False-positive results of galactomannan assays in patients administered glucose-containing solutions

False-positive results of galactomannan assays in patients administered glucose-containing solutions | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article False-positive results of galactomannan assays in patients administered glucose-containing solutions Dong Woo Shin, Jungwon Cho, Kyung Suk Choi, Jungwha Lee, Yunsang Choi, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3378741/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 31 Jan, 2024 Read the published version in Scientific Reports → Version 1 posted 9 You are reading this latest preprint version Abstract Galactomannan (GM) is a polysaccharide cell wall component released by Aspergillus spp., and an immunoenzymatic GM assay is used for the diagnosis of invasive pulmonary aspergillosis. We evaluated the cause of strong positivity for GM in patients with no typical signs of aspergillosis. Repeat assays were performed using different instruments and reagent lots, but there were no differences in results among the assays. Patients with strongly positive GM results were investigated. Medication histories revealed that 14 of 23 patients had been administered total parenteral nutrition solution from one manufacturer and 4 patients had been administered dextrose solution from a different manufacturer before being tested. The results of GM assays conducted on samples of dextrose solution and the glucose fraction of the total parenteral nutrition solution were strongly positive, confirming the causes of the false-positive reactions. We hypothesize that a trace amount of GM was introduced into the glucose-containing solutions because glucoamylase, which is necessary for the saccharification step of glucose synthesis, was derived from Aspergillus niger . To enhance patient care and prevent unnecessary antifungal prescriptions, healthcare providers and manufacturers of healthcare products need to be aware of the possibility of false-positive reactions for GM. Figures Figure 1 Figure 2 Introduction Galactomannan (GM) is a polysaccharide cell wall component released by Aspergillus spp. during growth 1 . An immunoenzymatic sandwich microplate assay using a rat anti-galactofuranose monoclonal antibody (EB-A2), which is directed against GM, was approved by the United States Food and Drug Administration in 2003 2,3 . The GM assay has high sensitivity and moderate accuracy for the diagnosis of invasive aspergillosis in immunocompromised patients 1 . Although the GM assay is used worldwide because it is easily performed and has good performance, false-positive results in patients with no clinical signs have been reported, including in those receiving piperacillin/tazobactam 4 , beta-lactams 5 , and other antibiotics 6 . Patients receiving total parenteral nutrition (TPN) 7 or crystalloid solutions 8 also had false-positive GM results. Moreover, patients with mucositis or an altered intestinal barrier showed false-positive GM results because of dietary factors 9 , 10 . The number of patients positive by GM assay with a high index but without typical signs of pulmonary invasive aspergillosis suddenly increased in our hospital. We evaluated the cause of the false-positive GM results in these patients. Results Timeline The timeline of this study is tabulated (Table 1 ). The laboratory was notified by medical departments of several patients suspected to have false-positive GM results. The assays were repeated using different instruments and reagent lots. The medication histories of patients with strongly positive GM results indicated that they had received TPN from manufacturer A before being tested. GM assays were performed on several lots of TPN solutions from manufacturers A (TPN-A) and B (TPN-B), and the glucose fraction of the TPN-A solution showed a strongly positive result. In addition, a patient with a false-positive result who had not been administered TPN-A before testing had been administered dextrose from manufacturer X (dextrose-X). A GM assay on dextrose-X showed a strongly positive result. Table 1 Timeline of investigation of the cause of false-positive results for galactomannan assay. Date Action Note 24 Nov Raising an issue Recent increase of patients with positive GM assay and high index but without typical signs of pulmonary invasive aspergillosis - Six patients from IMI and one patient from IMH Request to the laboratory for a check 25Nov Repeat assays with different instrument 29 Nov Request for recent cases with positive GM assay 30 Nov Repeat assays with a reagent with another lot The results did not differ according to reagent lot or instrument (Supplementary Table S1 ). Suspicious for drug interferences such as antibiotics → Investigation of medication records 1–5 Dec Selection of recent cases with strongly positive GM assay (index > 5) A total of 23 cases (from 11 Nov to 5 Dec) → Investigation of medication records from 1 Oct 1–6 Dec Investigation of medication records of selected cases TPN-A administration records in 15 cases (Fig. 1 ) → Analysis of TPN-A Literature review Contact with manufacturer A 6 Dec Contact with manufacturer A 7 Dec Notification of prescription stop and alternative nutritional solutions in hospital 7–8 Dec GM assay by samples from TPN-A and several medical solutions Strongly positive in glucose fraction of TPN-A (Table 2 ) 8 Dec Conference (medical/pharmaceutical department & manufacturer) Notice in the hospital: false positive of GM assay by TPN-A Addition of comments when reporting results Manufacturer's notice for all hospitals supplied with TPN-A Recall processing and distribution of new products The TPN-A-manufacturer recently changed the source of glucose to another company. A trace amount of GM was contaminated during manufacturing a fermentation enzyme. 12 Dec Investigation of four patients with positive results without TPN-A administration before testing 5% dextrose from manufacturer X was commonly administered to these patients. 