Shifting Sands: The Changing Epidemiology of Cryptococcus Infections

While common illnesses such as pneumonia, strep throat, and urinary tract infections dominate most discussions about infectious diseases, Dr. Daniel Chastain—a board-certified infectious diseases and HIV pharmacist at the College of Pharmacy’s extended campus in Albany—focuses on a different threat: Cryptococcus. This fungus, found worldwide, receives little attention or resources despite its global reach.

Cryptococcus, literally “hidden berry” in Latin, is a yeast-like, sphere-shaped fungus that appears to have a fuzzy halo surrounding it when observed under the microscope. That halo, explained Chastain, is “…the fungus’ relatively unique capsule, a wall of thick sugars that surrounds the core of Cryptococcus and makes destruction by the immune system challenging. It is why Cryptococcus gets the ‘hidden’ moniker—the thick wall allows the fungus to ‘hide’ from some of the immune system’s usual detection methods.”

Cryptococcus infections can be deceptive.  They mimic common illnesses, such as pneumonia or meningitis, making diagnosis and eradication a challenge. This often necessitates complex treatment regimens. These typically involve a combination of powerful antifungal medications initially, followed by a year or more of an oral antifungal medication, depending on any underlying health conditions. One of the utilized therapeutics, amphotericin, is casually called “ampho-terrible” because of its unpleasant side effects. Chastain explained, “While the risks of the drug are well known, they are numerous and can be traumatic for patients. The initial infusion of amphotericin often triggers severe chills and fever, a reaction nicknamed ‘shake and bake’.”

The complexity and poor tolerability of current Cryptococcus treatments are reasons why Chastain’s research focuses, in part, on exploring new potential treatment paradigms for the fungus and regularly reviewing the efficacy of current treatments. In a 2022 study examining 47 patients with Cryptococcus-related brain masses, Chastain found that surgery combined with medication resulted in generally better outcomes. In a 2023 publication in the European Journal of Pharmacology, Chastain and UGA colleagues Drs. Priya Narayanan, Associate Professor, and Somanath Shenoy, Assistant Head of the Clinical and Administrative Pharmacy Department’s Research and Graduate Education, demonstrated that acetazolamide, candesartan, and triciribine reversed Cryptococcus-induced brain and lung damage in mice models.

Recently, Chastain’s research has shifted to identify those most vulnerable to Cryptococcus infections. This fungus typically poses no threat to a healthy immune system. “Historically, Cryptococcus has been associated with HIV, because HIV weakens the immune system, making people susceptible to infections they would otherwise be able to fight off,” explained Chastain. During the past decade, however, he and his colleagues have observed a concerning rise in Cryptococcus cases among individuals without HIV.

“Cryptococcus can infect a wider range of people than previously thought. We see it in people who get organ transplants, those on long-term steroids, and individuals with diabetes and various other conditions, such as autoimmune diseases, liver cirrhosis, and even COVID-19,” he said. In a study spanning 2017 to 2019, Chastain collaborated with Dr. Henry Young, Head of the Department of Clinical and Administrative Pharmacy from the College; Dr. XianYan Chen from the Department of Epidemiology and Biostatistics in UGA’s College of Public Health; and Dr. Andrés F. Henao-Martínez, an infectious diseases physician at the University of Colorado, Anschutz Medical Campus, along with others. Their investigation found that 35% of patients with Cryptococcus infections were HIV-negative, and another 5% had received organ transplants. Among the HIV-negative group, almost 40% had a history of lower respiratory illnesses, while many others battled conditions such as cancer, diabetes, or other chronic health issues. Interestingly, around a quarter (24%) had no apparent underlying conditions.

“The key factor seems to be a weakened immune system—these comorbid conditions put patients at risk for opportunistic infections, including Cryptococcus. On top of that, many treatments for these conditions, such as steroids for chronic lung disease, can suppress the immune system,” said Chastain. “While steroids can prevent disease flare-ups and excess inflammation, steroids do so by silencing the immune system; this makes patients more susceptible to infections and can even lead to worse outcomes,” he added.

In a previous study led by Henao-Martínez, with Chastain as a co-author, involving more than 2,000 patients with Cryptococcus infections, a 30% increase in one-year mortality risk was observed among those with a history of long-term steroid exposure. Moreover, in a recent State of the Art Review published in Clinical Infectious Diseases, a journal of the Infectious Diseases Society of America, Chastain, Henao-Martínez, and their colleagues investigated the risk of opportunistic infections in patients receiving chronic steroid therapy. To address these risks proactively, the authors advocate for preventive strategies, including screening, antibiotic prophylaxis, and vaccinations, while also advocating for a patient-inclusive approach to decision-making.

As more patients are diagnosed with immunocompromised conditions or started on immunosuppressive medications, it’s increasingly important to recognize that opportunistic infections need to be proactively managed and prevented. “Today, in-hospital mortality rates for patients with Cryptococcus infections but without HIV or traditional risk factors are nearly three times higher than the mortality rates for patients with HIV. The demographic of those succumbing to this infection has drastically changed in the past two decades. We are witnessing a real-world epidemiological transition, and clinicians must be cognizant of this,” urged Chastain.

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