|Year : 2023 | Volume
| Issue : 1 | Page : 1-7
Options appraisal of various β‒D‒glucan assay systems for a diagnostic microbiology laboratory
Shazia Parveen1, Sanjay Bhattacharya2
1 Faculty of Biotechnology and Biosciences, School of Medical Science and Technology, Indian Institute of Technology, Kharagpur; Department of Microbiology, Tata Medical Center, Kolkata, West Bengal, India
2 Department of Microbiology, Tata Medical Center, Kolkata, West Bengal, India
|Date of Submission||15-Dec-2022|
|Date of Decision||17-Feb-2023|
|Date of Acceptance||16-Mar-2023|
|Date of Web Publication||1-Jun-2023|
Department of Microbiology, Tata Medical Center, 14 Major Arterial Road, Newtown, Kolkata - 700 160, West Bengal
Source of Support: None, Conflict of Interest: None
Invasive fungal infections (IFIs) have become a substantial concern in immunocompromised cancer patients, diabetics, hematopoietic stem cell transplant and solid organ transplant recipients with significant morbidity and mortality, Amongst IFIs, Candida and Aspergillus continue to be the most frequently reported, along with Fusarium and Zygomycetes. The need for tissue samples and the time required for cultures and histological investigation has made diagnosing IFIs problematic in the past. The detection of IFIs non-invasively by measuring biological markers such as the galactomannan antigen and the fungal wall component (1-3)-β-D-Glucan (BDG) have emerged as excellent options. In view of multiple kits available for detection and quantification of the fungal wall component (1-3)-BDG, it becomes essential to perform the options appraisal to find out the best available test option for a microbiology laboratory. Our work focuses on comparing various (1-3)-BDG detection systems available in the market.
Keywords: (1-3)-β-D-Glucan, biomarker, immunocompromised, invasive fungal infection, options appraisal
|How to cite this article:|
Parveen S, Bhattacharya S. Options appraisal of various β‒D‒glucan assay systems for a diagnostic microbiology laboratory. J Acad Clin Microbiol 2023;25:1-7
|How to cite this URL:|
Parveen S, Bhattacharya S. Options appraisal of various β‒D‒glucan assay systems for a diagnostic microbiology laboratory. J Acad Clin Microbiol [serial online] 2023 [cited 2023 Nov 30];25:1-7. Available from: https://www.jacmjournal.org/text.asp?2023/25/1/1/378068
| Introduction|| |
About 1.5 million individuals die every year from fungal illnesses, with a prevalence of more than a billion people. Fungal disease-related mortality, at 1.5 million, is comparable to tuberculosis and >3 times that of malaria. According to recent estimates, there are over 10 million cases of fungal asthma and over 3 million cases of chronic pulmonary aspergillosis annually. It was reported in 2017 that Cryptococcal meningitis with around 223,100 cases/year worldwide exacerbates conditions such as HIV/AIDS. Other fungal infections such as invasive candidiasis (IC), invasive aspergillosis (IA) and fungal keratitis have the annual occurrence of approximately 700,000, 250,000 and 1 million, respectively. Despite the fact that most deaths from fungal diseases are preventable, they are still a neglected area by public health authorities. Reporting and notifications of fungal infections are not efficient in most of countries. In the USA, the reportable fungal infections vary by state and may include blastomycosis, coccidioidomycosis, histoplasmosis, candidiasis and fungal meningitis. Other health issues, such as asthma, diabetes, AIDS, cancer, organ transplantation and corticosteroid therapy, can result in serious fungal infections. Amongst all the fungal diseases, invasive fungal infections (IFIs) are a significant cause of morbidity and mortality. Infections such as COVID-associated mucormycosis, diabetes-associated mucormycosis and fungal asthma are pervasive amongst both immunocompetent and immunocompromised people but are more pre-dominant in patients suffering from HIV/AIDS, solid organ and hematopoietic stem cell transplant recipients and cancer patients, especially those receiving chemotherapy.,,,,,,, The following risk variables were identified as being strongly related with invasive fungal diseases (IFDs) across a number of studies: Acute Physiology and Chronic Health Evaluation II (APACHE II) or APACHE III score, complete parenteral feeding, fungal colonisation, renal replacement therapy, infection and/or sepsis, mechanical ventilation and diabetes. Early and precise diagnosis allows for timely antifungal treatment. Conditions such as neutropenia, HIV, chronic immunosuppression and administration of broad-spectrum antibiotics also increase the risk of IFI. Increased use of contaminated invasive devices such as central venous catheters and other medical equipment can also enhance the risk of infection. Amongst all the IFIs, IC and candidemia cause almost three-fourths of all IFIs amongst hospitalised patients worldwide, followed by cryptococcosis and aspergillosis. Candidemia is a condition when Candida disseminates through the blood to reach multiple organs such as the kidney, liver, spleen, myocardium, eye and brain. Patients with IFIs are usually hospitalised, which leads to high health care costs.