13 Dec GM assay by dextrose solution Strongly positive, contact with the manufacturer X GM, galactomannan; IMI, Division of Infectious Diseases, Department of Internal Medicine; IMH, Division of Hematology, Department of Internal Medicine; TPN-A, total parenteral nutrition solution from manufacturer A. Results of GM assays using different lots and instruments GM assays were performed on two platforms using reagents of old and new lots (Supplementary Table S1 ). Although the sample index values were not identical, the results (positive or negative) of 16 samples did not differ according to reagent lot or instrument. Medication histories of patients with strongly positive results of GM assays There were 23 patients with strongly positive (index > 5.0) results and/or suspicion of a false-positive result. Of these 23 patients, 20 received TPN-A, and it was administered prior to testing in 14 patients (Fig. 1 ). Also, 12 of the 23 patients received piperacillin/tazobactam but no correlation was found between the timing of administration and testing. Therefore, TPN-A was suspected to be the cause of the false-positive results. Results of GM assays on medical solutions GM assays were performed on samples from TPN-A, TPN-B, dextrose-X, and dextrose from manufacturer Y (dextrose-Y) (Table 2 ). The results were positive for the glucose fractions of TPN-A in five of seven lots but negative for the other fractions of TPN-A and for the glucose fraction of TPN-B. TPN-A for a peripheral line showed higher index values than TPN-A for a central line. The GM assay result was positive for 5% dextrose-X but negative for 50% dextrose-Y. Table 2 Results of galactomannan assays performed on nutrition fluids and their fractions. Fluid * Fraction Index ** Result TPN-A (C, lot 1) Glucose 2.15, 2.35 Positive Amino acids & electrolytes 0.14, 0.15 Negative Lipids 0.23, 0.21 Negative Lipids (diluted) 0.30, 0.37 Negative TPN-A (P, lot 1) Glucose 8.45, 8.45 Positive Amino acids & electrolytes 0.24, 0.29 Negative Lipids 0.19, 0.22 Negative Lipids (diluted) 0.21, 0.20 Negative TPN-B (lot 1) Glucose 0.22, 0.19 Negative TPN-A (C, lot 2) Glucose 0.14, 0.15 Negative TPN-A (C, lot 3) Glucose 3.65, 3.75 Positive TPN-A (C, lot 4) Glucose 0.22, 0.19 Negative TPN-A (P, lot 2) Glucose 6.9, 6.9 Positive TPN-A (P, lot 3) Glucose 6.9, 6.9 Positive 5% Dextrose-X (lot 1) - 8.52, 8.52 Positive 50% Dextrose-Y (lot 1) - 0.16, 0.16 Negative * A, B, X, and Y are tentative names of manufacturers. ** Tests were performed in duplicate. TPN, total parenteral nutrition; C, for central line; P, for peripheral line. GM results after discontinuing administration of TPN-A Of the 13 patients with strongly false-positive results for GM due to administration of TPN-A (P1-P13 in Fig. 1 ), 3 had GM results that turn negative. P1, P9, and P10 all were administered TPN-A for more than a week, and their GM results changed to negative 125, 68, and 79 days after discontinuation of administration, respectively (Fig. 2 ). The remaining 11 had no follow-up GM results until they became negative. GM results were followed up to 4 months after stopping prescription of TPN-A and 5% dextrose-X, and no false-positive cases occurred in our hospital. Discussion Aspergillus spp. are common in the environment, and can cause invasive pulmonary aspergillosis (IPA) in immunocompromised patients such as recipients of hematopoietic stem cell transplants or solid organ transplants, patients undergoing chemotherapy, and those with human immunodeficiency virus infection 11 . Cases with positive GM results in this study were suspected to be false positives because the clinical manifestations of most of the patients did not indicate IPA. The medication histories of the patients revealed that they had been administered glucose-containing solutions, TPN-A and dextrose-X, which were identified as the causes of the false-positive results, proven by GM assays using direct samples of these solutions. Among the 23 patients, 13 were strongly false-positive for GM after being administered TPN-A (P1-13 in Fig. 1 ). GM assays were considered unnecessary in most of them, and they were not prescribed sufficiently until the results became negative. In 3 patients followed until GM results changed to negative, time to negativity after discontinuation of TPN-A administration ranged 68–125 days (Fig. 2 ). However, a previous study reported that the average time to negativity was estimated to be 5.5 days and the half-life of GM was estimated to be 2.4 days 12 . This difference is likely because the patients were administered TPN-A for a prolonged period and their index values of GM assays were high (> 5.0), and the metabolic pathways and structures of GM originating from infectious Aspergillus spp. and glucose-manufacturing may be different. P13 and P16 were weakly positive for GM (index < 2.0) in October due to administration of TPN-A, but strongly positive in November. This was because manufacturer A changed the enzyme used to manufacture the glucose-containing solution in November. For the same reason, the index values ​​of TPN-A differed among lots (Table 2 ). The index value of P14 was low, because this patient received TPN-A for a central line, which had a lower index value than TPN-A for a peripheral line. Patients who had received 5% dextrose-X (P19-22) were strongly positive for GM and remained positive for more than 1 week after cessation of 5% dextrose-X administration. P23 had a history of inpatient treatment at another hospital before being transferred to our hospital and may have received TPN-A or dextrose-X at that hospital. The glucose in medical solutions is produced from starch in a multi-step process. The saccharification step uses glucoamylase, an enzyme from A . niger or Bacillus licheniformis . Glucoamylase from A. niger is used in the industrial production of glucose from raw starch or soluble oligosaccharides because it is thermostable and highly active in near-neutral pH environments 13 . If there is a problem extracting or purifying glucoamylase from A. niger , GM from the cell wall of A. niger may be introduced, potentially explaining GM positivity in glucose-containing solutions. Manufacturers A and X recently changed their glucoamylase suppliers, resulting in false-positive GM results in subsequent lots of TPN-A and dextrose-X. However, the glucoamylase supplier reported that the enzyme was not contaminated with viable fungi. Manufacturer A notified customers in South Korea of this problem and recalled the problematic lots of TPN-A. The possibility of false-positive results for GM by TPN-A was relayed to the hospital staff, TPN-A prescription was suspended, and comments were added to the results of GM assays. Several causes of false-positive GM results were reported previously. Not only glucoamylase, but also citric acids are prepared from A. niger . A variety of anticoagulants and additive solutions used in platelet units contain citric acids, and there was a false-positive results of GM after platelet transfusion 14 . GM from Penicillium spp. is used in the manufacture of antibiotics, such as piperacillin/tazobactam and amoxicillin/clavulanate, and has been reported as a cause of false-positive results 15 . Other causes of false-positive GM results include crystalloid solutions, antibiotics, and dietary factors 4 – 10 . False-positive GM results may lead to antifungal prescriptions and additional workup such as chest computed tomography, resulting in unnecessary medical costs and even harm to patients. To enhance patient care, healthcare providers and manufacturers of healthcare products need to be aware of the possibility of false-positive results for GM. This study had several limitations. Other diagnostic tests for IPA, such as beta-D-glucan, Aspergillus lateral-flow assay, culture, and polymerase chain