is to start antiretroviral therapy if you test positive for the virus. The sooner you start therapy, the lower your risk of this and other opportunistic infections.

By starting antiretrovirals early, when your immune system is intact, your chances of living a normal to near-normal life expectancy are good. Even if you start late, antiretroviral therapy can bolster your immune defenses and greatly reduce your risk of opportunistic infections.

Other things you can do to help reduce your risk of cryptococcosis until your immune system is restored include:

• Avoid working in the soil where the yeast cells can thrive.
• Steer clear of chicken farms or areas where there are lots of pigeons or bird droppings.
• Wear a face mask when outdoors and avoid public gatherings if your immune system is severely compromised.

No vaccines or specific precautions can prevent Cryptococcus exposure in areas where the fungus is in the environment. As such, it is more important to know the signs of cryptococcal meningitis and seek treatment if symptoms appear.

If you don't know your HIV status, there is no better time than now to get tested. The U.S. Preventive Services Task Force (USPSTF) currently recommends once-off HIV testing for all people aged 15 to 65 as part of a standard medical visit.

Summary

Cryptococcal meningitis is a potentially fatal infection of the lining of your brain and spinal cord by the fungus Cryptococcus neoformans and, less commonly, Cryptococcus gattii. It is predominantly seen in people with advanced untreated HIV but can affect others who have severely weakened immune systems.

The diagnosis of cryptococcal meningitis involves a lumbar puncture (spinal tap) to check for the presence of the fungus in spinal fluids. The treatment involves the aggressive use of antifungal drugs, delivered first in hospital and later at home. If HIV is involved, antiretroviral therapy would also be started.