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Lille Researchers Use MALDI Mass Spec for Early Detection of Fungal Infections


NEW YORK (GenomeWeb) – Researchers from the University of Lille have developed a MALDI mass spec-based method for the early diagnosis of fungal infections.

Described in a study published this month in the Journal of Clinical Microbiology, the method relies on detection of a fungal disaccharide in patient serum. In a comparison of the assay to existing fungal diagnostics, researchers found it showed similar performance while providing additional information that could prove useful in early detection of infections.

The scientists have patented the method and are now looking to several large life sciences firms for help in further developing it and bringing it to market, Daniel Poulain, a University of Lille researcher and senior author on the JCM study, told GenomeWeb.

Fungal infections like invasive candidiasis and aspergillosis are a challenging clinical problem due in part to the difficulty of making an early diagnosis. This difficulty leads to high morbidity rates, particularly in immunocompromised patients. It also leads physicians to overprescribe antifungal drugs, which results in significant costs to healthcare systems.

Conventional microbiology tests require culturing of fungi from patients for diagnoses, a process that is time consuming and often unsuccessful, Poulain said. Because of this many scientists and microbiology firms are exploring methods for detecting infection directly from patient samples like serum.

Many such tests are immunoassays to molecules specifically expressed by fungi or to patient antibodies expressed in response to infection, Poulain said. He noted that his lab has collaborated with companies including Bio-Rad on ELISA-based fungal infection tests. However, he said that he believes mass spectrometry is one of the more promising methods for future test development.

"I really believe that this is the future for [fungal] diagnosis," he said. "Because you have [with mass spec] really precise identification of the [target] molecule, while with most of the biochemical tests you have an idea but not a precise identification."

Additionally, mass spec allows for easier measurement of multiple markers simultaneously, which Poulain said could improve test performance.

MALDI mass spec has in recent years carved out a significant role in microbiology with Bruker's MALDI Biotyper and BioMérieux's Vitek MS systems becoming commonly used for identification of microorganisms in both research and clinical environments. Both platforms have libraries for fungal identification, but they require culturing of isolates.

Poulain said he believed that the next goal for mass spec-based methods would be to make identifications directly from samples like serum, as he and his colleagues did in the JCM study.

"Up until now the mass spectrometry has been applied to the identification of isolates," he said. "But I think the next step will be serum biomarkers, because it saves a lot of time."

"And this probably won't be restricted to fungi," he added. "You can probably also apply it to other infectious agents."

Indeed, in previous interviews, microbiologists including Nathan Ledeboer, medical director for the clinical microbiology and molecular diagnostics laboratories at the Medical College of Wisconsin, and Susan Butler-Wu, associate professor of clinical pathology at the University of Southern California, cited direct identification of pathogens from patient samples as one of the key areas of interest in clinical microbiology.

"One of the things we are all talking about right now is direct identification of pathogens from clinical specimens using mass spec," Butler-Wu told GenomeWeb last year.

One technology that has shown promise in this regard is Waters' rapid evaporative ionization mass spectrometry (REIMS) platform, which Zoltan Takats, an Imperial College London researcher and developer of the technology, has used to identify bacteria directly from human colorectal tissue samples. MALDI-based methods would be particularly convenient, though, given that large numbers of microbiology labs are already outfitted with such devices in the form of Bruker's Biotyper or BioMérieux Vitek MS systems.

A key issue with regard to direct identification of microorganisms is establishing the most suitable markers. In the case of the REIMS work, Takats and his team used lipidomic markers. Poulain said he believed glycans could prove effective markers, at least for diagnosing fungal infections.

These glycans are components of fungi cell walls and are the targets of existing immunoassays used for direct detection of fungal infections. To effectively detect these molecules using MALDI mass spec, Poulain and his colleagues developed a sample prep and enrichment protocol they published in a 2015 paper in Clinical Microbiology and Infection. They also in that paper presented their glycan marker, a disaccharide present at m/z 365.

In the CMI study the researchers investigated the disaccharide as a marker for Candida, but in the recent JCM paper they also tested its performance in diagnosing aspergillosis and mucormycosis. Looking at a set of 48 patients (23 with candidiasis, 15 with aspergillosis, and 10 with mucormycosis) and 49 controls, they compared the performance of their MALDI method, which they termed MS-DS, to that of Bio-Rad's Platelia, an ELISA-based test that detects Aspergillus by measuring circulating galactomannan and Candida by measuring mannan; and Associates of Cape Cod's Fungitell, an immunoassay that measures levels of (1-3)-ß-D-glucan to diagnose organisms including Candida and Aspergillus.

For Candida, the tests performed with sensitivity and specificity of 62 percent and 84 percent for MS-DS, 82 percent and 60 percent for Fungitell, and 33 percent and 94 percent for Platelia. For Aspergillus performance was 83 percent and 81 percent for MS-DS, 62 percent and 95 percent for Fungitell, and 62 percent and 100 percent for Platelia. Additionally, nine out of 10 mucormycosis patients tested positive with the MS-DS assay.

The results, the authors noted, suggest that the MS-DS test could serve as a useful complement to the Platelia and Fungitell assays and could fill the existing gap in serological testing for mucormycosis.

Poulain also suggested the MS-DS test could be useful in guiding therapy. Clinicians, could, for instance, follow the levels of the marker to see whether or not an antifungal was working and to help decide when a course of treatment was complete.