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IDCM CME Issue 1-1: Fungal Diagnostics: A Review of Serum (1,3)-beta-D-glucan
Natasha Chida, MD, MSPH
Fungal Diagnostics: A Review of Serum (1,3)-beta-D-glucan
While invasive fungal infections (IFI) affect many populations, they are more likely to occur in immune compromised persons than in the general population.1 Epidemiologic studies show Candida spp. and Aspergillus spp. are the most frequently encountered IFIs in immune compromised persons.2 Given that IFIs are associated with high mortality among persons who have hematologic diseases, are transplant recipients, are critically ill, or who receive chemotherapy, it is important they be promptly diagnosed and treated.1
Unfortunately, diagnosing IFIs is often complicated by factors such as low clinical suspicion and nonspecific clinical findings, as well as suboptimal diagnostics that have low sensitivity (such as antibody-based tests) delayed results, or are difficult to obtain in ill patients (histopathology).3 Even culture, which is often the gold standard in infectious disease diagnosis, is plagued by variable sensitivity for IFI. For example, in persons who are immune compromised, the yield of bronchoalveolar lavage culture for invasive mold infections is 20-50% (relatively low).4 In addition, as the sensitivity of diagnostics is often dependent on the burden of organisms and the host, the yield of these tests can vary significantly. In response to these challenges, focus has been given to the development of alternative diagnostics for IFIs. This ID Clinical Minute reviews the 1,3-b-D-glucan (BDG) tests, which became commercially available during the last decade.
What is BDG? BDG is a polysaccharide found in the cell wall of many pathogenic fungi. Currently 4 assays are commercially available: Fungitell, Fungitec-G, Wako, and Maruha.5 Of these tests, only Fungitell has received US Food and Drug Administration (FDA) approval.
BDG tests rely on factor G, a serine protease zymogen that is extracted from amebocytes of horseshoe crab species. When a BDG-containing serum sample is combined with factor G it activates the factor, which initiates a coagulation cascade. BDG test results are the measurement of this reaction.2
What pathogens do BDG tests detect? BDG is found in Candida spp., Aspergillus spp., Fusarium spp., Pneumocystis jirovecii (PCP), Coccidioides immitis, Histoplasma capsulatum, Sporothrix schenckii, Trichosporon spp., and other fungi. Fungi that do not have significant amounts of BDG in their cell walls include Mucorales spp. (such as Mucor and Rhizopus), Cryptococcus spp., and Blastomyces dermatidis (although this organism can produce a small amount of BDG in the yeast phase).4 These organisms cannot be detected by BDG tests.
How well do BDG tests perform? Performance of the BDG tests, like many indirect tests, is dependent on the prevalence of the infection in question, the burden of disease, and the host. In addition, performance varies according to the organism involved.
Of note, when the performances of BDG tests are evaluated in systematic reviews and meta-analyses, the included studies evaluate different BDG tests. However, his should not significantly affect results, as individual studies have shown the diagnostic accuracy of the BDG tests is similar.
- Overall: In one meta-analysis of 16 studies, the performance of BDG tests was evaluated for IFI among 2979 patients; the pooled sensitivity was 77% and the specificity was 85%.2
- Hematologic malignancies: One systematic review and meta-analysis—which evaluated the performance of BDG tests in 1771 persons with hematologic malignancies and proven or probable IFI—found that 2 consecutive tests had a better diagnostic performance than a single test (odds ratio of 111.8 vs. 16.3 for two and one consecutive test, respectively).5 With one test the sensitivity was 62%; when 2 tests were used consecutively, the sensitivity and specificity were approximately 50% and 98% respectively.3-5 There is less data available on the performance of two tests versus one among patients who do not have hematologic malignancies.