| Diagnosis of Invasive Fungal Infections|| |
IFIs must be diagnosed and managed as quickly as possible to minimise mortality. Fungal culture or histological investigation is usually required for confirmation of IFIs. However, a fungal culture takes at least 2–4 days, and histological examinations are challenging to perform in most cases, making it difficult to identify IFI in clinical practice. While these traditional microbiological and histological approaches still remain necessary for a precise diagnosis of invasive fungal illness, novel rapid diagnostic tools, such as serologic and genetic biomarkers, are now available. These novel diagnostic technologies allow for the early detection of IFD and a preventative treatment strategy, which could lead to better outcomes and lower toxicity. However, there are limitations to conventional and newer diagnostic methods. In a recently conducted study from Spain, to compare Candida detection from serum polymerase chain reaction (PCR) versus blood culture, the detection rates were found similar, but quality indices for serum PCR relative to blood culture were: Sensitivity 21.4%; specificity 91.9%; positive predictive value (PPV) 18.8%; negative predictive value (NPV) 93.1% and kappa index 0.125 (1 = complete agreement; 0-agreement no better than expected by chance).
| (1-3)-β-D-Glucan Antigen for Detection of Invasive Fungal Infections|| |
(1-3)-β-D-Glucan (BDG) is present in the cell wall of fungi (yeasts and moulds), algae, some bacteria and plants, where they strengthen and maintain the wall's mechanical integrity, as shown in [Figure 1]a. The backbone of (1-3)-BDG is made primarily of glucose monomers linked in a linear pattern by carbons 1 and 3 by a glycosidic bond with a beta conformation [Figure 1]b. The enzyme responsible for the formation of this polysaccharide backbone is called (1-3)-BDG synthase. Usually, the length of the polysaccharide backbone is 1500 glucose subunits, but within each chain, branching occurs with either a (1–4) or (1–6) glycosidic bond. The branching assignments vary greatly and are unique to each fungus species. (1-3)-BDG, in contrast to galactomannan, is found in most fungal species except Cryptococcus and the agents of mucormycosis. It is synthesised by the transport of glucose subunits to the plasma membrane, where they are then transported across the plasma membrane and organised by a linear (1–3) glycosidic bond. During an infection, small amounts are released into the bloodstream.
|Figure 1: (a) The localization of in fungal cell wall and (b) 1-3 β glycosidic linkage of (1-3)-β-D-Glucan|
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The Limulus reagent (limulus amoebocyte lysate [LAL]), which is generated from the extract of blood cells of the horseshoe crabs, is used as an in vitro diagnostic reagent for the detection of (1-3)-BDG. It reacts with both (1-3)-BDG and endotoxin. For specific detection of (1-3)-BDG in a serum sample endotoxin is inactivated by the use of a non-ionic detergent and polymyxin B. Most soluble beta-glucans are triple-helix and must be converted to single-strand forms before the beta-glucan LAL reaction which is done by exposing the serum sample to an alkaline reagent. In addition, the inactivation of serine proteases and serine protease inhibitors by alkaline treatment, both of which are naturally abundant in human serum, appears to minimise the risks of false-positive and false-negative results. The beta-glucan LAL reaction is started by single-strand beta-glucan binding to the alpha-subunit of factor G, activating its serine protease subunit after pre-treatment with the alkaline reagent. The pre-clotting enzyme is then converted to an activated clotting enzyme by activated factor G, after which the active clotting enzyme cleaves p-nitroanilide from a synthetic peptide. When connected to a peptide, the chromogen, p-nitroanilide, is colourless, but when cleaved from the synthetic peptide, it turns yellow, as shown in [Figure 2]. While the original LAL was predicated on detecting the endpoint of gel clot formation, the advanced beta-glucan LAL is a colourimetric assay with the end-point determined by measuring absorbance at 450 nm wavelength. Later, it was observed that serum samples have an inherent yellow colour that can influence the final absorbance (overestimate); as a consequence, the diazo derivative of p-nitroanilide, which is purple, has been replaced in the LAL reagent. Since endotoxin and (1-3)-BDG both are elicitors of LAL cascade, to distinguish between them, two parameters, the maximum differential coefficient of the reaction (Dmax) and the reaction time required to obtain Dmax (Tp), are used. The logarithmic plot of Tp versus Dmax (Tp-Dmax plot) discriminated between endotoxin and (1-3)-BDG. Hence, (1-3)-BDG can be measured without being affected by the presence of a small amount of endotoxin using LAL with polymyxin B.
