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Current Fungal Infection Reports
Published in: Current Fungal Infection Reports 4/2018

01-12-2018 | Current Management of Fungal Infections (J Maertens, Section Editor)

Diagnosing Invasive Mold Infections: What Is Next

Authors: Toine Mercier, Ellen Guldentops, Ruth Van Daele, Johan Maertens

Published in: Current Fungal Infection Reports | Issue 4/2018

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Abstract

Purpose of Review

Currently, microbiological diagnosis of invasive mold infections is based largely on culture, direct microscopy, PCR, or antigen (such as β-D-glucan or galactomannan)-based tests. In this review, we look at novel and experimental diagnostic tests for invasive mold infections.

Recent Findings

Several new techniques have been proposed, and are in different stages of development. The JF5-antibody-based lateral flow device has recently been commercialized, and is closest to uptake in routine care. Other tests, such as the MAb476-antibody-based urine lateral flow device, gliotoxin or bis(methylthio)gliotoxin, mold-specific T cells, exhaled breath analysis, siderophores, mass spectrometry serum disaccharide, or cytokine analysis, are at an earlier stage of development.

Summary

Most proposed diagnostic tests for invasive mold infections are in the experimental stage and are not ready for routine clinical use. They still require further characterization and analytical and clinical validation by independent research groups.
Literature
1.
Lass-Flörl C, Cuenca-Estrella M. Changes in the epidemiological landscape of invasive mould infections and disease. J Antimicrob Chemother. 2017;72:i5–11.CrossRef
2.
Lamoth F, Calandra T. Early diagnosis of invasive mould infections and disease. J Antimicrob Chemother. 2017;72:i19–28.CrossRef
3.
Mennink-Kersten MA, Donnelly JP, Verweij PE. Detection of circulating galactomannan for the diagnosis and management of invasive aspergillosis. Lancet Infect Dis. 2004;4:349–57.CrossRef
4.
Marty FM, Koo S. Role of (1→3)-β-D-glucan in the diagnosis of invasive aspergillosis. Med Mycol. 2009;47:S233–40.CrossRef
5.
Pfeiffer CD, Fine JP, Safdar N. Diagnosis of invasive aspergillosis using a galactomannan assay: a meta-analysis. Clin Infect Dis. 2006;42:1417–727.CrossRef
6.
Zou M, Tang L, Zhao S, Zhao Z, Chen L, Chen P, et al. Systematic review and meta-analysis of detecting galactomannan in bronchoalveolar lavage fluid for diagnosing invasive aspergillosis. PLoS One 2012;7.
7.
Leeflang MMG, Debets-Ossenkopp YJ, Wang J, Visser CE, Scholten RJPM, Hooft L, et al. Galactomannan detection for invasive aspergillosis in immunocompromised patients. Cochrane Database Syst Rev. 2015;CD007394.
8.
Karageorgopoulos DE, Qu J-M, Korbila IP, Zhu Y-G, Vasileiou VA, Falagas ME. Accuracy of β-D-glucan for the diagnosis of pneumocystis jirovecii pneumonia: a meta-analysis. Clin Microbiol Infect Off Publ Eur Soc Clin Microbiol Infect Dis. 2013;19:39–49.
9.
Karageorgopoulos DE, Vouloumanou EK, Ntziora F, Michalopoulos A, Rafailidis PI, Falagas ME. β-D-glucan assay for the diagnosis of invasive fungal infections: a meta-analysis. Clin Infect Dis. 2011;52:750–70.CrossRef
10.
Onishi A, Sugiyama D, Kogata Y, Saegusa J, Sugimoto T, Kawano S, et al. Diagnostic accuracy of serum 1,3-β-D-glucan for pneumocystis jiroveci pneumonia, invasive candidiasis, and invasive aspergillosis: systematic review and meta-analysis. J Clin Microbiol. 2012;50:7–15.CrossRef
