Accelerating Progress in Fungal Diagnostics
On August 31-September 1, 2021, CIFAR convened a virtual roundtable that brought together members of CIFAR’s Fungal Kingdom program with the Fungal Diagnostics Laboratories Consortium (FDLC) and other international experts in academia, clinical medicine and industry. The goal of the meeting was to discuss opportunities to accelerate progress in diagnostics to mitigate the rising threat that fungal infections pose to health and to advance research knowledge about the fungal kingdom. Through short presentations and facilitated discussion, this roundtable overviewed the current needs for improved diagnostics for fungal diseases, existing and promising approaches for diagnostic tests, and proposals for multi-centre collaboration to promote diagnostics development. This roundtable served as a starting point for sustained cross-sectoral conversation and collaboration to spur technological innovation as well as contribute to fundamental research.
- Academic, clinical and industry researchers investigating fungal diseases
- Clinical and government diagnostic laboratories responsible for patient care and public health surveillance
- Biomedical and biotechnology companies developing new fungal diagnostics
- Nonprofit foundations and government policymakers involved in science funding and public health policies
- Government regulators responsible for the oversight and approval of medical devices, including diagnostic tests
- There is a growing need for more and better fungal diagnostic tools. A number of factors are contributing to increasing incidence and burden of invasive fungal diseases or mycoses, including climate change (which may be contributing to increasing incidence of coccidioidomycosis, or Valley fever) and the growing number of people living with compromised or suppressed immune systems (e.g., as a result of treatment of, or improved survival with, diseases and conditions such as cancer, HIV/AIDS and organ transplants). Fungal diseases are also common as coinfections for other diseases, such as the mould infection aspergillosis in the lungs of COVID-19 patients, or as a result of dysbiosis (disruption of a person’s microbial communities) due to antibiotic use.
- An important emerging fungal pathogen is the multidrug-resistant strains of the yeast Candida auris, a significant threat in healthcare settings.
- Other infections in need of better diagnostic tools include cryptococcosis, mucormycosis and pneumocystosis.
- Early and accurate diagnosis is important for appropriate medical treatment, but diagnosis for fungal diseases is often intellectually and technically complex. Moreover, many fungal diseases are rare, resulting in less interest among medical and biotechnology companies in developing fungal diagnostic tools compared to viral and bacterial diseases. This rarity also makes it more difficult to accrue enough cases in the clinic to conduct clinical trials of sufficient statistical power. The lack of good diagnostic tools for many fungal diseases could also be leading to an underestimation of the true prevalence of such diseases, in turn disincentivizing investments.
- Key considerations for new diagnostic tools include their sensitivity, specificity, complexity (which affects cost and the need for training), and speed. Outside of low-resource settings, the tests do not necessarily have to be point-of-care only (in which case tests do not need to be sent to a laboratory for processing), but turnaround must be sufficiently rapid (on the order of hours) to minimize the use of inappropriate therapies by clinicians. The need for batching, where multiple samples have to be collected to run a single test, should also be reduced given the relatively rare incidence of individual mycoses.
- Diagnostic tests will also need to work with the high diversity of sample matrices (the types of material collected from the patient, which could include blood serum, plasma, urine, tissue extracts, airway aspirates, cerebrospinal fluid, etc), all of which could affect test performance in different ways.
- Fungal diagnostic methods include immunoassays for detecting specific fungal antigens (which could be proteins, metabolites or other cell components) using antibodies produced in animal models such as mice, as well as molecular tests, which use techniques such as polymerase chain reaction (PCR) or genetic sequencing to detect fungal nucleic acids (DNA or RNA). Another form of molecular diagnosis, using a technique called matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), works by detecting specific patterns or “mass spectra” obtained from a specimen’s entire biomolecular milieu.