|Figure 2: Limulus Amoebocyte Lysate Assay for (1-3)-β-D-Glucan detection|
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| Options Appraisal of (1-3)-β-D-Glucan Assay Systems|| |
Currently, seven BDG assays are available for use: Fungitell (Associates of Cape Cod, East Falmouth, MA), Endosafe-PTS (Charles River Laboratories, Charleston, SC), Fungitec-G (Seikagaku Biobusiness, Tokyo, Japan), beta-Glucan test (Wako Pure Chemical Industries, Osaka, Japan), Dyanamiker (Dynamiker Biotechnology, China), Goldstream fungus (1-3)-BDG test (ERA biology) and BGSTAR β-Glucan test (Maruha, Tokyo, Japan). With a large number of kits available for detection and quantification of (1-3)-BDG, it becomes essential to perform the options appraisal to find out the best available test option for any microbiology laboratory. A review of the (1-3)-BDG assays in 2011, which compared five assays (Fungitell, Endosafe, Fungitec, Beta Glucan (BG) test of Waco and BGStar BG test), found that two of the tests were from the United States and rest from Japan. FDA approval was available with only the Fungitell assay. Limulus polyphemus was used as the crab species for the assays from the United States, whereas Tachypleus tridentalus was the crab species in the assays from Japan. The assays were colourimetric in all except the Waco BG test, which used a turbidimetric method. The cutoff of the assays was least for the assays from Japan (11 pg/mL for the Waco beta-D-glucan test and the BG Star test and 20 pg/ml for the Fungitek G-test). Assays manufactured in the USA had a higher cutoff (60–80 pg/ml for the Fungitell test). The Endosafe test has a dynamic range of 10–1000 pg/ml. Here, we have performed a detailed comparison and options appraisal of various (1-3)-BDG assays.
| Fungitell|| |
The Fungitell assay (Associates of Cape Cod, Inc. USA) is a kinetic colourimetric test that was approved by the Food and Drug Administration in 2003 and has European Conformité Européenne (CE) label for the presumptive diagnosis of IFIs. This assay is a kinetic enzyme-linked immunosorbent assay (ELISA)-based chromogenic, quantitative assay. In this assay, optical density (OD) values are recorded every 30 s over a 40-min period, and the absorbance is read at 405 nm. The detection of (1-3)-BDG is not affected by normal interferences. Antifungal medication does not suppress it, and the test is not cross-reactive with other polysaccharides. The detection range of Fungitell is 31–500 pg/mL. A 2019 meta-analysis of Fungitell studies for the estimation of (1-3)-BDG found the sensitivity and specificity to be 80% and 63%, respectively, for the diagnosis of IFIs amongst cancer patients. (1-3)-BDG values <60 pg/mL are interpreted as negative results whereas values from 60 to 79 pg/mL are considered indeterminate results and suggest a possible fungal infection. Values ≥80 pg/mL are interpreted as positive., To assure the validity of the test, the correlation coefficient (r) of the standard curve should be ≥0.980 and negative controls should have actual OD rate values <50% of the lowest standard.
Recently, there has been the development of the Fungitell STAT assay. This is a protease zymogen-based colorimetric assay for the qualitative detection of (1-3)-BDG in the serum of patients. This test can be done on single samples and need not be batch tested such as the quantitative Fungitell assay. Fungitell STAT assay can be done on 1–7 samples at a time in a single run using the Lab Kinetics Incubating 8-well Tube Reader and BG Analytics software. An index value of ≤0.74 is considered negative; values between 0.75 and 1.1 are considered indeterminate, whereas index values of ≥1.2 are considered positive for the presence of (1-3)-BDG.
