(Image credit: Adobe Stock/ Vera Kuttelvaserova)
In 2022, the World Health Organization released a list of priority fungal pathogens. Of the estimated 6 million known fungal species, less than 300 are linked to human fungal diseases. The most dangerous to humans contains just four fungal pathogens: Cryptococcus neoformans, Candida auris, Aspergillus fumigatus and Candida albicans.
Cryptococcus neoformans, an encapsulated fungus, is the leading cause of fungal meningitis, particularly affecting patients with acquired immune deficiency syndrome, or AIDS. It evolved its virulent traits through interactions with other organisms in its environment. Luis R. Martinez, Ph.D., an associate professor at the University of Florida College of Dentistry and a member of the UF Emerging Pathogens Institute, breaks down key questions surrounding this intriguing yet dangerous pathogen.
What follows has been edited for length and clarity.
What is C. neoformans, and where is it typically found in the environment?
Cryptococcus neoformans is a yeast with a polysaccharide capsule. It’s mostly found in the environment in association with pigeon excreta. Since pigeons are found where people are found, people get exposed to the spores as soon as they go to areas where there are pigeons, like, for example, in New York City.
A study in the early 2000s found that kids developed antibodies against C. neoformans as soon as they entered Central Park in New York City. That means that they got exposed to the fungus as soon as they went to the playground. In cases of those, most of those kids’ immune systems work well, so they simply develop antibodies to clear the infection.
Who is at most risk of severe infection, and how does the infection typically enter the body?
C. neoformans is an opportunistic pathogen, meaning immunosuppressed or immunocompromised individuals are very susceptible. The fungus enters the body via inhalation of particles or spores. Those with human immunodeficiency virus, or HIV, or those who receive therapy for transplants are especially vulnerable. Those undergoing cancer treatment are also susceptible to C. neoformans infection.
What are some typical symptoms that we see with C. neoformans infections?
It starts with an initial pulmonary infection acquired by inhalation, and people typically develop pneumonia, shortness of breath, cough and other respiratory complications. In cases of immunosuppression, the fungus can enter the bloodstream and reach the brain. Those individuals can show confusion, cognitive impairment, headaches and photosensitivity.
How quickly does it progress if left untreated?
If left untreated, the infection can progress rapidly, especially in immunocompromised individuals. Patients can experience these symptoms rapidly because the defense against fungi depends on T cells, a crucial cell type in our immune system. In the case of HIV, the virus affects T cells; therefore, cells that orchestrate the immune response against a C. neoformans infection don’t function properly, and the fungus is free to enter the brain. That’s unfortunately how people die.
How would this be diagnosed in a clinical setting?
It’s tricky — the symptoms of a C. neoformans infection are like those of other pulmonary infections. There are two techniques used, the first is called India ink. You take a sample from the lungs or cerebrospinal fluid, place it on a slide and stain it with ink. The stain highlights the C. neoformans capsules, which appear as halos around the fungus. Capsules present in the lungs confirm a pulmonary infection, but capsules in cerebrospinal fluid confirm a life-threatening central nervous system infection.
The second way is the Cryptococcal Antigen Latex Agglutination System, or CALAS. It is a diagnostic test that measures the cryptococcal antigen, specifically the polysaccharide capsule, in cerebrospinal fluid. In summary, a physician can test whether the fungus is present or if the body is reacting to the potential pathogen.
How does a physician go about treating the infection once it’s identified as C. neoformans?
Individuals receive antifungal treatment for a C. neoformans infection. The most used and most effective treatment is a combination of amphotericin B and flucytosine. However, there are challenges with this treatment option: amphotericin is toxic to the kidneys, and this treatment is expensive. Many areas have limited access to these two drugs. Instead, fluconazole is administered, but it can be less effective, thereby contributing to antimicrobial resistance.
Many people are trying to find new drugs, and even trying to use new formulations, particularly for amphotericin B, because it is so effective. But again, the problem is the side effects on the patient.
How significant is the global burden of C. neoformans infections?
Currently, the disease primarily affects individuals in Sub-Saharan Africa, a densely populated region. In the United States, during the mid-1980s, when the AIDS epidemic started, C. neoformans was a very significant pathogen. Even today, C. neoformans kills 20% of people with AIDS worldwide. Nearly 112,000 people die each year from it, and this only accounts for deaths, not active or cured infections.
Since the 1990s, C. neoformans infections have been less common due to advancements in HIV treatment. However, Florida has one of the highest incidences of HIV/AIDS in the country and is the second state — behind California — with the most cryptococcosis cases. In fact, when you talk to people in the infectious disease division here, they say they often see patients with cryptococcal infections. It’s not as isolated as we think.
What should clinicians and public health officials know about monitoring and responding to C. neoformans infections in the community?
The main strategy to safeguard those vulnerable populations is to supervise individuals who acquire HIV and are living with AIDS, or individuals who are immunosuppressed in general. For physicians, if they suspect C. neoformans, treat the patient right away. The mortality rates jump from 30% to 80% once the fungus reaches the brain.
Another common and often overlooked issue is that some individuals with brain tumors or suspected tumors actually have a cryptococcal infection. C. neoformans colonize the brain in circular shapes, and in a brain scan, appears as a solid mass. Such cases highlight the importance for healthcare providers — especially well-trained physicians familiar with past cases — to recognize these distinctions.
Written by: Sydney Burge