reaction 16 , were not performed. True or false positivity for Aspergillus spp. can be confirmed using other diagnostic tools. If the GM assay is problematic or not available, other diagnostic methods should be considered. Also, in most patients, GM assay results were not followed until they turned negative. As an observational study, this study was based on the dates of prescription of the medical solution and of the GM assay, and no patient intervention was performed. A systematic trial involving a regular follow-up after administration of several glucose-containing solutions is thus needed but may be controversial because of the benefit-risk balance. In conclusion, patients strongly positive for GM without typical signs of IPA had been administered glucose-containing solutions from several manufacturers. These solutions were confirmed to be the causes of the false-positive results. Healthcare providers and manufacturers of medical products should be aware of causes of false-positive results for GM. If a diagnostic test for Aspergillus is problematic, use of alternative diagnostic methods is recommended. Methods Repeat GM assays Repeat GM assays were performed on samples from patients suspected by physicians to have false-positive results and on samples from patients with positive or borderline values from 21–24 November, 2022. GM assays (Platelia Aspergillus Ag, Bio-Rad, Hercules, CA, USA) were performed on the GEMINI (Diatron, Budapest, Hungary) and Multiskan FC Microplate Photometer (Thermo Fisher Scientific, Waltham, MA, USA) platforms. To confirm reagent denaturation or contamination, GM assays were performed on old and new lots. An index value of ≥ 0.5 was classified as positive for GM. Medication records Patients who had strongly positive (index > 5.0) results or suspicion by physicians of false positivity for GM assays from 11 November to 5 December 2022 were included in the analysis. Medical histories and medication records from 1 October to 8 December were investigated to identify commonly prescribed medications. GM assays on samples from nutritional solutions Investigation of medication records revealed that the patients, who were strongly positive for GM, had received TPN-A. GM assays were performed on samples of the TPN-A and TPN-B, and dextrose-X and dextrose-Y. Because TPN solutions were divided into glucose, amino acid and electrolytes, and lipids fractions, GM assays were performed on samples of each. Follow-up GM results after discontinuing administration of TPN-A To confirm whether the GM results changed to negative after discontinuation of TPN-A administration, the GM results of patients suspected to have false-positive results were tracked. The time taken for GM results to become negative after TPN-A discontinuation was investigated. Declarations Acknowledgements None Author contributions D.W.S. drafted the manuscript. J.C., K.S.C, and J.L. contacted manufacturers, investigated information needed for the study, and supplied medical solutions. Y.C., S.J.C., S.A.K., S.M.M., E.S.K., H.B.K., and K.U.P. investigated the patient records and performed data curation. Y.J.H. and K.H.S. conceptualized the study, and review and edited the manuscript. All the authors approved the final version of the manuscript. Competing interests The authors declare no competing interests. Additional Information Supplementary Information The online version contains supplementary material. Correspondence and requests for materials should be addressed to Y.J.H. or K.H.S. References Pfeiffer, C. D., Fine, J. P. & Safdar, N. Diagnosis of invasive aspergillosis using a galactomannan assay: a meta-analysis. Clin Infect Dis . 42 , 1417-1427 (2006). Bio-Rad. Platelia Aspergillus Ag insert. Preprint at https://commerce.bio-rad.com/webroot/web/pdf/inserts/CDG/en/62794_881115_EN.pdf (2013). Berkeley, L., Dixon, C. & Bala, S. Detection of Galactomannan in Serum by Platelia TM Aspergillus Enzyme-linked Immunosorbent Assay (BioRad Laboratories and Sanofi Diagnostics). Preprint at https://www.fda.gov/media/90001/download (2011). Demiraslan, H. et al . Assessing the risk of false positive serum galactomannan among patients receiving piperacillin/tazobactam for febrile neutropenia. Med Mycol . 55 , 535-540 (2017). Aubry, A. et al . Occurrence and kinetics of false-positive Aspergillus galactomannan test results following treatment with beta-lactam antibiotics in patients with hematological disorders. J Clin Microbiol . 44 , 389-394 (2006). Boonsarngsuk, V., Niyompattama, A., Teosirimongkol, C. & Sriwanichrak, K. False-positive serum and bronchoalveolar lavage Aspergillus galactomannan assays caused by different antibiotics. Scand J Infect Dis . 42 , 461-468 (2010). Blijlevens, N. M., Donnelly, J. P., Meis, J. F., Verweij, P. E. & de Pauw, B. E. Aspergillus galactomannan antigen levels in allogeneic haematopoietic stem cell transplant recipients given total parenteral nutrition. Transpl Infect Dis . 4 , 64-65 (2002). Hage, C. A., Reynolds, J. M., Durkin, M., Wheat, L. J. & Knox, K. S. Plasmalyte as a cause of false-positive results for Aspergillus galactomannan in bronchoalveolar lavage fluid. J Clin Microbiol . 45 , 676-677 (2007). Ansorg, R., van den Boom, R. & Rath, P. M. Detection of Aspergillus galactomannan antigen in foods and antibiotics. Mycoses . 40 , 353-357 (1997). Gangneux, J. P., Lavarde, D., Bretagne, S., Guiguen, C. & Gandemer, V. Transient aspergillus antigenaemia: think of milk. Lancet . 359 , 1251 (2002). Weber, D. J., Peppercorn, A., Miller, M. B., Sickbert-Benett, E. & Rutala, W. A. Preventing healthcare-associated Aspergillus infections: review of recent CDC/HICPAC recommendations. Med Mycol . 47 Suppl 1 , S199-209 (2009). Aubry, A. et al. Occurrence and kinetics of false-positive Aspergillus galactomannan test results following treatment with beta-lactam antibiotics in patients with hematological disorders. J Clin Microbiol . 44 , 389-394 (2006). Lee, J. & Paetzel, M. Structure of the catalytic domain of glucoamylase from Aspergillus niger. Acta Crystallogr Sect F Struct Biol Cryst Commun . 67 , 188-192 (2011). Martín-Rabadán, P., Gijón, P., Alonso Fernández, R., Ballesteros, M., Anguita, J. & Bouza, E. False-positive Aspergillus antigenemia due to blood product conditioning fluids. Clin Infect Dis . 55 , e22-27; 10.1093/cid/cis493 (2012). Wheat, L. J. & Walsh, T. J. Diagnosis of invasive aspergillosis by galactomannan antigenemia detection using an enzyme immunoassay. Eur J Clin Microbiol Infect Dis . 27 , 245-251 (2008). Hoenigl, M. et al . Performance of galactomannan, beta-d-glucan, Aspergillus lateral-flow device, conventional culture, and PCR tests with bronchoalveolar lavage fluid for diagnosis of invasive pulmonary aspergillosis. J Clin Microbiol . 