| Endosafe-Portable Test System Glucan Assay|| |
The Charles River Endosafe PTS Glucan Assay (from Singapore) allows us to quantify (1-3)-BDG quickly and easily. However, the Endosafe-PTS and beta-Glucan test kits are intended for research use only and not for the diagnosis of IFI in clinical samples. The Charles River glucan cartridges have a dynamic range of 10–1000 pg/ml, can produce results in <30 min, and can be used on the same Charles River equipment as is used for PTS endotoxin detection or PTS gram ID. This system is also based on the Limulus enzyme cascades to detect (1-3)-BDG in the sample. This is a cartridge-based system where each cartridge contains a precise amount of glucan-specific LAL formulation, as well as chromogenic substrate and glucan standard. Quantification is done by monitoring colour intensity that directly relates to (1-3)-BDG concentration in a sample. Endosafe PTS assay kits can be used for LAL endotoxin assay, cell culture contamination detection and cellulose filter preparation. Hence, this system provides us with quantitative, single-step detection of (1-3)-BDG without the need for standard curve preparation.
| Dynamiker|| |
Dynamiker by Dynamiker Biotechnology (from China) is a CE-certified pan-fungal detection kit. Fungus (1-3)-BDG assay is based on spectrophotometry for the quantitative detection of (1-3)-BDG in human serum. Its detection range is 37.5–600 pg/mL with a sensitivity of 80%–88%. In a study, to compare the performance of the Dynamiker test to that of Fungitell, 72 serum samples were analysed, with Fungitell detecting 35 positives, 6 intermediate and 31 negative samples. A total of 31 positive, 5 intermediate and 36 negative samples were reported using the Dynamiker test. Considering the positive cutoffs for Fungitell and Dynamiker as 60 pg/mL and 70 pg/mL, respectively, the sensitivity, specificity, false-negative rate, false-positive rate, PPV and NPV were found to be 82.9%, 94.6%, 17.1%, 5.4%, 93.5% and 94.6%., In a study from Greece, the performance of the Dynamiker was highly consistent with that of the Fungitell, both quantitatively (rs = 0.913) and qualitatively (kappa = 0.725).
| B-Glucan Test Wako|| |
Beta-glucan test by Wako (manufactured in Germany) is a kinetic turbidimetric test based on the principle of LAL cascade. Both serum and plasma can be used as samples for detection. The time taken for the reaction is 90 min, with a dynamic detection range of 6–600 pg/ml. In this system, no significant interference has been observed through bilirubin, haemolysis and antifungal drugs. It also provides the facility of calibration by QR code scan. Here, the active component of (1-3)-BDG lentinan is used as standard. Lentinan is the backbone of (1-3)-BDG with beta-(1,6) branches and is one of the active ingredients purified from Shiitake mushrooms. Fungitell assay and the Wako β-glucan test performances were compared in sera of patients with IA, IC and Pneumocystis jirovecii pneumonia (PJP) with respect to sera of control patients. Using the manufacturer's cutoff values of 80 pg/mL and 11 pg/mL, the sensitivity and specificity for IA diagnosis were 92.5% and 99.5% for the Fungitell assay and 60.0% and 99.5% for the Wako β-glucan, respectively; for IC diagnosis were 100.0% and 97.3% for Fungitell assay and 91.0% and 99.5% for the Wako β-glucan test, respectively; for PJP diagnosis were 100.0% and 97.3% for the Fungitell assay and 88.2% and 99.5% for the Wako β-glucan test, respectively.
[Table 1] shows a detailed comparison of these four kits.
| Challenges and Sources of Error in Beta D Glucan Assay|| |
Bioreaders/spectrophotometers capable of reading at 405 nm (preferably capable of dual-wavelength monitoring at both 405 and 490 nm) with a dynamic range up to, at least 2.0 absorbance units, coupled with appropriate computer-based kinetic assay software are required. These readers usually use a Xenon Flash lamp as a light source with a photo-diode detector and also provide incubation at 37°C and various shaking profiles.
