From Aspergillus to antifungal resistance – an interview with Cornelia Lass-Flörl

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In line with our focus this month on fungal infections, we spoke to Cornelia Lass-Flörl from the Innsbruck Medical University (Austria) who has a special interest in the epidemiology, diagnosis, prevention and therapy of fungal infections.

In this interview, she talks about her research as part of three exciting programs, and highlights the necessity of fungal research. Find out more in our interview below.

First, could you introduce yourself and tell us a bit about your career to date?

I graduated from the Faculty of Medicine at Innsbruck Medical University (Austria) in 1986. Since then I have specialized in the field of medical microbiology, focusing on fungal infections in immunocompromised patients. My research interests include epidemiology, diagnosis, prevention and therapy of fungal infections and antifungal susceptibility testing.

“My research interests include epidemiology, diagnosis, prevention and therapy of fungal infections and antifungal susceptibility testing.”

Currently, I am chair of EFISG (European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Fungal Infection Study Group) and coordinator of the Aspergillus terreus Working Group of ISHAM (International Society for Human and Animal Mycology); in addition, I am member of several international committees, including the ESCMID Subcommittee on Antifungal Susceptibility Testing and the European Committee for Antimicrobial Susceptibility Testing. Previously, I was a board member of the European Confederation of Medical Mycology, and was Head of the Antifungal Chemotherapy Section of the Paul Ehrlich Society of Chemotherapy.

Could you describe your current research projects?

Presently, I focus on three main research topics, covering Candida, Mucorales and Aspergillus. First, I am part of the translational Marie Curie research training network OPATHY (From Omics to Patient: Improving Diagnostics of Pathogenic Yeasts), in which we explore the potential of next-generation high-throughput technologies, including genomics, transcriptomics and proteomics, and study the host–pathogen interactions of yeasts that cause disease to humans (e.g. Candida and Cryptococcus sp.). We are also hoping to develop new diagnostic tools to monitor yeast infections in the clinic. In addition, we aim to investigate the resistance mechanisms of three rare, but emerging yeasts – Candida rugosa species complex, C. inconspicua, and C. ciferrii.

“We aim to investigate the resistance mechanisms of three rare, but emerging yeasts – Candida rugosa species complex, C. inconspicua, and C. ciferrii.”

Second, within CD Fungus (Christian Doppler Laboratory for Invasive Fungal Infections) we deal with the following three main research questions: How to best find, treat and prevent infections due to Mucorales (MM)? Tackling these key questions requires 1) recognizing MM as such, 2) identification of the source and type of infection, 3) identification of the pathogen, 4) an understanding of the underlying pathomechanisms, 5) initiation of early, targeted treatment and 6) provision of a clean and safe hospital environment. CD Fungus will advance our understanding of fungal pathology, improve diagnosis and treatment of MM and enhance patients’ outcome and safety in terms of prevention of nosocomial and hospital-associated infections.

Finally, within HOROS (Doctoral programme of excellence host response in opportunistic infections) we have setup an in vitro, perfused, 3D human lung-tissue model to study respiratory tract infections in an environment as close as possible to human pathophysiology that also simulates as realistically as possible the dynamic and complex nature of biological responses. The tasks are to evaluate 1) the control of conidial germination and hyphal elongation, 2) fungal invasion of the lung tissues, 3) the kinetics of cytokine and biomarker release, 4) immune cell effects and 5) inflammatory response of the epithelia in the presence of Aspergillus and other fungal pathogens.

In addition, we are interested in delineating the mechanism of microbial pathogenesis under biological agents and immunosuppressants. Here, we aim to understand how such immune-modulating drugs interfere with the immune system and host–pathogen interactions. In vivo and various in vitro cellular models will be applied; we will use Candida and Aspergillus species as model organisms, as well as intracellular and extracellular bacterial species.

Why do you feel fungal infections are a research are of unmet need?

“Invasive fungal infections are a significant health problem in immunocompromised patients”

Invasive fungal infections are a significant health problem in immunocompromised patients; they are exceptionally rare in those with apparently normal immune systems. The clinical manifestations vary and may range from colonization to invasive infection. Early diagnosis is difficult to obtain and treatment is challenging as the number of available antifungals is limited and further complications include toxicity, drug interactions and the emergence of drug resistance. The death rate varies between 30% and 90% in immunosupressed patients – at risk are individuals with hematological malignancies, undergoing solid-organ and hematopoietic stem cell transplantation or suffering from any immunodeficiency.