11.
He S, Hang J-P, Zhang L, Wang F, Zhang D-C, Gong F-H. A systematic review and meta-analysis of diagnostic accuracy of serum 1,3-β-D-glucan for invasive fungal infection: focus on cutoff levels. J Microbiol Immunol Infect Wei Mian Yu Gan Ran Za Zhi. 2015;48:351–61.CrossRef
12.
Pauw BD, Walsh TJ, Donnelly JP, Stevens DA, Edwards JE, Calandra T, et al. Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of cancer/invasive fungal infections cooperative group and the National Institute of Allergy and Infectious Diseases mycoses study group (EORTC/MSG) consensus group. Clin Infect Dis. 2008;46:1813–21.CrossRef
13.
Arvanitis M, Ziakas PD, Zacharioudakis IM, Zervou FN, Caliendo AM, Mylonakis E. PCR in diagnosis of invasive aspergillosis: a meta-analysis of diagnostic performance. J Clin Microbiol. 2014;52:3731–42.CrossRef
14.
Millon L, Larosa F, Lepiller Q, Legrand F, Rocchi S, Daguindau E, et al. Quantitative polymerase chain reaction detection of circulating DNA in serum for early diagnosis of mucormycosis in immunocompromised patients. Clin Infect Dis. 2013;56:e95–101.CrossRef
15.
Machouart M, Larché J, Burton K, Collomb J, Maurer P, Cintrat A, et al. Genetic identification of the main opportunistic Mucorales by PCR-restriction fragment length polymorphism. J Clin Microbiol. 2006;44:805–10.CrossRef
16.
Baldin C, Soliman S, Jeon H, Gebremariam T, Alkhazraji S, Bruno V, et al. PCR-based diagnosis of Mucormycosis targeting Mucorales-specific genes. Open Forum Infect Dis. 2017;4:S612.CrossRef
17.
Ciardo DE, Lucke K, Imhof A, Bloemberg GV, Böttger EC. Systematic internal transcribed spacer sequence analysis for identification of clinical mold isolates in diagnostic mycology: a 5-year study. J Clin Microbiol. 2010;48:2809–13.CrossRef
18.
Bezdicek M, Lengerova M, Ricna D, Weinbergerova B, Kocmanova I, Volfova P, et al. Rapid detection of fungal pathogens in bronchoalveolar lavage samples using panfungal PCR combined with high resolution melting analysis. Med Mycol. 2016;54:714–24.CrossRef
19.
Valero C, de la Cruz-Villar L, Zaragoza Ó, Buitrago MJ. New panfungal real-time PCR assay for diagnosis of invasive fungal infections. J Clin Microbiol. 2016;54:2910–8.CrossRef
20.
Thornton CR. Development of an Immunochromatographic lateral-flow device for rapid serodiagnosis of invasive aspergillosis. Clin Vaccine Immunol. 2008;15:1095–105.CrossRef
21.
Swanink CM, Meis JF, Rijs AJ, Donnelly JP, Verweij PE. Specificity of a sandwich enzyme-linked immunosorbent assay for detecting Aspergillus galactomannan. J Clin Microbiol. 1997;35:257–60.PubMedPubMedCentral
22.
Mikulska M, Furfaro E, Del Bono V, Gualandi F, Raiola AM, Molinari MP, et al. Galactomannan testing might be useful for early diagnosis of fusariosis. Diagn Microbiol Infect Dis. 2012;72:367–9.CrossRef
23.
Dalle F, Charles PE, Blanc K, Caillot D, Chavanet P, Dromer F, et al. Cryptococcus neoformans galactoxylomannan contains an epitope(s) that is cross-reactive with aspergillus galactomannan. J Clin Microbiol. 2005;43:2929–31.CrossRef
24.
Huang Y-T, Hung C-C, Liao C-H, Sun H-Y, Chang S-C, Chen Y-C. Detection of circulating galactomannan in serum samples for diagnosis of Penicillium marneffei infection and cryptococcosis among patients infected with human immunodeficiency virus. J Clin Microbiol. 2007;45:2858–62.CrossRef
25.
