The growing concern of fungal infections

Consultant in Anaesthesia and Critical Care Medicine, James Watts discusses the growing field of fungal infections

 

Introduction

Fungal organisms are ubiquitous in the human population, but are an increasing problem for the vulnerable and immunosuppressed. There are millions of known fungal species, of which approximately 500 are associated with human; with less than 100 specifically associated with infection in the immunocompetent.

It is estimated that at any one time a billion people may have minor skin, nail and hair fungal infections; that tens of millions will have mucosal thrush; and that over 150 million may have a systemic disease which is serious or even fatal. Overall mortality globally is similar to that of TB, and greater than that attributable to malaria. [1-4]

To cause disease, fungi must also be able to invade the host, cause tissue lysis and resist natural and acquired immunity. However, the main barrier to serious fungal infection is the current inability of most fungi to survive at normal human body temperature. There is unfortunately increasing evidence that some fungi are adapting to live and reproduce at higher temperature ranges [5-8].

In addition, there is growing evidence of multi-drug resistance emerging in various fungal species. Candida auris seems to be particularly prevalent in this regard [9].

There are such serious concerns that the World Health Organisation (WHO) has produced a Fungal Pathogen Priority List to guide further research [10].

This article will attempt to briefly update the reader in this growing field.

 

Summary of Antifungal disease mechanisms, resistance

Antifungal resistance is not related to plasmid transmission. It is acquired within an infected individual by DNA mutation or protein synthesis drift; or by producing increased proteins at times of stress; or from selection from the increasing use of azoles and other chemicals in the environment [11].

Many fungi will form biofilms, which will make elimination from environments difficult, and which also help protect them from destruction by chemical agents. In addition, spores may remain in the environment for some time.

Systemic human infection is often associated with immunocompromise or indwelling devices. Infection may result in tissue lysis, severe sepsis or unfettered spread from immune underactivity.

The main pathogens in the UK are candida species, aspergillosis (haemato-oncology), and pneumocystis (particularly in those with HIV or organ transplants. Fungal infections can manifest up to 5 years following chemotherapy treatment [12].

Detection of infection may be difficult as the symptoms may be masked or attributed to other problems, and false negative cultures are common, partially because specimen preparation may actually destroy fungi.

Sampling should occur from the site assumed to be most seriously infected. Microscopy remains the most effective diagnostic test. Beta D Glucan tests can be falsely positive due to the presence of BDG in foods, haemofilters etc. [13] Galactomannan (used to diagnose aspergillus) is also present in food stuffs [14].

If a fungal infection is suspected, it may be prudent to start treatment until an infection can be disproved. Fluconazole remains the only antifungal that can penetrate the urine, although amphotericin B and flucytosine have also been used in this regard. [15, 16]

 

Antifungal treatments [17]

Azoles interfere with the manufacture of fungal cell membranes. Imidazoles, such as ketoconazole, are used for cutaneous and membrane infections. Triazoles are used for systemic infections. Examples include fluconazole (for candida) and itraconazole (for aspergillus infection).

Allylamines also affect cell membrane manufacture and are used to treat surface infections.

Echinocardins also inhibit cell wall manufacture. Anidulafungin and micafungin are particularly effective against candida; whilst caspofungin is also effective against aspergillus.

Polyenes make fungal cell walls porous. Examples include nystatin and amphotericin B (which is effective in aspergillosis, blastomycosis, cryptococcosis, histoplasmosis; mucosal or invasive Candida infections; and coccidioidomycosis).

Flucytosine prevents the manufacture of nucleic acids and proteins and is used particularly in the treatment of candida and cryptococcus. Griseofulvin prevents cell division and is used in cutaneous and nail infections.

Fosmanogepix, ibrexafungerp, olorofim, rezafungin, and opelconazole are newer antifungal agents that are being investigated for effectiveness. Opelconazole can be delivered by inhalation. [18]

 

Specific fungal organisms

Candida auris [19, 20]

C. auris can produce an invasive candidiasis which is associated with a high mortality (29-53%). Due to its increasing resistance profile, it has already produced several hospital outbreaks. It is intrinsically resistant to most available antifungals (eg 87-100% resistance to fluconazole) and some strains are pan-resistant. However, it remains susceptible to amphotericin B (8-35% resistance) and echinocandins (8% resistance).

Preventive measures are not well established as it is generally thermoresistant and also partially resistant to commonly use disinfectants. It may resist elimination from clinical environments by forming biofilms

Candida albicans [21, 22]

Although Candida albicans is a common fungal pathogen which can be part of the healthy human microbiome, it is associated with infections of the mucosae (thrush) and invasive candidiasis in the immunocompromised and the critically ill. Antifungal resistance has remained low. Invasive candidiasis can have a mortality of 20% to 50%. Identification of candidiasis can be difficult, especially if the disease is deep seated. Positive blood culture rate has been recorded as less than 10%. Candidiasis can be associated with blindness, and so urgent ophthalmological assessment is required.