52 , 2039-2045 (2014). Additional Declarations No competing interests reported. Supplementary Files SupplementaryTableS1.docx Cite Share Download PDF Status: Published Journal Publication published 31 Jan, 2024 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Revision requested 30 Dec, 2023 Reviews received at journal 12 Dec, 2023 Reviewers agreed at journal 28 Nov, 2023 Reviewers agreed at journal 12 Oct, 2023 Reviewers invited by journal 12 Oct, 2023 Editor assigned by journal 12 Oct, 2023 Editor invited by journal 27 Sep, 2023 Submission checks completed at journal 27 Sep, 2023 First submitted to journal 23 Sep, 2023 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3378741","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":236433012,"identity":"d1e20535-b43a-4fa7-a786-e4d8b6039437","order_by":0,"name":"Dong Woo Shin","email":"","orcid":"","institution":"Department of Laboratory Medicine, Seoul National University Bundang Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Dong","middleName":"Woo","lastName":"Shin","suffix":""},{"id":236433014,"identity":"911de3b0-c034-4e3b-8fd3-cd979775c377","order_by":1,"name":"Jungwon 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Gray boxes, administration of TPN-A; white boxes, administration of 5% dextrose-X. Numbers indicate GM assay index values (N, negative). P1-P14, patients with false-positive results for GM due to administration of TPN-A prior to testing. P15-P18, patients with probable invasive pulmonary aspergillosis and an abrupt increase of index values after administration of TPN-A. P19-P22, false-positive results for GM due to administration of 5% dextrose-X prior to testing. P20 received 5% dextrose-X 16-18 September (not shown). P23, medication history in another hospital (22 October to 25 November) prior to transfer to our hospital was not available.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-3378741/v1/8005e5385b2a30a55c32ff81.png"},{"id":44093722,"identity":"8a39492a-015b-48d5-952f-fe92efb5a61f","added_by":"auto","created_at":"2023-10-04 16:49:13","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":88440,"visible":true,"origin":"","legend":"\u003cp\u003eCases in which galactomannan assay results were confirmed to turn negative after discontinuing administration of total parenteral nutrition from manufacturer A (TPN-A). P2, P9, and P10 were administered TPN-A for more than a week and discontinued on 1 December, 12 November, and 26 October, respectively. It took 125, 68, and 79 days, respectively, for the galactomannan assay results of P2, P9, and P10 to change to negative after cessation of TPN-A.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-3378741/v1/b273f5d50dbf3fa36ebe2b86.png"},{"id":50674253,"identity":"96741036-9df1-42a9-945c-be925d26ba05","added_by":"auto","created_at":"2024-02-05 15:09:51","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":520823,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3378741/v1/f260e277-0f7e-4dc4-8cba-019161ba069b.pdf"},{"id":44093721,"identity":"05462cce-ccd8-4b6f-bbc4-848e8251c585","added_by":"auto","created_at":"2023-10-04 16:49:13","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":18270,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTableS1.docx","url":"https://assets-eu.researchsquare.com/files/rs-3378741/v1/3084d00061adda0fd74cf895.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"False-positive results of galactomannan assays in patients administered glucose-containing solutions","fulltext":[{"header":"Introduction","content":"\u003cp\u003eGalactomannan (GM) is a polysaccharide cell wall component released by \u003cem\u003eAspergillus\u003c/em\u003e spp. during growth\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. An immunoenzymatic sandwich microplate assay using a rat anti-galactofuranose monoclonal antibody (EB-A2), which is directed against GM, was approved by the United States Food and Drug Administration in 2003\u003csup\u003e2,3\u003c/sup\u003e. The GM assay has high sensitivity and moderate accuracy for the diagnosis of invasive aspergillosis in immunocompromised patients\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eAlthough the GM assay is used worldwide because it is easily performed and has good performance, false-positive results in patients with no clinical signs have been reported, including in those receiving piperacillin/tazobactam\u003csup\u003e4\u003c/sup\u003e, beta-lactams\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e, and other antibiotics\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. Patients receiving total parenteral nutrition (TPN)\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e or crystalloid solutions\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e also had false-positive GM results. Moreover, patients with mucositis or an altered intestinal barrier showed false-positive GM results because of dietary factors\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe number of patients positive by GM assay with a high index but without typical signs of pulmonary invasive aspergillosis suddenly increased in our hospital. We evaluated the cause of the false-positive GM results in these patients.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eTimeline\u003c/h2\u003e \u003cp\u003eThe timeline of this study is tabulated (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The laboratory was notified by medical departments of several patients suspected to have false-positive GM results. The assays were repeated using different instruments and reagent lots. The medication histories of patients with strongly positive GM results indicated that they had received TPN from manufacturer A before being tested. GM assays were performed on several lots of TPN solutions from manufacturers A (TPN-A) and B (TPN-B), and the glucose fraction of the TPN-A solution showed a strongly positive result. In addition, a patient with a false-positive result who had not been administered TPN-A before testing had been administered dextrose from manufacturer X (dextrose-X). A GM assay on dextrose-X showed a strongly positive result.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eTimeline of investigation of the cause of false-positive results for galactomannan assay.