Fungal Disease in Humans

Candida auris

(From John Hopkins Bloomberg School of Public Health, at https://publichealth.jhu.edu/2024/the-rising-threat-of-fungal-diseases)

Candida auris was not known to humanity until around 2009, when it began appearing in hospitals. The situation worsened over the next two years. From 2010 to 2012, it appeared independently in Venezuela, South Africa, and the Indian subcontinent. Since then, there have been two other emergences: one in Iran and one in Russia.

The important part is that these are not related. It's not like somebody's taking a plane from South Africa and carrying it to India or Venezuela. It came out of nowhere.

Last year, physicians and investigators in Singapore recovered a new clade, or variant, of Candida auris, which is very significant. Candida auris has become a major medical problem and is being declared a critical pathogen by the WHO.

How is Candida auris spreading? We don't know. I proposed a few years ago with some colleagues that it is the result of global warming. Fungi are not new. They've been living out there for a very long time, possibly millions of years.

Most fungi can't cause disease in humans because they can't grow at our temperature, which is 98 degrees Fahrenheit. But as the world gets warmer, fungi have to adapt to higher temperatures or perish. So the thought is that the fungus has been adapting to the environment, and then got into a situation where it can infect humans, and we have a new emergence.

COVID-19 and Fungi: Black Fungus (Mucor) Nightmare

(Arturo Casadevall, from the Johns Hopkins Bloomberg School of Public Health, at https://publichealth.jhu.edu/2021/covid-19-and-fungi-a-nightmare-in-the-making)

As India battles a devastating wave of COVID-19 cases, another crisis is waiting in the wings that could far outlast the pandemic—in the form of a chronic fungal disease that kills slowly and is extraordinarily difficult to treat.

Preying on recovering coronavirus patients, India has seen some 30,000 cases of mucormycosis, better known as black fungus, in recent months.

The illnesses caused by the fungus Mucor—mucormycosis—are well known, with an overall mortality rate of ~54%.

But the scale of India's outbreak is rare. Mucor, which can lodge deep into the sinuses or lungs, has already killed hundreds in India, and forced others to have an eye excised to remove the fungus.

Why is it sweeping India at the same time as COVID? Arturo Casadevall, a leading expert on fungi and Bloomberg Distinguished Professor in Molecular Microbiology and Immunology at the Johns Hopkins Bloomberg School of Public Health, explains why the liberal use of steroids in treating COVID-19 is a key factor, and why India's Mucor crisis is a warning sign for the rise of fungal infections across the globe.

What exactly is Mucor, or black fungus?

We are all breathing in fungal spores constantly—for example when we walk by construction sites, or compost piles—but healthy people clear them easily without experiencing illness.

Mucor is a particularly nasty fungus—and for those who can't clear it, it tends to kill slowly.

If it lands in the sinuses or brain, it can cause facial swelling, nasal congestion, and headache. In the lungs: fever, cough, and shortness of breath.

What's with the name?

The name black fungus comes not from the fungus itself, but from black lesions in patients sickened with mucormycosis.

The fungus itself is not particularly black, even though it makes melanin, a pigment that is a secret weapon to almost all fungi, including Mucor.

When Mucor lands in the lung, it begins to grow and kill tissue as it expands into a fungal mass which kills tissue, which causes scarring that makes the tissue appear black.

The fungus—in fact most fungi—uses this black melanin pigment as armor which enables it to survive the body's immune defenses and evade drugs. This is quite different from how humans use melanin, for protection against sunlight.

Why is this particular fungus so dangerous to COVID patients?

Mucor preys on those with weakened immune systems—and COVID patients have two hits against them when it comes to Mucor: One, they have damaged lungs. Scar tissue from COVID-related lung damage makes it more difficult for the immune system to clear the spores—scar tissue does not respond very well to infection. Two, to treat inflammation, many of these patients have been put on steroids, which are immunosuppressants.

What's the big picture lesson for treatments here?

I think one of the problems that this crisis has exposed is overuse of steroids—it's an epidemic, really. Doctors are putting many patients on steroids, yet the data [show] that steroids are only beneficial in COVID-19 patients who are very severely ill.

COVID is an infectious disease; steroids are an immunosuppressant. If you give them too early, this is going to work against you. So I think physicians need to be more careful with steroid use.

When a coronavirus patient is not improving as expected, doctors need to [suspect] fungal disease. You're always better [off] treating an amount of fungi the size of a dime than treating something the size of an apple.

Why is India being so hard-hit by this fungus?