Metan G, Keklik M, Dinç G, Pala Ç, Yıldırım A, Saraymen B, et al. Performance of galactomannan antigen, beta-d-glucan, and Aspergillus-lateral-flow device for the diagnosis of invasive aspergillosis. Indian J Hematol Blood Transfus Off J Indian Soc Hematol Blood Transfus. 2017;33:87–92.CrossRef
26.
•• Heldt S, Hoenigl M. Lateral flow assays for the diagnosis of invasive aspergillosis: current status. Curr Fungal Infect Rep. 2017;11:45–51. Comprehensive overview of lateral flow devices. CrossRef
27.
Pan Z, Fu M, Zhang J, Zhou H, Fu Y, Zhou J. Diagnostic accuracy of a novel lateral-flow device in invasive aspergillosis: a meta-analysis. J Med Microbiol. 2015;64:702–7.CrossRef
28.
White PL, Parr C, Thornton C, Barnes RA. Evaluation of real-time PCR, galactomannan enzyme-linked immunosorbent assay (ELISA), and a novel lateral-flow device for diagnosis of invasive aspergillosis. J Clin Microbiol. 2013;51:1510–6.CrossRef
29.
Held J, Schmidt T, Thornton CR, Kotter E, Bertz H. Comparison of a novel Aspergillus lateral-flow device and the Platelia galactomannan assay for the diagnosis of invasive aspergillosis following haematopoietic stem cell transplantation. Infection. 2013;41:1163–9.CrossRef
30.
Hoenigl M, Eigl S, Heldt S, Duettmann W, Thornton C, Prattes J. Clinical evaluation of the newly formatted lateral-flow device for invasive pulmonary aspergillosis. Mycoses. 2018;61:40–3.CrossRef
31.
32.
33.
Dufresne SF, Datta K, Li X, Dadachova E, Staab JF, Patterson TF, et al. Detection of urinary excreted fungal galactomannan-like antigens for diagnosis of invasive aspergillosis. PLoS One. 2012;e42736:7.
34.
35.
Dweik RA, Boggs PB, Erzurum SC, Irvin CG, Leigh MW, Lundberg JO, et al. An official ATS clinical practice guideline: interpretation of exhaled nitric oxide levels (FeNO) for clinical applications. Am J Respir Crit Care Med. 2011;184:602–15.CrossRef
36.
Graham DY, Klein PD, Evans DJ, Evans DG, Alpert LC, Opekun AR, et al. Campylobacter pylori detected noninvasively by the 13C-urea breath test. Lancet Lond Engl. 1987;1:1174–7.CrossRef
37.
Phillips M, Boehmer JP, Cataneo RN, Cheema T, Eisen HJ, Fallon JT, et al. Heart allograft rejection: detection with breath alkanes in low levels (the HARDBALL study). J Heart Lung Transplant Off Publ Int Soc Heart Transplant. 2004;23:701–8.CrossRef
38.
•• Pereira J, Porto-Figueira P, Cavaco C, Taunk K, Rapole S, Dhakne R, et al. Breath analysis as a potential and non-invasive frontier in disease diagnosis: an overview. Metabolites. 2015;5:3–55. Overview of breath based diagnostics. CrossRef
39.
Chambers ST, Syhre M, Murdoch DR, McCartin F, Epton MJ. Detection of 2-Pentylfuran in the breath of patients with Aspergillus fumigatus. Med Mycol. 2009;47:468–76.CrossRef
40.
Syhre M, Scotter JM, Chambers ST. Investigation into the production of 2-Pentylfuran by Aspergillus fumigatus and other respiratory pathogens in vitro and human breath samples. Med Mycol. 2008;46:209–15.CrossRef
41.
Bhandari S, Chambers S, Pearson J, Syhre M, Epton M, Scott-Thomas A. Determining the limits and confounders for the 2-pentyl furan breath test by gas chromatography/mass spectrometry. J Chromatogr B Anal Technol Biomed Life Sci. 2011;879:2815–20.CrossRef
42.
Heddergott C, Calvo AM, Latgé JP. The Volatome of Aspergillus fumigatus. Eukaryot Cell. 2014;13:1014–25.CrossRef
43.
Koo S, Thomas HR, Daniels SD, Lynch RC, Fortier SM, Shea MM, et al. A breath fungal secondary metabolite signature to diagnose invasive aspergillosis. Clin Infect Dis. 2014;59:1733–40.CrossRef
44.
