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New Assays to Detect Disseminated Fungal Infections

Michael S. Singer, MD, PhD
Contributing Editor
Harvard Medical School

The yeast Candida and mold Aspergillus represent two of the most important classes of fungi in clinical medicine. They live in virtually every environment, and hospitals are no exception. Perhaps they are best known as causes of vaginitis (Candida) and pulmonary hypersensitivity (Aspergillus). Healthy hosts suffer from these localized conditions, but by virtue of intact physical barriers and active immune surveillance, do not develop disseminated infections. For susceptible patients, however, disseminated Candida and Aspergillus are common concerns. These multi-system infections remain difficult to diagnose and frequently end in death, with mortality rates such as 50% for disseminated candidiasis. As opportunistic infections, these fungi show an affinity for the critically ill, for example in the setting of immunosuppression, chemotherapy, transplantation, hyperalimentation, burns, and ulcers. With advances in critical care, oncology, and transplant medicine, more and more patients enter the ranks of those susceptible to disseminated disease.

With the advent of medications such as voriconazole, liposomal amphotericin, intravenous itraconazole, and caspofungin, treatment can be effective if instituted early. This has placed renewed emphasis on the need for early diagnosis of disseminated Candida and Aspergillus. Unless a specific nidus of infection is suspected (for example, a pulmonary Aspergillus lesion), a mainstay of diagnosis is blood cultures, which have suboptimal speed and sensitivity (estimated at 50% in some series). Aspergillus, which is usually acquired by the airborne route, can be identified microscopically from bronchoscopy samples, but sensitivity is still only 50%. Traditionally, clinicians have been forced to start empiric antifungal therapy in response to any unexpla ined fever or shock in susceptible patients. It is not uncommon for a disseminated Aspergillus infection to be discovered only at autopsy. Fortunately, a number of new assays offer solutions to these problems.

Fungitell, manufactured by Associates of Cape Cod Incorporated, is a reliable serum-based assay that takes 40 minutes to run. A key feature of this test is that it does not require culture. It is an enzymatic assay for (1,3)-beta-D glucan, a unique component of the fungal cell wall. Glucan is found in a number of medically important fungi such as Candida, Aspergillus, Fusarium, Acremonium, and Saccharomyces. The molecular basis for the test is the Limulus (horseshoe crab) coagulation cascade, which glucan readily activates. Fungitell is prepared from lysed amebocytes (crab blood cells), which are treated to remove the factor C (lipopolysaccharide-dependent) pathway and restrict the assay to the factor G (glucan-dependent) pathway. The pathway activates a clotting enzyme that cleaves p-nitroaniline from a chromogenic peptide substrate. This in turn allows photometric readout. The entire test can be carried out with standard laboratory equipment. A related assay, Glucatell, is available for non-diagnostic purposes, for example, to test for fungal contamination in buildings, water supplies, or pharmaceutical lots.

Other tests provide the ability to detect particular fungi. Platelia Aspergillus EIA, manufactured by Bio-Rad Laboratories, is a serum immunoassay for galactomannan, a specific component of the Aspergillus cell wall. Galactomannan is recognized by a specific rat antibody, which then allows enzyme-linked photometric readout. Like Fungitell, the test is independent of culture and supports turnaround time of about 3 hours. It is supplied on 96-well sandwich microplates and runs on standard equipment.

Clinical trials in immunosuppressed patients have shown that bo th Fungitell and Platelia Aspergillus EIA have excellent test characteristics for invasive infections. For detection of Candida, Fungitell has demonstrated a negative predictive value of 100% and a favorable positive predictive value when serial assays are performed. For detection of Aspergillus, a head-to-head comparison of the two products showed similar accuracy, with positive predictive value of 70% and negative predictive value of 96%.

Syscan3, made by Rockeby Biomed, is another ELISA test for host antibodies (IgG) to Candida. It detects all clinically important Candidal types except C. krusei. It is supplied as 96-well microplates coated with purified Candidal antigen. The test has a turnaround time of 3 hours, with enzyme-linked readout achieved by an anti-IgG antibody. A trial has been conducted on invasive candidiasis. For immunocompetent hosts, positive predictive value was 62% and negative predictive value 84%. Perhaps because Syscan3 depends on the host immune response to create detectable antibodies, the test proved less sensitive for immunocompromised hosts, with a positive predictive value of 1.7%. It nevertheless demonstrated a negative predictive value of 93% in this sample. The results imply that Syscan 3 is relatively useful to rule out disseminated candidiasis.

PCR assays will soon be available for Candida and Aspergillus. And lest it seem difficult to select one of these new assays, the literature has already shown that a combination of assays can yield even better accuracy.

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