Karen Titus
May 2024—If anything keeps Arturo Casadevall, MD, PhD, lying awake at night, it’s the frogs. And the bats. Also, the patients (relatively few, at least for now) who are affected by invasive fungal diseases.
Second of two parts on fungal infection. Part one in the April issue.
Dr. Casadevall is a microbiologist and infectious diseases expert in the Johns Hopkins Division of Infectious Diseases, Department of Medicine, and the Bloomberg School of Public Health, where he’s a professor of medicine and chairs the Department of Molecular Microbiology and Immunology.
In his waking hours, he looks deeply and broadly at the natural world and how the disturbing growth of fungal infections might impact the medical world. Though the arrows haven’t hit the bull’s-eye, they seem to be flying in that direction, says Dr. Casadevall, who has written widely on this topic, including “Immunity to Invasive Fungal Diseases” (Casadevall A. Annu Rev Immunol. 2022;40:121–141).
In a recent interview with CAP TODAY, Dr. Casadevall spoke about how he and others in the field are thinking about how medicine might respond to this potential threat.
There are good reasons fungal infections draw limited scrutiny, he says. Fungal diseases don’t tend to affect people who are immunologically intact. While healthy people can get some fungal diseases, it’s relatively rare. Moreover, most are not communicable.
“When people worry about infectious diseases,” he says, “they worry about viruses. They worry about bacteria. They worry about parasites. You don’t hear them worry about Cryptococcus or something like that.” Hence, fungal diseases tend to be underfunded and unstudied, he says.
In a world where scientists in multiple disciplines are looking at climate change and regularly saying We’ve never seen this before, this is, essentially, old news—overlooking fungal diseases has long been the norm in medicine. “What has changed in recent decades,” Dr. Casadevall says, “is they’ve become a major problem for immunosuppressed patients,” a population that has grown as medicine has advanced. As he observes in his Annual Review of Immunology article, corticosteroids, broad-spectrum antimicrobial therapy, and chemotherapy have all increased patients’ vulnerability to fungal infections. And parenteral lipid nutrition is associated with systemic infection with Malassezia spp.
Impaired immunity also emerged with the AIDS epidemic, with patients at high risk for candidiasis, cryptococcosis, and histoplasmosis, he further notes. But environmental disruption has also played a role in outbreaks of coccidioidomycosis and histoplasmosis.
The rise tracks with the rise in immunocompromised patients each year, he continues. “Anyone who survives cancer—some of the survivors need to be on immunosuppressive drugs.” Ditto for those who receive transplants. The benefits of living longer, more normal lives are inarguable. “But they are at risk for some of these fungal diseases,” Dr. Casadevall says.
That risk is compounded by shortcomings in testing. One of the biggest gaps, he says, is that “the diagnostics are often lacking” (see “Confronting diagnostic gaps in fungal infection,” CAP TODAY, April 2024). That leads to late diagnoses, which creates another problem: More advanced disease is harder to treat. Oftentimes when a test result is positive, “it’s because the patient has overwhelming disease.”
Developing tests to detect disease sooner is possible, Dr. Casadevall says. “It’s a technical problem. It’s not an insurmountable problem. But it is a circular problem,” he says. “Because there are few cases, the market is small; because the market is small, you don’t invest in it. Therefore, you don’t have it.”
While Dr. Casadevall does see progress, it is, like so much else in this field, incremental. And there’s no guarantee that the tortoise will ultimately beat the hare in this story.
The same is true of antifungal susceptibility testing. Physicians tend to start antifungal therapy without testing for susceptibility first, he says. If the therapy fails, that’s usually the best available clue that the agent is resistant. The same knowledge that guides bacterial treatment resistance simply doesn’t exist yet for fungal diseases.
“But we are having increasing resistance,” he says. “There’s no question about that.” The problem is exacerbated by the paucity of antifungal drugs. “There are very few,” he says. “So when you get resistant to one, you lose a major part of your therapeutic tools.” Sounding a more hopeful note, he says that more drugs have entered the developmental pipeline more recently. “That’s something positive I can say that I couldn’t have said five years ago.”
Understanding the biological basis of fungal infections should help improve patient care.
This is where medicine joins forces with mushroom hunters. Says Dr. Casadevall: “One area that’s been interesting and exciting is that last year we reported in PNAS that fungi are colder than their environment” (Cordero RJB, et al. Proc Natl Acad Sci USA. 2023;120[19]:e2221996120).There are implications not only for climate change, he says, but for possibly interrupting the movement of fungi to the warm-blooded human environment. “It suggests that there may be—not today but in the future—new ways to try to inhibit fungal disease. In other words, the temperature adaptation they have to make could be targeted.”
C. auris presents its own compelling biological mystery, Dr. Casadevall says.
“This is an organism that was not known to medicine up until around 2009 or so, and then it appeared on three continents simultaneously. And the isolates are not related,” he says. “So it’s not like somebody took a plane from one region to another.”
“We were unprepared for this,” he adds. “Where did Candida auris come from? We don’t have a lot of knowledge about the natural world—we don’t really have a lot of knowledge about fungal diversity even in the backyard. And this is where a lot of fungi are coming from; they’re coming from the environment. So better methods to map the environment could be helpful for identifying future threats.”
It’s possible, says Dr. Casadevall, “that it may have been the first fungus to adapt to climate change.”