- PCP: One systematic review and meta-analysis of the diagnostic accuracy of BDG tests for PCP analyzed 14 studies and found the sensitivity and specificity were approximately 95% and 86%, respectively.6 Of the 14 studies, two exclusively included HIV infected patients; the others were among patients with a mix of immune compromised states. In another systematic review and meta-analysis, the accuracy of BDG tests for PCP, invasive candidiasis, and invasive aspergillosis was evaluated. For PCP there were 12 studies; the pooled sensitivity and specificity were 96% and 84%, respectively.7
- Invasive candidiasis: In one study of 107 persons with known candidemia, the positive predictive value of BDG tests was 89%.1 In the same systematic review noted above for PCP, on subgroup analysis for invasive Candida infection the sensitivity and specificity of BDG tests was 81% for each.7
- Aspergillus spp: In terms of Aspergillus spp., in the same systematic review noted above for PCP and candidiasis, on subgroup analysis the sensitivity and specificity for invasive aspergillosis were 77% and 83%, respectively.7
How well do non-serologic BDG tests perform? BDG tests performed in bronchoscopic alveolar lavage (BAL) should theoretically be of use, given that the site of mold IFIs is often the lungs. However, a meta-analysis of 6 studies evaluating the utility of BAL BDG found a pooled sensitivity of 52% and a pooled specificity of 58%. Thus, BAL BDG is not a high yield diagnostic test at this time.8
Can anything interfere with BDG test results? False positives are known to occur in the following settings:
- The use of cellulose membranes (such as those used in hemodialysis; this is not seen with synthetic materials)9
- Exposure to glucan-containing gauze
- Products delivered through glucan-containing filters (such as blood or albumin)
- IV amoxicillin/clavulanic acid (note that piperacillin/tazobactam was previously implicated as a cause of false positive BDG test results, but new formulations have apparently eliminated this problem)4
- Some studies have found bacteremia with certain organisms, such as Pseudomonas aeurginosa, Escherichia coli, and certain Streptococcus spp., can be associated with false positive BDG results. However, a more recent study questions if bacteremias were truly the cause of the positive result in these scenarios10-11
In terms of false negatives, high triglycerides, hemolyzed hemoglobin, and bilirubin can lead to a false negative assay.11
Bottom line: The diagnostic accuracy of BDG tests is high for PCP and moderate for IFI. BDG tests are valuable diagnostic tools, but results must be interpreted in the context of individual clinical situations.
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- Arvanitis M, et al. Molecular and nonmolecular diagnostic methods for invasive fungal infections. Clin Microbiol Rev. 2014;27(3):490-526. PMID 24982319.
- Karageorgopoulos DE, et al. b-D-glucan assay for the diagnosis of invasive fungal infections: a meta-analysis. Clin Infect Dis. 2011;52(6):750-70. PMID: 21367728.
- Falci DR, Stadnik CMB, Pasqualotto AC. A review of diagnostic methods for invasive fungal diseases: challenges and perspectives. Infect Dis Ther. 2017;6(2):213-223. PMID: 28357708.
- Lamoth F, Calandra T. Early diagnosis of invasive mould infections and disease. J Antimicrob Chemother. 2017;72(suppl_1):i19-i28. PMID: 28355464.
- Lamoth F, et al. β-glucan antigenemia assay for the diagnosis of invasive fungal infections in patients with hematological malignancies: a systematic review and meta-analysis of cohort studies from the Third European Conference on Infections in Leukemia (ECIL-3). Clin Infect Dis. 2012;54(5):633-43. PMID: 22198786.
- Karageorgopoulos DE, et al. Accuracy of b-D-glucan for the diagnosis of Pneumocystis jirovecii pneumonia: a meta-analysis. Clin Microbiol Infect. 2013;19(1):39-49. PMID: 22329494
- Onishi A, et al. Diagnostic accuracy of serum 1,3-D-glucan for pneumocystis jiroveci pneumonia, invasive candidiasis, and invasive aspergillosis: systematic review and meta-analysis. J Clin Microbiol. 2012; 50(1):7-15. PMID 22075593.
- Shi XY, et al. Diagnostic value of (1 /3)-b-D-glucan in bronchoalveolar lavage fluid for invasive fungal disease: A meta-analysis. Respir Med. 2016;117:48-53. PMID: 27492513.
- Prattes J, Schilcher G, Krause R. Reliability of serum 1,3-beta-D-glucan assay in patients undergoing renal replacement therapy: a review of the literature. Mycoses. 2015;58(1):4-9. PMID: 25339221.
- Mennink-Kersten MA, Ruegebrink D, Verweij PE. 2008. Pseudomonas aeruginosa as a cause of 1,3-beta-D-glucan assay reactivity. Clin Infect Dis. 46:1930–1931. PMID: 18540808.
- Tran T, Beal SG. Application of the 1,3-b-D-glucan (Fungitell) assay in the diagnosis of invasive fungal infections. Arch Pathol Lab Med. 2016;140(2):181-5. PMID: 26910223.