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDate\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAction\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNote\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e24 Nov\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRaising an issue\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRecent increase of patients with positive GM assay and high index but without typical signs of pulmonary invasive aspergillosis\u003c/p\u003e \u003cp\u003e - Six patients from IMI and one patient from IMH\u003c/p\u003e \u003cp\u003eRequest to the laboratory for a check\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e25Nov\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRepeat assays with different instrument\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e29 Nov\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRequest for recent cases with positive GM assay\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e30 Nov\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRepeat assays with a reagent with another lot\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eThe results did not differ according to reagent lot or instrument (Supplementary Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eSuspicious for drug interferences such as antibiotics\u003c/p\u003e \u003cp\u003e\u0026rarr; Investigation of medication records\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u0026ndash;5 Dec\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSelection of recent cases with strongly positive GM assay (index\u0026thinsp;\u0026gt;\u0026thinsp;5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eA total of 23 cases (from 11 Nov to 5 Dec)\u003c/p\u003e \u003cp\u003e\u0026rarr; Investigation of medication records from 1 Oct\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u0026ndash;6 Dec\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInvestigation of medication records of selected cases\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTPN-A administration records in 15 cases (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) \u0026rarr; Analysis of TPN-A\u003c/p\u003e \u003cp\u003eLiterature review\u003c/p\u003e \u003cp\u003eContact with manufacturer A\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6 Dec\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eContact with manufacturer A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7 Dec\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNotification of prescription stop and alternative nutritional solutions in hospital\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7\u0026ndash;8 Dec\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGM assay by samples from TPN-A and several medical solutions\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eStrongly positive in glucose fraction of TPN-A (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e8 Dec\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eConference (medical/pharmaceutical department \u0026amp; manufacturer)\u003c/p\u003e \u003cp\u003eNotice in the hospital: false positive of GM assay by TPN-A\u003c/p\u003e \u003cp\u003eAddition of comments when reporting results\u003c/p\u003e \u003cp\u003eManufacturer's notice for all hospitals supplied with TPN-A\u003c/p\u003e \u003cp\u003eRecall processing and distribution of new products\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eThe TPN-A-manufacturer recently changed the source of glucose to another company.\u003c/p\u003e \u003cp\u003eA trace amount of GM was contaminated during manufacturing a fermentation enzyme.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e12 Dec\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInvestigation of four patients with positive results without TPN-A administration before testing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5% dextrose from manufacturer X was commonly administered to these patients.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e13 Dec\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGM assay by dextrose solution\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eStrongly positive, contact with the manufacturer X\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eGM, galactomannan; IMI, Division of Infectious Diseases, Department of Internal Medicine; IMH, Division of Hematology, Department of Internal Medicine; TPN-A, total parenteral nutrition solution from manufacturer A.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eResults of GM assays using different lots and instruments\u003c/h3\u003e\n\u003cp\u003eGM assays were performed on two platforms using reagents of old and new lots (Supplementary Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e). Although the sample index values were not identical, the results (positive or negative) of 16 samples did not differ according to reagent lot or instrument.\u003c/p\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eMedication histories of patients with strongly positive results of GM assays\u003c/h2\u003e \u003cp\u003eThere were 23 patients with strongly positive (index\u0026thinsp;\u0026gt;\u0026thinsp;5.0) results and/or suspicion of a false-positive result. Of these 23 patients, 20 received TPN-A, and it was administered prior to testing in 14 patients (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Also, 12 of the 23 patients received piperacillin/tazobactam but no correlation was found between the timing of administration and testing. Therefore, TPN-A was suspected to be the cause of the false-positive results.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eResults of GM assays on medical solutions\u003c/h2\u003e \u003cp\u003eGM assays were performed on samples from TPN-A, TPN-B, dextrose-X, and dextrose from manufacturer Y (dextrose-Y) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The results were positive for the glucose fractions of TPN-A in five of seven lots but negative for the other fractions of TPN-A and for the glucose fraction of TPN-B. TPN-A for a peripheral line showed higher index values than TPN-A for a central line. The GM assay result was positive for 5% dextrose-X but negative for 50% dextrose-Y.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eResults of galactomannan assays performed on nutrition fluids and their fractions.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFluid\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFraction\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIndex\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eResult\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003eTPN-A (C, lot 1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGlucose\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.15, 2.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAmino acids \u0026amp; electrolytes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.14, 0.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLipids\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.23, 0.21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLipids (diluted)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.30, 0.37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003eTPN-A (P, lot 1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGlucose\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e8.45, 8.45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAmino acids \u0026amp; electrolytes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.24, 0.29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLipids\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.19, 0.