Clare Kenyon
Today, the World Health Organisation (WHO) released the first ever ‘Watchlist’ for Fungal Pathogens.
Experts say it’s a wake-up call for everyone: medical practitioners, farmers and the general public.
The 19 fungi within the report are categorised into three priority groups (critical, high and medium) in terms of their threat to public health, although all of them are of serious concern for the WHO.
The fungi of greatest concern on the list are the four ‘critical priority’ pathogens, ranked highest due to their public health impact and/or risk of antifungal resistance.
Aspergillus fumigatus, which mainlyaffects the lungs, is becoming increasingly resistant to azole medicines (a group of antifungals). Infections caused by azole resistant strains kill between 47 percent and 88 percent of affected patients.
Candida albicans can cause invasive infections, typically in vulnerable patients, and kills 20 percent to 50 percent of people it affects. It and Aspergillus fumigatus are the two most common fungal pathogens globally.
Cryptococcus neoformans has a propensity to infect the brain, especially in immunocompromised individuals. The main risk factor globally is HIV infection, and it is a leading killer in this population.
Candida auris is a newly emerged pathogen. It is resistant to most antifungal medications and presents a huge treatment challenge for hospitals
Antifungal resistance: a growing problem
The WHO initiated and led the project with support from researchers at the University of Sydney and the Australia and New Zealand Mycology Interest Group.
According to Dr Justin Beardsley from the University of Sydney Infectious Diseases Institute, the report is, in part, a reflection of the fact that fungal infections have been largely ignored by the general medical community for some time.
“The real heyday of medical mycology research has been related to HIV, but it never really spilled over into mainstream medicine. So, HIV specialists knew a bit about it, and medical mycologists knew a bit about it, but the broader infectious disease and general medical community didn’t pay much attention. And because of that, problems appeared without anybody really having been keeping an eye on it.”
The problems Beardsley refers to are twofold: a developing resistance to current antifungal treatments (of which the options are relatively few and side effects sometimes severe) and a proliferation in the range over which these fungi are found.
One example is Cryptococcal meningitis. “Before the HIV pandemic, it was a really rare infection that happened in tropical places, but its epidemiology has changed over time. And now, it’s not just HIV-associated, and it’s not just tropical, it has spread its range and nobody knows why. It’s now affecting populations on the northwest seaboard of the US, for example.”
Of the fungal pathogens traditionally associated with HIV, five (C. neoformans, Crytococcus gattii, Pneumocystis jirovecii, Histoplasma spp. and Talaromyces marneffei) have made it to the WHO’s priority list.
A related factor, which contributes to the increased range of the fungi, is that medicine to treat various illness has improved and become more targeted.
“The way that we’re doing medicine is so much more sophisticated now. We do better surgery; we have longer intensive care unit stays”, says Beardsley. “Now, we’re using better medicines for cancer, for COVID. Rather than just giving everyone steroids, which completely flattens the immune response, we intensely target one specific pathway in the immune system. Those pathways are sometimes fungal-specific too, which increases the population who’s at risk. So, we’re seeing suddenly tonnes more fungal infections, and that’s now got everyone’s attention.”
Like the growing number of antibiotic resistant bacteria, the developing resistance to current antifungal treatments by dangerous fungal pathogens present an ‘existential threat.’ While there are more than 20 different classes of medicines to treat bacteria, there are only four classes of antifungals.
Also, unlike antibiotic resistance, antifungal resistance is not primarily driven by overuse of treatment in humans.
“It’s not because people are going in to see their GP and getting an antifungal and that is causing this quite rapid and recent increase in resistance – it’s because of the way we use antifungals in agriculture and in the environment.”
“Some of the antifungals we’re using for human health are pretty similar to the ones that we use to protect crops and also in animal husbandry – to stop chickens getting fungal lung infections, for example,” he says. The Netherlands is this hotspot of resistance because of the tulip industry and the way tulips are dipped in antifungals.”
Still, four classes of antifungals seems too few.
Why haven’t we developed more antifungals?
One of the main reasons is that fungi are similar to mammalian cells – they are far more similar to humans than they are to bacteria.
