Emergent Fungal Concerns to Human Health: A Wake-Up Call
Article by Sam Swingler, PhD; Medical Writer at EPG Health
Despite mycoses causing over 1.5 million fatalities a year with billions of reported infections, the overall impact of fungal diseases on human health has been relatively understudied in comparison to bacterial infections. It has been reported that systemic infections caused by fungi were relatively rare pre-1940s, which coincides with the advent of antibiotic use in healthcare settings1.
During the 1950s, medical advancements in immunosuppressive medicine began to grow; agents such as chemotherapy for cancer, corticosteroids and prolific antibiotic use flourished2. These novel medical treatments paved the way to allow microorganisms to exploit a weakened body and cause previously unseen infections. With the high levels of antibiotic regimens being administered, a plethora of fungal infections began to take hold3.
Filamentous fungi and yeasts with pathogenic capabilities account for up to 1.5 million deaths a year
The type of fungi, be it filamentous fungi or yeast, along with the immunocompetency of an individual, determines the nature of infection with which they have become inflicted4. Infections considered superficial include nail, scalp and skin infections responsible for over 1 billion diagnoses a year and are commonly caused by the fungi Candida spp., Microsporum spp., Epidermophyton spp. and Aspergillus spp5,6.
Fungal infections of the mucosa often affect the mucosal orifices of the body, which include the eyes, mouth and vagina, with over 135 million women a year seeking medical attention for vaginal candidiasis (thrush)7. Invasive fungal infections like vaginal candidiasis present as deep routed infections reaching the lower layers of the dermis, with the possibility of causing chronic illnesses and above average mortality8. Localised fungal infections such as chromoblastomycosis and paracoccidioidomycosis, prolific in tropical regions of the globe, were classified by the WHO as neglected tropical diseases due to their relative infrequency9.
Similarly, more widespread fungi, namely the Aspergillus species, frequently cause severe lung infections – especially in those with pre-existing conditions such as asthma, cystic fibrosis, tuberculosis and other pulmonary illnesses10. Aspergillus spp. is well documented in causing severe allergic reactions in individuals (aspergillosis), which can exacerbate conditions such as asthma and cystic fibrosis, usually initiated by inhalation of spores11. Due to the aggressive nature of invasive fungal infections, they can become lethal if they are not adequately treated with a specific drug treatment plan.
Aspergillus spp. and Candida spp. account for up to 76.3% of fungal infections, primarily affecting immunocompromised individuals
Very few species of fungi naturally have the infectious capacity to cause illnesses in healthy people. However, fungi with low pathogenicity can potentially cause invasive infections in individuals with an impaired immune system as result of a defective acquired or innate immunity, or through immunosuppressive medications12. Invasive fungal infections have also been observed to take an opportunistic stance as there has been a surge in SARS-CoV-2 patients suffering from pneumonia who have acquired fungal lung infections13.
The prevalence of fungal infections causes a significant imposition on public health, with mortality rates ranging from 30% to 90%, dependent on the species of fungi and the demographic of patients. It is estimated that around 90% of fatalities from invasive fungal infections are caused by Cryptococcus spp., Aspergillus spp., Candida spp. and Pneumocystis spp. Further health threats are emerging from Histoplasma spp. and Coccidioides spp., which are highly pathogenic under the right circumstances and have been shown to infect immunocompetent individuals readily14.
Aspergillus spp. can cause chronic fungal infections such as invasive aspergillosis, which affects over 3,000,000 people a year due to allergies, comorbidities and over-exposure to fungal spores15. The most common malefactor is Aspergillus fumigatus which is responsible for approximately 50% of fatalities in infected individuals, even when treatment is administered expeditiously15. Due to the emergence and appreciation of the pathogenicity of Aspergillus spp. and the illnesses it can cause, it is becoming more widely understood that it can be a life-limiting allergen which predominantly affects people living with severe asthma and those who are immunosuppressed16.
The World Health Organisation has listed the closely related species Cryptococcus neoformans and Cryptococcus gattii as the causative agents of cryptococcosis and a severe threat to public health17. Cryptococcosis is responsible for over 220,000 infections per year, with a mortality rate of 180,000 in HIV positive patients each year18. Another fungal infection predominantly present in individuals with AIDS is Pneumocystis pneumonia19.
Candida spp. is the leading cause of nosocomial invasive fungal infections, with Candida albicans causing 10% of all candidemia and 25% of urinary tract infections. Invasive candidiasis causes up to 40% of deaths associated with fungal infections in America20. The pathogenesis of Candida auris is still unclear; however, rising nosocomial infections indicate that this yeast can survive in healthcare settings. However, there are varying reports on the virulence of C. auris in comparison to other species of Candida21.
The CDC has announced that invasive mycoses, primarily candidiasis, is causing chronic infection in hospitalised SARS-CoV-2 patients
Current microbiological tests to diagnose systemic fungal infections are routinely based on blood cultures which are only accurate 40% of the time22. Susceptible tests, such as polymerase chain reaction and β-glucan identification, are not widely accessible and are costly. Due to the low accuracy of testing and diagnoses, many cases of candidiasis go undetected, which results in an underestimation of the prevalence of invasive fungal infections23,24.
The CDC has classified Candida as a significant threat to health due to multi-drug resistant strains, most notably Candida auris. This has led to a greater appreciation for the danger of emerging fungal outbreaks from antifungal resistant strains associated with high mortality rates25,26. Candida auris is a multi-drug resistant species implicated in 35% of deaths from nosocomial infections of candidiasis. C. auris was first observed in Japanese patients with ear infections in 2009 and was subsequently identified as the causative agent of simultaneous infections in multiple countries worldwide27.
To combat Candida auris infection, methods of detection and diagnosis need to improve with a focus on more rapid processing and sufficient differentiation between Candida haemulonii and Candida auris to reduce inaccurate diagnoses28. Additional antimicrobial screening protocols and expansion of antimicrobial resistance within healthcare settings to include more resistant strains of yeasts and fungi would also be beneficial, along with more attention to developing new antifungal drugs to target antifungal resistance29. Skin colonisation screening in patients who have been identified as being at higher risk would also allow for earlier detection30.
The CDC has reported that C. auris has shown high levels of resistance to all three major groups of antifungal drugs; the azoles, echinocandins and polyenes31. These antifungal drugs are crucial in treating invasive fungal infections, and with rising resistance and relatively few new drugs being developed, it is clear that new antifungal drugs need to be developed.
Aside from C. auris, several other fungal outbreaks which display antifungal resistance are emerging, primarily in southeast Asian countries such as Indonesia and Thailand. These countries are combating a rise in terbinafine-resistant strains of invasive fungal species; attributed to the overexposure to antifungal drugs32.
Aspergillus species are increasingly becoming resistant to azole antifungal drugs, which pose a significant concern for patients with asthma, a compromised immune system or other comorbidities of the lungs33,34. This resistance is thought to have arisen from the overuse of agricultural fungicides that regularly use azoles35.
The emergence of antifungal-resistant mycoses is considerably concerning. However, it is hoped that the development of several new classes and variations of antifungals which include hexapeptides such as rezafungin and depsipeptides such as aureobasidin A, triterpenoids such as ibrexafungerp, tetrazoles, orotomides (olorofim), siderophores, and arylamidines will allow health care professionals to better control resistant mycoses36. With the exponential rise of multi-drug resistant bacteria, which have been shown to cause millions of deaths a year, allowing fungi to follow the same route would be highly irresponsible37.
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