According to a case study, after allogeneic hematopoietic stem cell transplantation, a patient's serum-D-glucan level increased sharply but the serum galactomannan antigen test remained negative. This was discovered to be due to daily oral intake of kelp, which caused a false-positive result in the serum-D-glucan assay. Kelp is a type of seaweed used to make many products such as toothpaste, shampoos, salad dressings, puddings, cakes, dairy products, frozen foods and even pharmaceuticals. Another study found that during the administration of Penicillin G for osteomyelitis caused by Streptococcus pneumoniae infection, a patient experienced false-positive (1-3)-BDG elevation, which came down after the antibiotic was stopped. (1-3)-BDG present in the Penicillin G preparation was found to be the reason for the high levels. Furthermore, intravenous immunoglobulin G injection has also been observed to raise BDG levels, which return to normal after three weeks. This could be related to the high concentration of (1-3)-BDG in Ig preparations. In a study from Germany, 25 antimicrobials (20 antibiotics and all the tested antifungals) contained enough BDG to trigger a positive test. Depending on the substance, BDG varied between 9 and 2818 pg/mL. Many antibiotics including colistin, ertapenem, cefazolin, trimethoprim-sulfamethoxazole, cefotaxime, cefepime and ampicillin-sulbactam tested positive for BG at reconstituted-vial concentrations but not when diluted to usual maximum plasma concentrations. As BDGs are present in various food products such as cereals, mushrooms and seaweeds, ingestion of such food may lead to elevated BDG levels. Moreover, surgical gauzes and sponges can leach high level of beta-D-glucan and can give false-positive tests. Serum of haemodialysis patients may contain high levels of beta-D-glucan from cellulose in dialysis membranes. All materials must be free of interfering glucan. Glassware must be dry-heat depyrogenated for at least seven hours at a minimum of 235°C (or a validated equivalent) to be considered suitable for use. Glucan as well as fungal contamination from the human body, clothes, containers, water and airborne dust may cause interference with the Fungitell assay. Cellulosic materials such as gauze, paper wipes and cardboard may contribute (1-3)-BDG to the environment where the assay is performed. It is recommended to use suitable protective clothing and powder-free gloves when handling patient specimens.
The kit insert states that haemolysed, lipaemic and icteric samples may cause interference. The tissue locations of fungal infection, encapsulation and the amount of (1-3)-BDG produced by certain fungi may affect the serum concentration of the analyte.
Mislabelled or unlabelled samples, bacterial- or fungal-contaminated equipment and non-calibrated spectrophotometer can act as a source of error and lead to the unreliability of the result.
| Conclusion|| |
The detailed comparison and options appraisal of various (1-3)-BDG assay systems show that Fungitell is the maximally accredited kit with high throughput and clinical sample type flexibility as both serum and plasma can be used, but it lacks flexibility in terms of sample number. Dynamiker assay has the technical advantage of being able to be performed utilising eight well strips rather than 96 well plates, as is the case with the Fungitell test. The manufacturer additionally includes four vials of the main reagent, which increases testing versatility and efficiency. A local test showed that the main reagent may be frozen and thawed at least once following resuspension without impacting reaction kinetics for up to 5 days. As a result, the main reagent could be administered in single-use aliquots after preparation and spread out over the working week for daily testing of low sample numbers. Hence, Dynamiker tests are beneficial in a laboratory where the sample numbers are low. BG test by Wako provides highest specificity and sensitivity amongst all of the other kits. In terms of reaction time, Endosafe PTS glucan takes the minimum time while Wako takes the maximum. With respect to cost per test, it has been shown that Dynamiker is the least expensive while Fungitell is the most expensive. After considering all the aspects, we conclude that the best kit for any laboratory depends on the sample load, sample type available, infrastructure, turnaround time, human resource availability and expenditure.
(1-3)-BDG assay has emerged as an important test for the diagnosis of IFDs [Figure 3]. However, according to the revised and updated the Consensus Definitions of IFD from the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium, (1-3)-BDG was not considered to provide mycological evidence of any invasive mould disease. The same guideline suggested (1-3)-BDG to be one of the diagnostic criteria for candidiasis and pneumocystosis with (1-3)-BDG (Fungitell) ≥80 pg/mL detected in at least two consecutive serum samples provided that other aetiologies have been excluded. It is clear, therefore, that (1-3)-BDG is likely to stay as an important analyte in the diagnosis of IFD. The assay is, however, expensive, labour intensive and susceptible to false-positive results from environmental contamination or cross-reactivity with antibiotics/certain dietary factors. The equipment used for performing this assay (microplate incubator and reader) is more expensive than a standard ELISA reader. Scrupulous attention to avoid glucan contamination is required while performing this assay which includes the use of glucan free environment and lab ware. Despite these challenges, the (1-3)-BDG assay represents an important non-culture-based test which is more sensitive than culture, microscopy of PCR or other antigen tests (galactomannan/mannan) for the diagnosis of IFD. Using this test judiciously and accurately has the potential to diagnose more IFD and help in reducing morbidity and mortality.
|Figure 3: Venn diagram showing various invasive fungal infections where beta-D-glucan, galactomannan and mannan antigens may be detectable in patient serum samples|
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]