Fungal infections: the unknown pandemic

Although the memory of human beings tends to be forgetful, the planetary catastrophe of Covid has come to remind us that pandemics of infectious origin are not a nightmare of bygone times. A fact that was previously corroborated by the terrible AIDS pandemic, or others of lesser intensity such as the flu epidemic of 2009 and the outbreaks of Ebola, Zika and dengue, the latter two transmitted by insects.

However, a latent pandemic remains among us, little known, but of enormous prevalence and increasing mortality: that caused by microscopic fungi.

From supporting actors to protagonists
Historically – apart from their nutritional value – fungi caused superficial diseases (pityriasis, ringworm, athlete's foot, etc.) that were cured almost without treatment. Furthermore, they were treated as secondary opportunistic pathogens that intervened after an initial pathology, mainly bacterial or viral. The number of infectious fungi identified was relatively small.

This panorama has changed radically since the end of the 20th century. Certain fungi are the primary agents causing potentially lethal infections, with high clinical incidence. At the same time, it is very common for fungal species classified as harmless to be responsible for serious hospital outbreaks, while fungal strains resistant to the few antifungal drugs available are increasing alarmingly.

In epidemiological terms, it is estimated that more than 1,5 million people die each year from fungal infections. It is a figure higher than that caused by tuberculosis or malaria, without going any further.

The list of the most dangerous
Assuming the magnitude of the problem, the WHO has established a list of especially dangerous fungi. This classification alerts us that – despite their threat – these pathogens do not receive sufficient attention or resources, which makes it difficult to estimate their global impact and prevents a more precise action program.

Among the most significant, they include pathogenic species of yeast, filamentous and/or dimorphic fungi (that develop differently depending on the growth temperature) belonging to the genera Candida, Aspergillus, Cryptococcus, Histoplama, Blastomyces and Coccidioides, among others. In particular, Candida albicans is listed as the fourth cause of systemic infections spread through the bloodstream.

However, the emergence of Candida auris has been much more serious. The United States Centers for Infection and Disease Control (CDC) considers it an “urgent threat.” This yeast shows unusual resistance to treatments, which has increased the recorded cases of multi-resistance. In addition, it has low susceptibility to common sanitary disinfectants, can be spread from hospital equipment and instruments (fomites) and is easily transmissible between people.

Vulnerable population increases
The reasons that explain this disturbing situation are multiple and complex. On the one hand, in recent decades the world population susceptible to fungal infections has increased considerably, such as the elderly, neonates or patients with chronic debilitating diseases.

Closely associated with these categories are people with damage to their immune system or who are directly immunosuppressed, such as AIDS patients, individuals who receive invasive surgery or transplants, and those who undergo prolonged therapies with antibiotics or chemotherapy. Likewise, long periods of hospitalization increase the risk of nosocomial infections (acquired in the hospital) caused by fungi.

Recently, the British newspaper The Guardian warned about this worrying situation. The article highlighted the serious deficiencies in adequate infrastructure and sufficient research to deal with the possible outbreak of a fungal pandemic.

Few drugs available
The absence of a safe and effective antifungal therapy represents a problem of utmost concern: since fungi are eukaryotic organisms, like us, the toxicity that the compounds can incorporate is low.

Furthermore, we have a very limited arsenal of antifungals. In fact, there are only three families: the polyenes (amphotericin B), the azoles (ketoconazole or fluconazole) and the echinocandins (caspofungin or micafungin). The first two target ergosterol, a basic compound of the fungal plasma membrane; while echinocandins block the synthesis of its cell wall.

Some compounds are also applied against certain localized mycoses (terbinafine, griseofulvin,ciclopirox...). However, its effectiveness is often weak, since it does not kill cells (fungicidal action), but only stops their growth (fungistatic).

And meanwhile, strains resistant to conventional antifungals are multiplying. Several molecules are in an advanced phase of research, pending future authorization.

Another obstacle comes from the absence of vaccines against fungal diseases in humans. Although there are some trials underway, it is a complicated issue to address. Firstly, because a significant number of potentially harmful fungi coexist with the microbiota of the healthy individual. Furthermore, the clinical course of a fungal infection usually depends on the patient and their immune response capacity.

Therefore, and without falling into extreme alarmism, we should pay more attention to fungi. Without forgetting, of course, other more worrying microbiological threats, such as those caused by bacteria that are multi-resistant to antibiotics or the presence of genetically new viruses unknown to the human population.

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Source: The Conversation. Authorship:

Juan Carlos Argüelles Ordóñez
Professor of Microbiology. Signaling and stress response in pathogenic yeasts. Mechanisms of antifungal action: new natural products., University of Murcia