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLipids (diluted)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.21, 0.20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTPN-B (lot 1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGlucose\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.22, 0.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTPN-A (C, lot 2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGlucose\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.14, 0.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTPN-A (C, lot 3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGlucose\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3.65, 3.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTPN-A (C, lot 4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGlucose\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.22, 0.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTPN-A (P, lot 2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGlucose\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6.9, 6.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTPN-A (P, lot 3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGlucose\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6.9, 6.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5% Dextrose-X (lot 1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e8.52, 8.52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e50% Dextrose-Y (lot 1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.16, 0.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003csup\u003e*\u003c/sup\u003eA, B, X, and Y are tentative names of manufacturers.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003csup\u003e**\u003c/sup\u003eTests were performed in duplicate.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eTPN, total parenteral nutrition; C, for central line; P, for peripheral line.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eGM results after discontinuing administration of TPN-A\u003c/h2\u003e \u003cp\u003eOf the 13 patients with strongly false-positive results for GM due to administration of TPN-A (P1-P13 in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e), 3 had GM results that turn negative. P1, P9, and P10 all were administered TPN-A for more than a week, and their GM results changed to negative 125, 68, and 79 days after discontinuation of administration, respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The remaining 11 had no follow-up GM results until they became negative. GM results were followed up to 4 months after stopping prescription of TPN-A and 5% dextrose-X, and no false-positive cases occurred in our hospital.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003e \u003cem\u003eAspergillus\u003c/em\u003e spp. are common in the environment, and can cause invasive pulmonary aspergillosis (IPA) in immunocompromised patients such as recipients of hematopoietic stem cell transplants or solid organ transplants, patients undergoing chemotherapy, and those with human immunodeficiency virus infection\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. Cases with positive GM results in this study were suspected to be false positives because the clinical manifestations of most of the patients did not indicate IPA. The medication histories of the patients revealed that they had been administered glucose-containing solutions, TPN-A and dextrose-X, which were identified as the causes of the false-positive results, proven by GM assays using direct samples of these solutions.\u003c/p\u003e \u003cp\u003eAmong the 23 patients, 13 were strongly false-positive for GM after being administered TPN-A (P1-13 in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). GM assays were considered unnecessary in most of them, and they were not prescribed sufficiently until the results became negative. In 3 patients followed until GM results changed to negative, time to negativity after discontinuation of TPN-A administration ranged 68\u0026ndash;125 days (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). However, a previous study reported that the average time to negativity was estimated to be 5.5 days and the half-life of GM was estimated to be 2.4 days\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. This difference is likely because the patients were administered TPN-A for a prolonged period and their index values of GM assays were high (\u0026gt;\u0026thinsp;5.0), and the metabolic pathways and structures of GM originating from infectious \u003cem\u003eAspergillus\u003c/em\u003e spp. and glucose-manufacturing may be different. P13 and P16 were weakly positive for GM (index\u0026thinsp;\u0026lt;\u0026thinsp;2.0) in October due to administration of TPN-A, but strongly positive in November. This was because manufacturer A changed the enzyme used to manufacture the glucose-containing solution in November. For the same reason, the index values ​​of TPN-A differed among lots (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The index value of P14 was low, because this patient received TPN-A for a central line, which had a lower index value than TPN-A for a peripheral line. Patients who had received 5% dextrose-X (P19-22) were strongly positive for GM and remained positive for more than 1 week after cessation of 5% dextrose-X administration. P23 had a history of inpatient treatment at another hospital before being transferred to our hospital and may have received TPN-A or dextrose-X at that hospital.\u003c/p\u003e \u003cp\u003eThe glucose in medical solutions is produced from starch in a multi-step process. The saccharification step uses glucoamylase, an enzyme from \u003cem\u003eA\u003c/em\u003e. \u003cem\u003eniger\u003c/em\u003e or \u003cem\u003eBacillus licheniformis\u003c/em\u003e. Glucoamylase from \u003cem\u003eA. niger\u003c/em\u003e is used in the industrial production of glucose from raw starch or soluble oligosaccharides because it is thermostable and highly active in near-neutral pH environments\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. If there is a problem extracting or purifying glucoamylase from \u003cem\u003eA. niger\u003c/em\u003e, GM from the cell wall of \u003cem\u003eA. niger\u003c/em\u003e may be introduced, potentially explaining GM positivity in glucose-containing solutions. Manufacturers A and X recently changed their glucoamylase suppliers, resulting in false-positive GM results in subsequent lots of TPN-A and dextrose-X. However, the glucoamylase supplier reported that the enzyme was not contaminated with viable fungi. Manufacturer A notified customers in South Korea of this problem and recalled the problematic lots of TPN-A. The possibility of false-positive results for GM by TPN-A was relayed to the hospital staff, TPN-A prescription was suspended, and comments were added to the results of GM assays.