Bikov A, Paschalaki K, Logan-Sinclair R, Horváth I, Kharitonov SA, Barnes PJ, et al. Standardised exhaled breath collection for the measurement of exhaled volatile organic compounds by proton transfer reaction mass spectrometry. BMC Pulm Med. 2013;13:43.CrossRef
45.
Thekedar B, Oeh U, Szymczak W, Hoeschen C, Paretzke HG. Influences of mixed expiratory sampling parameters on exhaled volatile organic compound concentrations. J Breath Res. 2011;5:016001.CrossRef
46.
de Heer K, van der Schee MP, Zwinderman K, vanden Berk IAH, Visser CE, van Oers R, et al. Electronic nose technology for detection of invasive pulmonary aspergillosis in prolonged chemotherapy-induced neutropenia: a proof-of-principle study. J Clin Microbiol. 2013;51:1490–5.CrossRef
47.
Wang Y, Chen L, Liu X, Cheng D, Liu G, Liu Y, et al. Detection of Aspergillus fumigatus pulmonary fungal infections in mice with 99mTc-labeled MORF oligomers targeting ribosomal RNA. Nucl Med Biol. 2013;40:89–96.CrossRef
48.
Davies G, Rolle A-M, Maurer A, Spycher PR, Schillinger C, Solouk-Saran D, et al. Towards translational ImmunoPET/MR imaging of invasive pulmonary aspergillosis: the humanised monoclonal antibody JF5 detects Aspergillus lung infections in vivo. Theranostics. 2017;7:3398–414.CrossRef
49.
Rolle A-M, Hasenberg M, Thornton CR, Solouk-Saran D, Männ L, Weski J, et al. ImmunoPET/MR imaging allows specific detection of Aspergillus fumigatus lung infection in vivo. Proc Natl Acad Sci U S A. 2016;113:E1026–33.CrossRef
50.
Haas H, Petrik M, Decristoforo C. An iron-mimicking, Trojan horse-entering fungi—has the time come for molecular imaging of fungal infections? PLoS Pathog. 2015;11:e1004568.CrossRef
51.
Orasch T, Prattes J, Faserl K, Eigl S, Düttmann W, Lindner H, et al. Bronchoalveolar lavage triacetylfusarinine C (TAFC) determination for diagnosis of invasive pulmonary aspergillosis in patients with hematological malignancies. J Inf Secur. 2017;75:370–3.
52.
Petrik M, Haas H, Dobrozemsky G, Lass-Flörl C, Helbok A, Blatzer M, et al. 68Ga-siderophores for PET imaging of invasive pulmonary aspergillosis: proof of principle. J Nucl Med Off Publ Soc Nucl Med. 2010;51:639–45.
53.
Petrik M, Franssen GM, Haas H, Laverman P, Hörtnagl C, Schrettl M, et al. Preclinical evaluation of two 68Ga-siderophores as potential radiopharmaceuticals for Aspergillus fumigatus infection imaging. Eur J Nucl Med Mol Imaging. 2012;39:1175–83.CrossRef
54.
Petrik M, Haas H, Laverman P, Schrettl M, Franssen GM, Blatzer M, et al. 68Ga-triacetylfusarinine C and 68Ga-ferrioxamine E for Aspergillus infection imaging: uptake specificity in various microorganisms. Mol Imaging Biol. 2014;16:102–8.CrossRef
55.
Lewis RE, Wiederhold NP, Chi J, Han XY, Komanduri KV, Kontoyiannis DP, et al. Detection of gliotoxin in experimental and human aspergillosis. Infect Immun. 2005;73:635–7.CrossRef
56.
Waring P, Newcombe N, Edel M, Lin QH, Jiang H, Sjaarda A, et al. Cellular uptake and release of the immunomodulating fungal toxin gliotoxin. Toxicon Off J Int Soc Toxinology. 1994;32:491–504.CrossRef
57.
Dolan SK, Bock T, Hering V, Owens RA, Jones GW, Blankenfeldt W, et al. Structural, mechanistic and functional insight into gliotoxin bis-thiomethylation in aspergillus fumigatus. Open Biol 2017;7.
58.
Domingo MP, Colmenarejo C, Martínez-Lostao L, Müllbacher A, Jarne C, Revillo MJ, et al. Bis(methyl)gliotoxin proves to be a more stable and reliable marker for invasive aspergillosis than gliotoxin and suitable for use in diagnosis. Diagn Microbiol Infect Dis. 2012;73:57–64.CrossRef