Candida tropicalis [23]

Candida tropicalis is the second most common cause of candidaemia in South America. It forms a robust biofilm, excretes lytic enzymes and has a particular affinity for buccal mucosa. Mortality ranges from 26% (children) to 60% (adults). It is treated with echinocandins.

Candida parapsilosis [24, 25]

C. parapsilosis is not an obligate human pathogen. However, it can form biofilm on indwelling cannulae, and is of particular concern on neonatal ICU. It is treated with echinocandins. Invasive disease has a mortality of 25-40%

Aspergillus fumigatus [26]

A. fumigatus is the cause of aspergillosis in humans. Aspergillosis presents with a range of symptoms, from allergic type reactions to invasive disease. It is usually contracted through the inhalation of spores. Aspergillosis primarily affects the lungs, but can spread to organs and cavities such as the brain and nasal sinuses.

Azole-resistant invasive aspergillosis is a life-threatening disease with very high mortality, which has developed following the widespread use of azoles in the environment.

Cryptococcus neoformans [27]

Cryptococcosis is widespread throughout the general environment. It is contracted through the inhalation of spores, but does not cause infection in healthy individuals. Invasive cryptococcal disease, can infect the CNS, and carries a mortality of 40-60%. Prophylactic and pre-emptive therapy in the highest-risk groups significantly reduces the incidence of cryptococcal meningitis. Localized cryptococcosis can be treated with fluconazole, while severe and disseminated cases are treated with amphotericin B in combination with flucytosine followed by step-down to fluconazole.

Scedosporium spp. [28]

Scedosporium spp. can infect humans to cause scedosporiosis, an invasive disease with a mortality greater than 40%. It is typically prevalent in those with haematological malignancy, or those who have experienced near drowning.

Antifungal resistance is high. Voriconazole is typically the most active antifungal against these species.

Lomentospora prolificans (formally Scedosporium prolificans) [29, 30]

This can cause invasive lomentosporiosis in immunocompromised patients, which is associated with a high mortality rate. Multiple antifungal agents are used due to the high chance of resistance.

Coccidioides spp. [31]

Coccidioides spp. are virulent fungal pathogens, acquired by inhalation of spores. The symptoms of coccidiomycosis range from viral-type symptoms to invasive disease. Lifelong treatment may be required. Infection can be treated by a variety of antifungal agents, although resistance is of concern

Pichia kudriavzeveii (also known as Candida krusei) [32, 33]

P.kudriavzeveii can cause mucosal infections and invasive candidiasis. It is increasingly used in the food and biotechnology industries, particularly in promoting fermentation, the processing of coffee and cocoa beans and for its probiotic applications.

Cryptococcus gattii [34]

C. gattii is traditionally described in tropical and subtropical areas, although it can adapt to different temperate settings. It can cause lung and CNS infections. Invasive disease carries a 10-25% mortality. Antifungal treatment may need to be prolonged.

Talaromyces marneffei [35]

The systemic illness associated with T.marneffei is called penicilliosis.

Recommended antifungals are currently unavailable in many countries.

Pneumocystis jirovecii (formally Pneumocystis carinii) [36]

P. jirovecii is an opportunistic fungal pathogen which can be acquired by atmospheric person-to-person spread. Resulting pneumonia (PJP/PCP) has a mortality which can be in excess of 60% if ventilatory support is required. Treatment for a presumed PJP should be started when infection is suspected in patients who have appropriate risk factors, and not be delayed to await diagnostic measures. PJP is usually treated with cotrimoxazole. Antifungal resistance is currently unknown, but agents may be unavailable in some countries.

Paracoccidioides spp. [37]

This is particularly prevalent in South America, particularly Brazil

Paracoccidioidomycosis is a life-threatening disease with medium mortality despite antifungal therapy particularly prevalent in South America. Death can be caused by adrenal involvement. Current antifungal options are cotrimoxazole, triazoles, and amphotericin B.

 

Conclusion

There is growing concern about the role of fungal pathogens in human illness, and resistance is becoming an increasing concern. A high level of suspicion, coupled with appropriate antifungal stewardship and microbiological advice, is the key to management.

 

References

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Author

James Watts
BSc MBChB FRCA FFICM RCPathME
Consultant in Anaesthesia and Critical Care Medicine
East Lancashire NHS University Hospitals trust

Image: Computer image of Candida auris. Source: Canva