- Beyond detecting the presence of specific types of pathogenic fungi, nucleic-acid based molecular diagnostics could allow for obtaining additional information such as specific genetic markers (e.g., to determine whether the fungus is resistant to certain antifungal drugs) or gene expression levels (which could provide information about how the fungus is behaving). By multiplexing the probe sets used in a single test, molecular diagnostics could also potentially be deployed as “universal” tests for multiple types of fungal, bacterial and other pathogens.
Priorities and Next Steps
- Currently, many labs develop their own tests, which makes it difficult to standardize or to push towards commercial development and regulatory approval. Multi-centre alpha-stage collaborations, conducted by a network of research and diagnostic labs and industry partners, could potentially recruit enough patients and collect enough samples to facilitate test development.
- Development of new tests requires samples for validation and verification. However, because fungal infections are rare, and often detected at the end of the diagnostic process after specimens are already depleted or discarded, it can be difficult to have enough fungal samples for test development. A shared biorepository could be established to collect samples as well as metadata from multiple partner labs and make these quickly and easily available when needed.
- In addition to biobanks, a networked tool evaluation platform that involves multiple centres but does not require the centralized collection of samples could also facilitate test development. The involvement of labs across North America, and potentially the world, would provide access to a larger number of cases (including reaching into non-”hotspot” locations), account for regional differences in patient population and pathogen type, and allow for more rapid evaluation of test performance. Having a single entity to manage all contracts for the network may also ease and incentivize participation by industry.
- Key questions that need to be tackled for successful collaboration include:
- Which diseases should the collaboration focus on? What specimens and metadata would be needed, and what are the storage and logistical challenges?
- Who will pay – governments (such as the US National Institutes of Health), nonprofit foundations (such as the Gates Foundation), or industry?
- What would incentivize competing companies to collaborate (and pay)?
- Will smaller centres participate, particularly if their expenses and workload may be increased?
- What are the legal, ethical, privacy and institutional hurdles to the sharing of samples and data between different centres – nationally and internationally?
- What support would be provided for clinicians at each centre, for example to coordinate specimen collection and shipping, given the potentially low case volume per centre?
- At what stage of development of multi-centre collaborations should regulators such as Health Canada or the US Food and Drug Administration be engaged?
- What lessons can be learned from existing initiatives such as the NIH-supported Aspergillus Technology Consortium (AsTeC), or the Institut Pasteur-FungiBank in France?
- Efforts to accelerate the development of fungal diagnostics could potentially tap into existing collaborative networks such as those addressing antimicrobial resistance, or the heightened interest in centralized or collaborative efforts for pandemic preparedness in the wake of COVID-19.
- Given that pets, farm animals and wildlife get a number of similar fungal infections as humans, clinical labs may also consider increasing collaboration with veterinary labs.
- David AuCoin, Professor and Chair, University of Nevada, Reno
- Esther Babady, Director, Clinical Microbiology Service, Memorial Sloan Kettering Cancer Center / Co-chair, FDLC
- Joan-Miquel Balada-Llasat, Director, Immunology, and Professor, Ohio State University Wexner Medical Center / Member, FDLC
- Sean Bauman, President and CEO, IMMY
- Amrita Bharat, Research Scientist and Head of Mycology and Molecular Enteric Antimicrobial Resistance, National Microbiology Laboratory, Public Health Agency of Canada / Member, FDLC
- David Blehert, Chief, Laboratory Sciences Branch, National Wildlife Health Center, United States Geological Survey / Fellow, Fungal Kingdom program, CIFAR
- Leah Cowen, Professor, Canada Research Chair in Microbial Genomics and Infectious Disease, and Associate Vice-President, Research, University of Toronto / Co-director, Fungal Kingdom program, CIFAR
- Christina Cuomo, Associate Director, Genomic Center for Infectious Disease, Senior Group Leader, Fungal Genomics Group, and Institute Scientist, the Broad Institute of MIT and Harvard / Fellow, Fungal Kingdom program, CIFAR
- David Denning, Professor, University of Manchester / Advisor, Fungal Kingdom program, CIFAR
- Tanis Dingle, Clinical Microbiologist, Alberta Precision Laboratories, and Assistant Professor, University of Alberta / Member, FDLC
- Philippe Dufresne, Head of Mycology Department, Laboratoire de santé publique du Québec / Member, FDLC
- Sherry Dunbar, Senior Director, Global Scientific Affairs, Luminex
- Iuliana Ene, Assistant Professor, Institut Pasteur / Azrieli Global Scholar, Fungal Kingdom program, CIFAR
- Malcolm Finkelman, Director, Clinical Development, Associates of Cape Cod, Inc.