\u003c/p\u003e \u003cp\u003eSeveral causes of false-positive GM results were reported previously. Not only glucoamylase, but also citric acids are prepared from \u003cem\u003eA. niger\u003c/em\u003e. A variety of anticoagulants and additive solutions used in platelet units contain citric acids, and there was a false-positive results of GM after platelet transfusion\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. GM from \u003cem\u003ePenicillium\u003c/em\u003e spp. is used in the manufacture of antibiotics, such as piperacillin/tazobactam and amoxicillin/clavulanate, and has been reported as a cause of false-positive results\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. Other causes of false-positive GM results include crystalloid solutions, antibiotics, and dietary factors\u003csup\u003e\u003cspan additionalcitationids=\"CR5 CR6 CR7 CR8 CR9\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. False-positive GM results may lead to antifungal prescriptions and additional workup such as chest computed tomography, resulting in unnecessary medical costs and even harm to patients. To enhance patient care, healthcare providers and manufacturers of healthcare products need to be aware of the possibility of false-positive results for GM.\u003c/p\u003e \u003cp\u003eThis study had several limitations. Other diagnostic tests for IPA, such as beta-D-glucan, \u003cem\u003eAspergillus\u003c/em\u003e lateral-flow assay, culture, and polymerase chain reaction\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e, were not performed. True or false positivity for \u003cem\u003eAspergillus\u003c/em\u003e spp. can be confirmed using other diagnostic tools. If the GM assay is problematic or not available, other diagnostic methods should be considered. Also, in most patients, GM assay results were not followed until they turned negative. As an observational study, this study was based on the dates of prescription of the medical solution and of the GM assay, and no patient intervention was performed. A systematic trial involving a regular follow-up after administration of several glucose-containing solutions is thus needed but may be controversial because of the benefit-risk balance.\u003c/p\u003e \u003cp\u003eIn conclusion, patients strongly positive for GM without typical signs of IPA had been administered glucose-containing solutions from several manufacturers. These solutions were confirmed to be the causes of the false-positive results. Healthcare providers and manufacturers of medical products should be aware of causes of false-positive results for GM. If a diagnostic test for \u003cem\u003eAspergillus\u003c/em\u003e is problematic, use of alternative diagnostic methods is recommended.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eRepeat GM assays\u003c/h2\u003e \u003cp\u003eRepeat GM assays were performed on samples from patients suspected by physicians to have false-positive results and on samples from patients with positive or borderline values from 21\u0026ndash;24 November, 2022. GM assays (Platelia \u003cem\u003eAspergillus\u003c/em\u003e Ag, Bio-Rad, Hercules, CA, USA) were performed on the GEMINI (Diatron, Budapest, Hungary) and Multiskan FC Microplate Photometer (Thermo Fisher Scientific, Waltham, MA, USA) platforms. To confirm reagent denaturation or contamination, GM assays were performed on old and new lots. An index value of \u0026ge;\u0026thinsp;0.5 was classified as positive for GM.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eMedication records\u003c/h2\u003e \u003cp\u003ePatients who had strongly positive (index\u0026thinsp;\u0026gt;\u0026thinsp;5.0) results or suspicion by physicians of false positivity for GM assays from 11 November to 5 December 2022 were included in the analysis. Medical histories and medication records from 1 October to 8 December were investigated to identify commonly prescribed medications.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eGM assays on samples from nutritional solutions\u003c/h2\u003e \u003cp\u003eInvestigation of medication records revealed that the patients, who were strongly positive for GM, had received TPN-A. GM assays were performed on samples of the TPN-A and TPN-B, and dextrose-X and dextrose-Y. Because TPN solutions were divided into glucose, amino acid and electrolytes, and lipids fractions, GM assays were performed on samples of each.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eFollow-up GM results after discontinuing administration of TPN-A\u003c/h2\u003e \u003cp\u003eTo confirm whether the GM results changed to negative after discontinuation of TPN-A administration, the GM results of patients suspected to have false-positive results were tracked. The time taken for GM results to become negative after TPN-A discontinuation was investigated.\u003c/p\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eAuthor contributions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eD.W.S. drafted the manuscript. J.C., K.S.C, and J.L. contacted manufacturers, investigated information needed for the study, and supplied medical solutions. Y.C., S.J.C., S.A.K., S.M.M., E.S.K., H.B.K., and K.U.P. investigated the patient records and performed data curation. Y.J.H. and K.H.S. conceptualized the study, and review and edited the manuscript. All the authors approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eAdditional Information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSupplementary Information\u003c/strong\u003e The online version contains supplementary material.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCorrespondence\u003c/strong\u003e and requests for materials should be addressed to Y.J.H. or K.H.S.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003ePfeiffer, C. D., Fine, J. P. \u0026amp; Safdar, N. Diagnosis of invasive aspergillosis using a galactomannan assay: a meta-analysis. \u003cem\u003eClin Infect Dis\u003c/em\u003e. \u003cstrong\u003e42\u003c/strong\u003e, 1417-1427 (2006).\u003c/li\u003e\n\u003cli\u003eBio-Rad. Platelia Aspergillus Ag insert. Preprint at https://commerce.bio-rad.com/webroot/web/pdf/inserts/CDG/en/62794_881115_EN.pdf (2013).\u003c/li\u003e\n\u003cli\u003eBerkeley, L., Dixon, C. \u0026amp; Bala, S. Detection of Galactomannan in Serum by Platelia\u003csup\u003eTM\u003c/sup\u003e Aspergillus Enzyme-linked Immunosorbent Assay (BioRad Laboratories and Sanofi Diagnostics). Preprint at https://www.fda.gov/media/90001/download (2011).\u003c/li\u003e\n\u003cli\u003eDemiraslan, H. \u003cem\u003eet al\u003c/em\u003e. Assessing the risk of false positive serum galactomannan among patients receiving piperacillin/tazobactam for febrile neutropenia. \u003cem\u003eMed Mycol\u003c/em\u003e. \u003cstrong\u003e55\u003c/strong\u003e, 535-540 (2017).\u003c/li\u003e\n\u003cli\u003eAubry, A. \u003cem\u003eet al\u003c/em\u003e. Occurrence and kinetics of false-positive Aspergillus galactomannan test results following treatment with beta-lactam antibiotics in patients with hematological disorders. \u003cem\u003eJ Clin Microbiol\u003c/em\u003e. \u003cstrong\u003e44\u003c/strong\u003e, 389-394 (2006).