I think the most likely explanation right now is that it reflects local climate conditions and large numbers of COVID-19 patients who are susceptible.

What I would like to know is, what is in the air in India, and whether this reflects local farming conditions and how vegetation is disposed of. Compost piles, for example, contain enormous amounts of fungal spores. Anywhere you have decaying vegetation [and] rotting wood are places you tend to get a lot of fungi. It could be as simple as vegetation rots faster in the tropics, resulting in more spores.

In weaker health systems, poorly filtered air in hospitals can also encourage spores to spread.

So fungal infections aren't just spreading in India?

While India is getting a lot of Mucor, other parts of the world are seeing a rise in other fungi. The Netherlands and United States are seeing a rise in another fungus—Aspergillus—among COVID-19 patients.

The common theme is, with the combination of damaged lungs and steroids, you're going to get fungal disease. Depending where you are, you're going to end up with different ones.

Looking beyond India, the bigger story is that amid this pandemic, fungal infections are a major calamity because they are so hard to diagnose and treat.

Why is this infection so hard to treat?

The only thing that can be used to treat this is a drug called amphotericin B—which doesn't work very well and has to be given for months intravenously. In India, there are shortages of it because of the COVID crisis.

Because the antifungal drugs don't work well with Mucor, often the only option is to remove a piece of the lung or an eye, surgically, depending on where the fungus took hold.

How is mucormycosis diagnosed?

There is not a simple blood test. Sadly, the way it would manifest is that people don't get better as expected.

Mucor [mycosis] only gets diagnosed when the symptoms get sufficiently bad, and once Mucor is causing symptoms, the immune system cannot clear it.

First the lung will show a lesion. At first, you don't know if this lesion is just scar tissue from COVID, whether it's a bacterial pneumonia, or whether it's a fungal pneumonia.

One of the only ways to make a diagnosis is very invasive—using a scope to take a piece of lung tissue and look at it under the microscope. Then you see the fungus growing into the tissue.

Given the extremely limited ability to diagnose, the cases seen so far are probably the tip of the iceberg, sadly.

India is going to have a big problem going forward with patients who survived COVID but now have chronic mucor [mycosis]—and that will kill them down the line.

It's just nightmarish.

The Future Threat of Fungal Disease

The future threat of fungal diseases is escalating due to climate change, which facilitates the spread of fungi to new environments and enables them to develop resistance to antifungal drugs. Compounding this are increasing antimicrobial resistance, limited treatment options, and a growing number of vulnerable, immunocompromised people, all leading to rising incidence of fungal infections. This perfect storm of factors is driving the emergence of novel fungal pathogens, like Candida auris, and the expansion of existing ones, posing serious risks to human and food security.

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Key factors driving the threat:

• Climate Change: Rising temperatures allow fungal pathogens to thrive in previously inhospitable areas and promote the development of drug-resistant strains.
• Antimicrobial Resistance: The increased use of antibiotics and the emergence of naturally resistant fungi contribute to a dwindling arsenal of effective treatments.
• Vulnerable Populations: An aging population and an increase in immunocompromised individuals, including those undergoing chemotherapy or organ transplants, are more susceptible to fungal infections.
• Emergence of New Pathogens: New fungal pathogens, such as the drug-resistant Candida auris, are appearing and spreading globally.
• Extreme Weather and Natural Disasters: Events like wildfires and floods can disperse fungal spores and impact immune systems, increasing the risk of outbreaks.
• Impact on Food Security: Fungal diseases are a threat to agriculture, with fungal colonisation of crops capable of significantly reducing yields.

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Examples of escalating threats

• Candida auris: A multidrug-resistant fungus that spreads rapidly in healthcare settings and is difficult to eradicate, posing an urgent threat according to the CDC.
• Aspergillus species: Research predicts significant spread of Aspergillus into new regions due to global warming, increasing respiratory infections in Europe.
• Coccidioides: This fungus, which causes potentially fatal respiratory infections, is expanding its range as droughts become more common.

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Consequences and concerns:

• Public Health Crisis The World Health Organization (WHO) has identified fungal diseases as a growing global public health problem, creating a need for improved diagnostics, treatments, and preventative measures.
• Lack of Effective Antifungals A significant lack of effective treatments and vaccines for fungal diseases, alongside emerging resistance, creates a critical public health challenge.
• Food Security Risks The spread of fungal diseases in agriculture could jeopardize global food supplies by reducing crop yields

(AI Overview, by Google)

Candida Albicans

Dr Lenardon has been studying the cell and molecular biology of Candida albicans, which was identified as one of the four fungi of critical priority. Candida species cause non-serious infections like thrush in tens of millions of people per year. But of more concern are the 700,000 invasive infections that can kill people, about half of which are caused by, well, C. albicans.

