Serum (1 →3) β-D-glucan Assay for Diagnosis of Invasive Fungal Infection
Abstract & Commentary
By Dean L. Winslow, MD, FACP, FIDSA, Chief, Division of AIDS Medicine, Santa Clara Valley Medical Center; Clinical Professor, Stanford University School of Medicine, Section Manager, HIV, is Associate Editor for Infectious Disease Alert
Synopsis: A retrospective study was performed on 279 patients to evaluate the performance of a (1 →3)-β-D-glucan (BG) assay for the diagnosis of invasive fungal infection. 117 patients had probable or proven invasive fungal infection (IFI) by European Organization for Research and Treatment of Cancer (EORTC) criteria, 40 blood donors, and 122 hospitalized patients at risk for IFI, but in whom, IFI had not been diagnosed. For overall IFI diagnosis, the BG assay had 77.8% sensitivity, with specificity of 92.5% in blood donors and 70.5% specificity in patients at risk for IFI. The BG assay demonstrated 100% sensitivity in the 20 patients who had Pneumocystis jiroveci pneumonia (PCP).
Source: Persat F, et al. Contribution of the (1'3)-B-D-glucan assay for diagnosis of invasive fungal infections. J Clin Microbiol. 2008; 46:1009-1013.
For this study, 279 patients from five groups (including 70 with proven or probable invasive pulmonary aspergillosis, 27 patients with blood cultures positive for a fungal pathogen, and 20 with PCP) were evaluated. BG levels were measured with the Fungitell test kit. Using a cutoff of ≥ 80 pg/mL, the assay showed a sensitivity/specificity of 77.8%/92.5% for diagnosis of IFI compared to blood donors. When using total patients at risk as a control, sensitivity/specificity was 77.8%/70.5%. For diagnosis of pulmonary aspergillosis vs patients at risk the sensitivity/specificity was 68.6%/73.0%. For fungemia vs patients at risk the sensitivity/specificity was 85.2%/64.4%. All 20 patients with PCP had positive BG titers.
Commentary
Antemortem diagnosis of invasive fungal infection remains problematic. While the use of antifungal prophylaxis has likely reduced the frequency of yeast infections, IFI due to molds including Aspergillus, Zygomycetes, Fusarium species, and others remains problematic. Due to the high mortality rate associated with these latter infections, despite appropriate therapy and the toxicity of many antimicrobials used to treat these infections (particularly amphotericin), is high, more sensitive diagnostic methods are needed. The use of high-resolution CT scanning in febrile neutropenic patients coupled with presumptive therapy in patients with suspicious lesions on chest CT has been somewhat helpful, but this strategy also lacks sensitivity and specificity. Enzyme immunoassays to detect Aspergillus galactomannan and Candida mannan antigens have been developed but have lacked sensitivity in most studies and suffer from frequent false positive results in the presence of certain drugs, most importantly piperacillin/tazobactam.
Several colorimetric assays using horseshoe crab (Limulus or Tachypleus species) amebocyte lysate have been developed. The Fungitell assay developed by Associates of Cape Cod has received FDA marketing clearance as a 510(k) in vitro diagnostic device. In another paper published earlier this year, the Seikagaku Corporation's Fungitec G-test MK also displayed excellent sensitivity (78%) and specificity (98.4%) using a cutoff value of 80 pg/mL in a large autopsy series.1 Using this latter assay and a lower cutoff value of 30 pg/mL, sensitivity increased to 95.1% but specificity fell to 85.7%. An in vitro comparison of four commercially available kits using spiked serum samples demonstrated that the FDA-cleared Fungitell assay was the least sensitive, with a measurable range of 31.25-500 pg/mL, while the other three assays demonstrated lower limits of sensitivity ranging from 1.2-6 pg/mL.1 A small in vivo study in rabbits comparing the Wako-WB003 and the Fungitec G BG assays demonstrated weak interassay correlation and greater sensitivity of the Fungitec G assay.2
It is unclear what the "best" assay for diagnosis of IFI is in humans due to the lack of comparative data in humans. One interesting fungal disease where absolute sensitivity of the BG assay appears to be less important than it is with invasive mold infections is Pneumocystis pneumonia. In the 20 patients with PCP studied in the Persat paper, the lowest BG level was 103 pg/mL and the majority of cases had BG levels of > 500 pg/mL with the Fungitell assay. A recent letter to CID reported three patients with clinical findings consistent with PCP but with negative microscopic examination results all had BG levels > 500 pg/mL.3 This strongly suggests that BG assays will be a useful tool in the diagnosis of invasive fungal infections and have particular sensitivity in the diagnosis of Pneumocystis infection.
References
- Obayashi T, et al. Reappraisal of the serum (1'3)-B-D-glucan assay for the diagnosis of invasive fungal infections- a study based on autopsy cases from 6 years. Clin Infect Dis. 2008;46:1864-1870.
- Hossain MA, et al. Comparison between Wako-WB003 and Fungitec G tests for detection of (1'3)-beta-D-glucan in systemic mycosis. J Clin Lab Anal. 1997;11:73-77.
- Pisculi ML, Sax PE. Use of a serum B-glucan assay for diagnosis of HIV-related Pneumocystis jiroveci pneumonia in patients with negative microscopic examination results. Clin Infect Dis. 2008;46:1928-1930.
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