“Fungi have very similar biochemical pathways to us”, says Beardsley. “Something that is toxic to a fungus is very often toxic to humans as well, and most antifungals have a lot of side effects. It’s very difficult to target something that will kill a fungus without killing human cells around it.”
Amphotericin, a first line drug for serious fungal infections, for example can only be administered intravenously in hospitals and can cause permanent renal damage and failure if used for more than two weeks.
“This is not to mention side effects whilst being administered the drug,” says Beardsley. “People can shake uncontrollably, or experience rigour, which can be pretty nasty.”
Read more: Antibiotic found in potato disease thwarts fungal infections
The other problem is funding.
“Studies have shown that less than 1.5% of all infection immunology funding goes to fungal pathogens,” says Beardsley. “That’s despite the fact that they cause as many deaths annually as TB and more than malaria.”
A WHO’s who of serious fungal pathogens
Of the four fungal pathogens making the critical priority list, Candida auris piques Beardsley’s interest the most.
“It’s not the one that’s killing the most people now, but it is a mystery,” he says. “It literally appeared in 2009 – before then it didn’t exist in humans and was never seen before – but it suddenly appeared all over the world at once.”
It’s possible that C. auris developed in salt marshes in India, which are hotspots of antifungal resistance due to contamination from human health and agriculture, and was then spread by migratory birds. There is a suggestion, too, that it has been able to make the jump from birds to humans due to increasing temperatures from climate change.
It’s super resistant to antifungals and very hard to clean out.
“It gets into hospitals and is very transmissible between patients,” says Beardsley. “If it gets into an intensive care unit, they have to close down for months and do a really deep clean because it’s simply too risky to expose vulnerable patients to this essentially untreatable infection.”
Beardsley describes another fungal pathogen of critical priority, A. fumigatus, as the canary in the coalmine for antifungal resistance. “It’s one of the main causes of infection,” he says. “Fungal pathogens have been a big issue in COVID patients. So, whenever somebody gets lung damage, this fungal pathogen comes in on top and causes a secondary infection. And with so many people sick with COVID, we saw a massive spike in Aspergillus. The infections even got their own name: COVID-Associated Pulmonary Aspergillosis, or CAPA.
“It used to be susceptible to all of the antifungal agents, but now, in some cases, it’s not susceptible any of the first line drugs at all. It’s changing so quickly. So that’s pretty scary.”
The fungal pathogens on the list were ranked in priority according to several criteria, including public health importance (such as deaths, annual incidence, global distribution and trends), antifungal resistance, preventability, access to diagnostic tests and the state of evidence-based treatments.
Just because a fungal pathogen is categorised as being of medium priority, doesn’t mean it isn’t a problem now or it won’t be a problem in the future, explains Beardsley.
“Some pathogens like T. marneffei, Coccidioides spp., Paracoccidioides spp. (in the medium priority group) and Histoplasma spp. (in the high priority group) are currently only in certain areas, so not affecting global populations. But they are a huge problem where they do exist. So, the category is not necessarily representative of the local concern for specific pathogens.”
The future
The WHO report is largely about bringing attention to the growing problem of serious fungal pathogens.
Beardsley points to the last 2 decades, particularly. “People are really worried about bacterial and viral pathogens. But over the last 20 years, fungal pathogens are responsible for more species extinctions than bacteria or viruses combine – something like a third of amphibian species are at risk of becoming or have become extinct, and bats in Australia are dying because of fungal pathogens. They’re a huge threat, basically, an underappreciated threat and still really low on our radar.
“We need to focus on funding research and development and surveillance (including fostering research relationships between hospitals). We were able to respond to COVID so quickly because people had invested time and energy into RNA vaccines. When it came to it, they could build that up quickly. The basic science was in place. We haven’t invested in that basic science for decades in mycology research. So, it’s going from a standing start, and we really need to catch up and make up for lost time.”
Update Nov 11, 2022: The initial article reported that the University of Sydney led the research. This is not correct. WHO initiated and led the project with expert support from researchers at the University of Sydney and the Australia and New Zealand Mycology Interest Group.