Severity and pattern of fungal diseases are usually directed by the interplay of the pathogen and host immunity. For successful infection, fungi adapt to hosts’ stressors and evade hosts’ immunity; any failure to restore host immunity leads to worse outcomes. Several risk factors are well known (e.g., neutropenia), however, the shift to new patient populations such as Intensive Care Unit patients is unclear. A better understanding of fungus and host cell interactions is essential for the development of safe and successful management strategies.

Patient outcome of fungal infection relies significantly on diagnosis – what are the current technical advances occurring in diagnostic mycology?

Diagnosing fungal infections is a challenge, particularly in the immunocompromised host. Signs and symptoms are nonspecific, colonization is difficult to distinguish from invasive disease, blood cultures are commonly negative and patients are often unable to undergo invasive diagnostic procedures. Culture and microscopic examination remain the ’gold standard’ but are insensitive. Antigen assays such as the galactomannan and glucan detection systems are frequently used, yet these tests vary in sensitivity and specificity depending on the patient population involved. Various new molecular-based assays are coming up, however, most of them are not yet clinically validated.

“Various new molecular-based assays are coming up, however, most of them are not yet clinically validated.”

Presently it seems that the T2MR technology is outstanding; latest data demonstrate that this technology is highly sensitive, specific, simple and fast; it takes between three and five hours to achieve results. Promising results are provided by the detection of IL-17, a cytokine which is produced by a subset of CD4+ T helper cells. IL-17-producing cells were found in healthy individuals exposed to C. albicans.

Is there increasing concern around hospital-acquired fungal infections, for example, with the rise of resistance to antifungals?

Three classes of antifungal agents are available for the treatment of aspergillosis including polyenes, azoles and echinocandins. Appropriate therapy depends on the host’s immune status, organ function, prior therapies and species included. Voriconazole (VCZ) and posaconazole (PCZ) are widely used for the management of Aspergillus-related infections. VCZ is the drug of choice as first-line treatment for invasive aspergillosis followed by liposomal amphotericin B (L-AMB). PCZ and the echinocandins are preserved for patients who are refractory to or intolerant of primary antifungal therapy (salvage treatment). PCZ is recommended for prophylaxis against fungal infections in patients at risk. PCZ and VRZ are orally available, which is essential for outpatient management. Alarmingly, triazole resistance and pan-azole resistance in Aspergillus species has been reported recently. Case series suggest poor outcome in patients with documented infections due to azole-resistant strains.

Currently there are no clinical randomized trials available showing how to best treat azole-resistant aspergillosis.

Currently there are no clinical randomized trials available showing how to best treat azole-resistant aspergillosis. The current practice suggests that L-AMB or a combination of high dosing VCZ or PCZ with an echinocandin may be effective. In Austria, it seems that the problem of azole-resistance in A. fumigatus does not currently exist. However, we face azole-resistance in Candida species, which is a clinical threat.

Finally, what research do you think needs to be done in the next 5–10 years in this field?

Of particular concern of invasive fungal infections is the high rate of mortality, which may exceed 50% despite the availability of adequate drugs. Early recognition and diagnosis of fungal infections is a key issue for improved patient management.

Early recognition and diagnosis of fungal infections is a key issue for improved patient management.

This situation forces us to tackle three key issues: 1) we need faster and more sensitive diagnostic tests, leading to early diagnosis, hence improving patient management. The development of new molecular based methods offers good perspectives. 2) We need safer and more effective antifungal drugs. The number of available antifungals is limited and drugs differ from their spectrum of activity, route of administration, and bioavailability in target tissues. Further complications include toxicity, drug interactions and the emergence of drug resistance. 3) we need a better understanding how to prevent fungal infections. Lung exposure to Aspergillus species may translate into invasive infections in individuals with impaired immune functions. The use of clean (fungus free) rooms in hospitals reduced cases of invasive aspergillosis, yet did not solve the problem as a whole. Hence more studies are needed to define patients at risk and to understand which measures are helpful in which patient population for prevention of fungal infections.

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