- Aleeza Gerstein, Assistant Professor, University of Manitoba / Azrieli Global Scholar, Fungal Kingdom program, CIFAR
- Heather Glasgow, Clinical Microbiologist and Assistant Member Faculty, St. Jude Children’s Research Hospital / Member, FDLC
- Thomas Grys, Director, Clinical Microbiology Lab, and Associate Professor, Mayo Clinic / Member, FDLC
- Amanda Harrington, Director, Clinical Microbiology Laboratory, and Associate Professor, Loyola University Medical Center / Member, FDLC
- Joseph Heitman, Professor and Chair, Duke University School of Medicine / Co-director, Fungal Kingdom program, CIFAR
- Jennifer Johnson, Director, Clinical Microbiology, and Professor, University of Maryland Medical Center / Member, FDLC
- Bruce Klein, Professor, University of Wisconsin-Madison / Fellow, Fungal Kingdom program, CIFAR
- Thomas Kozel, Professor, University of Nevada, Reno
- Julianne Kus, Clinical Microbiologist, Public Health Ontario Laboratory / Member, FDLC
- Paige Larkin, Director, Molecular Microbiology, NorthShore University HealthSystem / Member, FDLC
- Shawn Lockhart, Senior Clinical Laboratory Advisor, Centers for Disease Control and Prevention / Co-chair, FDLC
- Paul Luethy, Associate Director, Clinical Microbiology Laboratory, and Assistant Professor, University of Maryland Medical Center / Member, FDLC
- Isabella Martin, Medical Director, Clinical Microbiology Laboratory, and Assistant Professor, Dartmouth-Hitchcock Medical Center / Member, FDLC
- Kaede Ota-Sullivan, Professor, Temple University / Member, FDLC
- Preeti Pancholi, Director, Clinical Microbiology, and Professor, Ohio State University Wexner Medical Center / Member, FDLC
- John Perfect, Chief, Division of Infectious Diseases, and Professor, Duke University School of Medicine / Member, FDLC
- Amir Seyedmousavi, Director, Mycology Diagnostics, and Senior Scientist, National Institutes of Health Clinical Center / Member, FDLC
- Rebecca Shapiro, Assistant Professor, University of Guelph / Azrieli Global Scholar, Fungal Kingdom program, CIFAR
- Don Sheppard, Director, McGill Interdisciplinary Initiative in Infection and Immunity, and Professor, McGill University / Fellow, Fungal Kingdom program, CIFAR
- Leal Sixto, Director, Clinical Microbiology, Fungal Reference Laboratory, and Assistant Professor, University of Alabama at Birmingham / Member, FDLC
- Michelle Tabb, Chief Scientific Officer, DiaSorin Molecular
- Paschalis Vergidis, Assistant Professor, Mayo Clinic / Member, FDLC
- Nathan Wiederhold, Director, Fungus Testing Laboratory, and Associate Professor, UT Health San Antonio / Member, FDLC
- Sean Zhang, Director, Clinical Mycology Laboratory, Johns Hopkins Medicine / Co-chair, FDLC
Threats Posed by the Fungal Kingdom to Humans, Wildlife, and Agriculture, by Matthew Fisher et al.
Recognition of Diagnostic Gaps for Laboratory Diagnosis of Fungal Diseases: Expert Opinion from the Fungal Diagnostics Laboratories Consortium (FDLC), by Sean Zhang et al.
Molecular diagnostics in medical mycology, by Brian Wickes & Nathan Wiederhold
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