When defences are compromised, it can leave us vulnerable to infection. In immunocompromised people, C. albicans can escape the gut, circulate throughout the blood, and invade organs.

While the likelihood of acquiring a severe fungal infection is rare, infection is often deadly. At least 40 per cent of systemic C. albicans infections are fatal, opens in a new window despite the availability of antifungals. By comparison, a nasty bacterial infection like Staphylococcus aureus (golden staph) kills in around 25 per cent of cases, opens in a new window.

The number of deaths from fungal infections is also likely underreported, Dr Lenardon says. Usually, an existing health condition is recorded as the cause of death when the fungal infection was responsible.

Exploiting a Weakness for Copper

(Valeria Culotta writing in ...)

Earth's ancient history can still be seen in modern-day bacterial pathogens, which will scavenge iron from their host to satisfy their voracious appetite for this essential micronutrient. Eukaryotes, or organisms that have a nucleus, evolved after Earth's iron-rich heyday and tolerate iron shortages much more readily than their prokaryotic (that is, nuclei-lacking) cousins. To counter bacteria, humans and other animals will rapidly sequester the body's available iron to starve out the invaders. But this strategy doesn't work on fungi. As fellow eukaryotes, these organisms can readily withstand low iron levels.

Fungi, however, are much more sensitive to levels of copper in the environment and need a precise Goldilocks level of it to survive. As both a toxic heavy metal and an essential micronutrient, copper is a double-edged sword: Both copper starvation and copper toxicity can kill.

Culotta began exploring the metallochemistry of fungi in the 1990s as a postdoc at the NIH, where she worked on the nonpathogenic baker's yeast Saccharomyces cerevisiae. This model organism has a similar window of tolerance to copper as its disease-causing cousins Candida albicans and Candida auris.

As you move up the evolutionary tree, organisms evolved ways to deal with the extremes of copper much more efficiently, she says. We are very good at tolerating high copper, and we have ways of acquiring it, regardless of how scarce it is.

Fungi, she says, are not so flexible.

Over the years, Culotta and others have found that the human immune system utilizes both copper toxicity and copper starvation in responding to fungal infections. Culotta writes in a July 2021 review article in Seminars in Cell and Developmental Biology that copper sits at the core of many microbial enzymes that are needed to invade the host.

Culotta discovered a new type of copper-dependent enzyme in pathogenic fungi that effectively combats some of the chemical weapons used by the host immune system. When scientists inactivated these enzymes in various fungal pathogens, the host's immune system rapidly killed off the yeast. These enzymes sit on the outside of the cell, making them ideal drug targets since researchers don't have to figure out how to get it into the fungi.

The potential new vaccines and therapies Casadevall and Culotta are advancing are desperately needed. Pharma hasn't developed a new class of antifungal therapies in more than 20 years, nor have they created any vaccines to prevent these infections. And given that the pool of immunocompromised people is likely to grow, an increasing segment of the world's population will need them.

Although the prognosis for fungal disease hasn't changed much since the 1980s, Casadevall is hopeful. Just as AIDS was transformed from a death sentence to a chronic disease, so, too, he thinks that we will one day do the same for fungi. What can I say? I'm an optimist, he says.

Antifungals

Antifungals can be grouped into three classes based on their site of action: azoles, which inhibit the synthesis of ergosterol (the main fungal sterol); polyenes, which interact with fungal membrane sterols physicochemically; and 5-fluorocytosine, which inhibits macromolecular synthesis. Many different types of mechanisms contribute to the development of resistance to antifungals. These mechanisms include alteration in drug target, alteration in sterol biosynthesis, reduction in the intercellular concentration of target enzyme, and overexpression of the antifungal drug target.

For nearly 30 years, amphotericin B, which is known to cause significant nephrotoxicity, was the sole drug available to control serious fungal infections. The approval of the imidazoles and the triazoles in late 1980s and early 1990s were major advances in our ability to safely and effectively treat local and systemic fungal infections.

The high safety profile of triazoles, in particular fluconazole, has led to their extensive use. Fluconazole has been used to treat in excess of 16 million patients, including over 300,000 AIDS patients, in the United States alone since the launch of this drug. Concomitant with this widespread use, there have been increasing reports of antifungal resistance.