He’s not the only one with that thought. An April 16 article in JAMA (Phillips MC, et al. JAMA. 2024;331[15]:1318–1319) included fungal diseases, along with those that are vector-borne, zoonotic, and waterborne, among those impacted by climate-related changes. While acknowledging that only about 300 of the millions of recognized species of fungi infect humans, the authors write that the narrowing temperature differential between humans and the environment could affect epidemiology and suggest that Candida auris and Sporothrix brasiliensis may be early such examples. Other fungi on the move include the spread of Coccidioides (identified recently in Nebraska); Histoplasma appearing in Alberta, Minn., and Wisconsin; and Blastomyces heading West, including a novel species (B. helicus) seen in the Rocky Mountain region.
Comparisons to the COVID-19 pandemic are inevitable, but this too is theoretical and speculative, Dr. Casadevall says. “What I would say is, look at the frogs,” noting that the chytrid fungus has decimated frog populations across the continents. Other species, including salamanders and snakes, are also seeing population declines due to fungal infections. “Look at the bats in North America that are dying of white-nose syndrome,” he says, referring to the fungus Pseudogymnoascus destructans.
“If you look at our history,” he continues, “we don’t have an example of a pandemic caused by fungi. So people say it likely won’t happen.” He pauses before continuing. “Well, I would tell you that when I went to medical school, I was taught that retroviruses did not cause disease. At the time there were only models for studying cancer.” Everything changed in 1981, with the advent of AIDS.
A more recent example, of course, is COVID-19. “I was taught coronaviruses only caused the sniffles,” Dr. Casadevall says.
Looking to the past to understand future threats is valuable, he says.
“We should be worrying about influenza. But just because something hasn’t happened doesn’t mean you don’t have to worry.”
The recent pandemic highlights other potential shortcomings in medicine. Because fungal diseases are not reportable—because they’re not communicable—disease surveillance “is almost nonexistent,” Dr. Casadevall says. In the event of a widespread outbreak, he says, the medical community would be scrambling to keep up, at least at first. “It would be reported pretty quickly. But right now it’s very hard. It’s very hard to get the incidence or prevalence of fungal diseases” in different cities, versus the easy availability of such data of, say, influenza and HIV.
The COVID-19 pandemic invites other comparisons as well. Even with the current gaps Dr. Casadevall and others have identified in fungal testing and treatments, the medical community would by no means be starting from scratch to address future outbreaks. As everyone looks back and critiques the responses—successes and failures—to the pandemic, a fair amount of criticism is understandable, he says. “But we have learned a lot as a result of this calamity.”
An even more pressing concern, he says, is bird flu. Sporadic human infections of highly pathogenic avian influenza A(H5N1) have been reported in recent decades, and the CDC reports that the H5N1 viruses currently circulating in wild birds and poultry are genetically different from earlier versions of the virus. “If that was to break into human populations, we would have a huge problem on our hands,” he says.
How well does Dr. Casadevall sleep at night? “You could say what I am most worried about today is whether bird flu will jump into human populations. Because the mortality is not one percent. And the contagiousness is enormous. Another flu pandemic—that is, I think, what we are all worried about.” It has spread to bird populations on all seven continents, he notes, and has begun to affect some mammal populations.
“Will it get to us? I don’t know,” he says. “But that’s, to me, from an infectious disease standpoint, what most people are probably worried about now. They’re thinking about another attack from nature.”
Moreover, given the variety of responses to COVID-19, a similar outbreak could resurrect many of the same problems as well as successes. “We would probably have the political and resistance problems,” he predicts. “But at least we did learn a lot in the past four years.
“Many people thought that society was better protected,” he continues. “And what we learned was that there are a lot of vulnerabilities [in] communication, even among experts, so even if you make vaccines, people may not take them. None of that was anticipated.”
“I think we thought we were in better shape. COVID exposed a lot of vulnerabilities” in the health care system, he says. “But I also think a lot of things got corrected during the pandemic. Communication did improve.” In early 2020, with the lack of testing, “we essentially lost a month. A month in a pandemic—it’s enormous.”
One vulnerability laboratories can address now is simple, Dr. Casadevall says: Put fungal infections on the list of possible diagnoses.
“That will at least force you to think about it. If you’re in a place that you just don’t see fungal infections very often, you may not be thinking about them.” Putting them on the list could lead to earlier diagnoses and treatment.
Granted, the presentation of many fungal diseases is highly variable. This Achilles’ heel, he says, “makes it hard for anybody to get a lot of experience. You have to think about it, but then you also have to realize that these diseases can sometimes present in unusual ways.”
There are a considerable number of rare fungal diseases as well, and pathologists often have to try to make the diagnosis on histology because the pathogen was picked up only on a formalin-fixed, paraffin-embedded tissue sample. That takes expert knowledge, but mycology experts are few and far between, he says, further slowing things down. “Everything happens slowly, and you have a patient who’s getting worse.”
In other words, the process moves slowly—until suddenly it doesn’t. Explains Dr. Casadevall: “You take a cancer patient, and they get a fever, and then initially people may think, Well, it may be bacterial, something like that. And at the time the fungal disease is the size of a quarter. What happens is as it grows, fungi kill tissue around it. If one could learn very early on when they had a fungal disease, that could make a big difference for our patients.”
The responsibility lies beyond the walls of the laboratory, he says. “Awareness needs to come from everyone. This is an all-hands-on-deck problem.”
Karen Titus is CAP TODAY contributing editor and co-managing editor.