59.
Hammarström H, Aspelund AS, Christensson B, Heußel CP, Isaksson J, Kondori N, et al. Prospective evaluation of a combination of fungal biomarkers for the diagnosis of invasive fungal disease in high-risk hematology patients. Mycoses 2018. Available from: https://​doi.​org/​10.​1111/​myc.​12773
60.
Sugui JA, Rose SR, Nardone G, Swamydas M, Lee C-CR, Kwon-Chung KJ, et al. Host immune status-specific production of gliotoxin and bis-methyl-gliotoxin during invasive aspergillosis in mice. Sci Rep. 2017;7:10977.CrossRef
61.
Sendid B, Poissy J, François N, Mery A, Courtecuisse S, Krzewinski F, et al. Preliminary evidence for a serum disaccharide signature of invasive Candida albicans infection detected by MALDI mass spectrometry. Clin Microbiol Infect. 2015;21:88.e1–6.CrossRef
62.
Johnson GL, Sarker S-J, Nannini F, Ferrini A, Taylor E, Lass-Flörl C, et al. Aspergillus-specific lateral-flow device and real-time PCR testing of bronchoalveolar lavage fluid: a combination biomarker approach for clinical diagnosis of invasive pulmonary aspergillosis. J Clin Microbiol. 2015;53:2103–8.CrossRef
63.
Boch T, Spiess B, Cornely OA, Vehreschild JJ, Rath PM, Steinmann J, et al. Diagnosis of invasive fungal infections in haematological patients by combined use of galactomannan, 1,3-β-D-glucan, Aspergillus PCR, multifungal DNA-microarray, and Aspergillus azole resistance PCRs in blood and bronchoalveolar lavage samples: results of a prospective multicentre study. Clin Microbiol Infect. 2016;22:862–8.CrossRef
64.
Heldt S, Eigl S, Prattes J, Flick H, Rabensteiner J, Prüller F, et al. Levels of interleukin (IL)-6 and IL-8 are elevated in serum and bronchoalveolar lavage fluid of haematological patients with invasive pulmonary aspergillosis. Mycoses. 2017;60:818–25.CrossRef
65.
Gonçalves SM, Lagrou K, Rodrigues CS, Campos CF, Bernal-Martínez L, Rodrigues F, Silvestre R, Alcazar-Fuoli L, Maertens JA, Cunha C, Carvalho A Evaluation of bronchoalveolar lavage fluid cytokines as biomarkers for invasive pulmonary aspergillosis in at-risk patients. Front Microbiol 2017;8. Available from: https://​www.​ncbi.​nlm.​nih.​gov/​pmc/​articles/​PMC5712575/​
66.
Potenza L, Barozzi P, Vallerini D, Bosco R, Quadrelli C, Mediani L, et al. Diagnosis of invasive aspergillosis by tracking Aspergillus-specific T cells in hematologic patients with pulmonary infiltrates. Leukemia. 2007;21:578–81.CrossRef
67.
Camargo JF, Husain S. Immune correlates of protection in human invasive aspergillosis. Clin Infect Dis. 2014;59:569–77.CrossRef
68.
Potenza L, Vallerini D, Barozzi P, Riva G, Forghieri F, Beauvais A, et al. Characterization of specific immune responses to different Aspergillus antigens during the course of invasive aspergillosis in hematologic patients. PLoS One. 2013;8:e74326.CrossRef
69.
Potenza L, Vallerini D, Barozzi P, Riva G, Forghieri F, Zanetti E, et al. Mucorales-specific T cells emerge in the course of invasive mucormycosis and may be used as a surrogate diagnostic marker in high-risk patients. Blood. 2011;118:5416–9.CrossRef
Metadata
Title
Diagnosing Invasive Mold Infections: What Is Next
Authors
Toine Mercier
Ellen Guldentops
Ruth Van Daele
Johan Maertens
Publication date
01-12-2018
Publisher
Springer US
Published in
Current Fungal Infection Reports / Issue 4/2018
Print ISSN: 1936-3761
Electronic ISSN: 1936-377X
DOI
https://doi.org/10.1007/s12281-018-0322-0

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