\u003c/li\u003e\n\u003cli\u003eBoonsarngsuk, V., Niyompattama, A., Teosirimongkol, C. \u0026amp; Sriwanichrak, K. False-positive serum and bronchoalveolar lavage Aspergillus galactomannan assays caused by different antibiotics. \u003cem\u003eScand J Infect Dis\u003c/em\u003e. \u003cstrong\u003e42\u003c/strong\u003e, 461-468 (2010).\u003c/li\u003e\n\u003cli\u003eBlijlevens, N. M., Donnelly, J. P., Meis, J. F., Verweij, P. E. \u0026amp; de Pauw, B. E. Aspergillus galactomannan antigen levels in allogeneic haematopoietic stem cell transplant recipients given total parenteral nutrition. \u003cem\u003eTranspl Infect Dis\u003c/em\u003e. \u003cstrong\u003e4\u003c/strong\u003e, 64-65 (2002).\u003c/li\u003e\n\u003cli\u003eHage, C. A., Reynolds, J. M., Durkin, M., Wheat, L. J. \u0026amp; Knox, K. S. Plasmalyte as a cause of false-positive results for Aspergillus galactomannan in bronchoalveolar lavage fluid. \u003cem\u003eJ Clin Microbiol\u003c/em\u003e. \u003cstrong\u003e45\u003c/strong\u003e, 676-677 (2007).\u003c/li\u003e\n\u003cli\u003eAnsorg, R., van den Boom, R. \u0026amp; Rath, P. M. Detection of Aspergillus galactomannan antigen in foods and antibiotics. \u003cem\u003eMycoses\u003c/em\u003e. \u003cstrong\u003e40\u003c/strong\u003e, 353-357 (1997).\u003c/li\u003e\n\u003cli\u003eGangneux, J. P., Lavarde, D., Bretagne, S., Guiguen, C. \u0026amp; Gandemer, V. Transient aspergillus antigenaemia: think of milk. \u003cem\u003eLancet\u003c/em\u003e. \u003cstrong\u003e359\u003c/strong\u003e, 1251 (2002).\u003c/li\u003e\n\u003cli\u003eWeber, D. J., Peppercorn, A., Miller, M. B., Sickbert-Benett, E. \u0026amp; Rutala, W. A. Preventing healthcare-associated Aspergillus infections: review of recent CDC/HICPAC recommendations. \u003cem\u003eMed Mycol\u003c/em\u003e. \u003cstrong\u003e47 Suppl 1\u003c/strong\u003e, S199-209 (2009).\u003c/li\u003e\n\u003cli\u003eAubry, A. et al. Occurrence and kinetics of false-positive Aspergillus galactomannan test results following treatment with beta-lactam antibiotics in patients with hematological disorders. \u003cem\u003eJ Clin Microbiol\u003c/em\u003e. \u003cstrong\u003e44\u003c/strong\u003e, 389-394 (2006).\u003c/li\u003e\n\u003cli\u003eLee, J. \u0026amp; Paetzel, M. Structure of the catalytic domain of glucoamylase from Aspergillus niger. \u003cem\u003eActa Crystallogr Sect F Struct Biol Cryst Commun\u003c/em\u003e. \u003cstrong\u003e67\u003c/strong\u003e, 188-192 (2011).\u003c/li\u003e\n\u003cli\u003eMart\u0026iacute;n-Rabad\u0026aacute;n, P., Gij\u0026oacute;n, P., Alonso Fern\u0026aacute;ndez, R., Ballesteros, M., Anguita, J. \u0026amp; Bouza, E. False-positive Aspergillus antigenemia due to blood product conditioning fluids. \u003cem\u003eClin Infect Dis\u003c/em\u003e. \u003cstrong\u003e55\u003c/strong\u003e, e22-27; 10.1093/cid/cis493 (2012).\u003c/li\u003e\n\u003cli\u003eWheat, L. J. \u0026amp; Walsh, T. J. Diagnosis of invasive aspergillosis by galactomannan antigenemia detection using an enzyme immunoassay. \u003cem\u003eEur J Clin Microbiol Infect Dis\u003c/em\u003e. \u003cstrong\u003e27\u003c/strong\u003e, 245-251 (2008).\u003c/li\u003e\n\u003cli\u003eHoenigl, M. \u003cem\u003eet al\u003c/em\u003e. Performance of galactomannan, beta-d-glucan, Aspergillus lateral-flow device, conventional culture, and PCR tests with bronchoalveolar lavage fluid for diagnosis of invasive pulmonary aspergillosis. \u003cem\u003eJ Clin Microbiol\u003c/em\u003e. \u003cstrong\u003e52\u003c/strong\u003e, 2039-2045 (2014).\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-3378741/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3378741/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eGalactomannan (GM) is a polysaccharide cell wall component released by \u003cem\u003eAspergillus\u003c/em\u003e spp., and an immunoenzymatic GM assay is used for the diagnosis of invasive pulmonary aspergillosis. We evaluated the cause of strong positivity for GM in patients with no typical signs of aspergillosis. Repeat assays were performed using different instruments and reagent lots, but there were no differences in results among the assays. Patients with strongly positive GM results were investigated. Medication histories revealed that 14 of 23 patients had been administered total parenteral nutrition solution from one manufacturer and 4 patients had been administered dextrose solution from a different manufacturer before being tested. The results of GM assays conducted on samples of dextrose solution and the glucose fraction of the total parenteral nutrition solution were strongly positive, confirming the causes of the false-positive reactions. We hypothesize that a trace amount of GM was introduced into the glucose-containing solutions because glucoamylase, which is necessary for the saccharification step of glucose synthesis, was derived from \u003cem\u003eAspergillus niger\u003c/em\u003e. To enhance patient care and prevent unnecessary antifungal prescriptions, healthcare providers and manufacturers of healthcare products need to be aware of the possibility of false-positive reactions for GM.\u003c/p\u003e","manuscriptTitle":"False-positive results of galactomannan assays in patients administered glucose-containing solutions","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-10-04 16:49:08","doi":"10.21203/rs.3.rs-3378741/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2023-12-30T05:42:36+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2023-12-12T16:56:16+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"78e168da-22ae-4dc7-9e73-50d5fbc34bc7","date":"2023-11-28T09:55:47+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"7d81e702-b10c-4c7f-a1a9-9eb98cfadf31","date":"2023-10-12T10:40:55+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2023-10-12T09:50:22+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2023-10-12T07:36:39+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2023-09-27T13:26:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2023-09-27T13:24:36+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2023-09-23T06:56:14+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"70a4e0dd-526c-4770-9dad-0c9aaabc40e7","owner":[],"postedDate":"October 4th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-02-05T15:06:42+00:00","versionOfRecord":{"articleIdentity":"rs-3378741","link":"https://doi.org/10.1038/s41598-024-53116-x","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2024-01-31 15:01:13","publishedOnDateReadable":"January 31st, 2024"},"versionCreatedAt":"2023-10-04 16:49:08","video":"","vorDoi":"10.1038/s41598-024-53116-x","vorDoiUrl":"https://doi.org/10.1038/s41598-024-53116-x","workflowStages":[]},"version":"v1","identity":"rs-3378741","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3378741","identity":"rs-3378741","version":["v1"]},"buildId":"WrCJVZZCHTDjtuVLN7oU0","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}