血液領域の侵襲性真菌感染症診断における真菌バイオマーカーの基礎知識
侵襲性真菌感染症の診断において培養は基本かつ重要な検査であり，培養検査，病理組織学的な検査はその確定診断（proven diagnosis）に必要な項目となっている．一方で培養検査は感度が十分ではなく，結果判明までに時間を要することも多いため，モニタリングや早期診断に用いるには限界がある．そこで重要となるのが真菌の構造から産生される生物学的産物である真菌バイオマーカーを含む培養以外の菌学的検査，non-culture-based testsになる．国内の血液診療で広く用いられているのは真菌の細胞壁の構成成分を検出し，ムーコルなど一部の真菌を除く真菌全般のバイオマーカーとして用いられている(1→...
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| Published in | 日本医真菌学会雑誌 Vol. 65; no. 3; pp. 67 - 72 |
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| Main Author | |
| Format | Journal Article |
| Language | Japanese |
| Published |
一般社団法人 日本医真菌学会
31.07.2024
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| Subjects | |
| Online Access | Get full text |
| ISSN | 2434-5229 2434-5237 |
| DOI | 10.11534/ishinkin.24.006 |
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| Abstract | 侵襲性真菌感染症の診断において培養は基本かつ重要な検査であり，培養検査，病理組織学的な検査はその確定診断（proven diagnosis）に必要な項目となっている．一方で培養検査は感度が十分ではなく，結果判明までに時間を要することも多いため，モニタリングや早期診断に用いるには限界がある．そこで重要となるのが真菌の構造から産生される生物学的産物である真菌バイオマーカーを含む培養以外の菌学的検査，non-culture-based testsになる．国内の血液診療で広く用いられているのは真菌の細胞壁の構成成分を検出し，ムーコルなど一部の真菌を除く真菌全般のバイオマーカーとして用いられている(1→3)-β-Dグルカン（BDG），アスペルギルスの細胞壁の構成成分であるアスペルギルスガラクトマンナン抗原（GM）である．海外からは侵襲性アスペルギルス症の診断におけるlateral flow assayやpolymerase chain reaction（PCR），侵襲性カンジダ症の診断におけるT2カンジダなどの新しい真菌バイオマーカーの有用性も報告されている．本稿では，BDG，GMを中心に，新たな真菌バイオマーカーにも触れながら，血液領域の侵襲性真菌感染症診断における真菌バイオマーカーについてまとめる．本稿の内容は2023年10月の第67回日本医真菌学会総会・学術集会のシンポジウム12「血液領域の侵襲性真菌感染症診断におけるバイオマーカーの基礎知識」の内容に加筆修正したものである． |
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| AbstractList | 侵襲性真菌感染症の診断において培養は基本かつ重要な検査であり，培養検査，病理組織学的な検査はその確定診断（proven diagnosis）に必要な項目となっている．一方で培養検査は感度が十分ではなく，結果判明までに時間を要することも多いため，モニタリングや早期診断に用いるには限界がある．そこで重要となるのが真菌の構造から産生される生物学的産物である真菌バイオマーカーを含む培養以外の菌学的検査，non-culture-based testsになる．国内の血液診療で広く用いられているのは真菌の細胞壁の構成成分を検出し，ムーコルなど一部の真菌を除く真菌全般のバイオマーカーとして用いられている(1→3)-β-Dグルカン（BDG），アスペルギルスの細胞壁の構成成分であるアスペルギルスガラクトマンナン抗原（GM）である．海外からは侵襲性アスペルギルス症の診断におけるlateral flow assayやpolymerase chain reaction（PCR），侵襲性カンジダ症の診断におけるT2カンジダなどの新しい真菌バイオマーカーの有用性も報告されている．本稿では，BDG，GMを中心に，新たな真菌バイオマーカーにも触れながら，血液領域の侵襲性真菌感染症診断における真菌バイオマーカーについてまとめる．本稿の内容は2023年10月の第67回日本医真菌学会総会・学術集会のシンポジウム12「血液領域の侵襲性真菌感染症診断におけるバイオマーカーの基礎知識」の内容に加筆修正したものである． |
| Author | 木村, 俊一 |
| Author_xml | – sequence: 1 fullname: 木村, 俊一 organization: 自治医科大学附属さいたま医療センター 血液科 |
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| Copyright | 2024 一般社団法人日本医真菌学会 |
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Am J Med 1986; 81: 249–54. 16） Kappe R, Schulze-Berge A: New cause for false-positive results with the Pastorex Aspergillus antigen latex agglutination test. J Clin Microbiol 1993; 31: 2489–90. 39） Maertens J, Lodewyck T, Donnelly JP, Chantepie S, Robin C, Blijlevens N, et al: Empiric vs preemptive antifungal strategy in high-risk neutropenic patients on fluconazole prophylaxis: a randomized trial of the European Organization for Research and Treatment of Cancer. Clin Infect Dis 2023; 76: 674–82. 25） White PL, Price JS, Posso RB, Barnes RA: An evaluation of the performance of the Dynamiker® Fungus (1-3)-β-D-Glucan Assay to assist in the diagnosis of invasive aspergillosis, invasive candidiasis and Pneumocystis pneumonia. Med Mycol 2017; 55: 843–50. 9） Garey KW, Rege M, Pai MP, Mingo DE, Suda KJ, Turpin RS, et al: Time to initiation of fluconazole therapy impacts mortality in patients with candidemia: a multi-institutional study. Clin Infect Dis 2006; 43: 25–31. 5） Maertens J, Maertens V, Theunissen K, Meersseman W, Meersseman P, Meers S, et al: Bronchoalveolar lavage fluid galactomannan for the diagnosis of invasive pulmonary aspergillosis in patients with hematologic diseases. Clin Infect Dis 2009; 49: 1688–93. 19） Kimura S, Akahoshi Y, Nakano H, Harada N, Kameda K, Ugai T, et al: False-positive Aspergillus galactomannan and its kinetics in allogeneic hematopoietic stem cell transplantation. J Infect 2015; 70: 520–40. 23） Lamoth F, Akan H, Andes D, Cruciani M, Marchetti O, Ostrosky-Zeichner L, et al: Assessment of the role of 1,3-β-d-glucan testing for the diagnosis of invasive fungal infections in adults. Clin Infect Dis 2021; 72 (Suppl 2): S102–8. 18） Asano-Mori Y, Kanda Y, Oshima K, Kako S, Shinohara A, Nakasone H, et al: False-positive Aspergillus galactomannan antigenaemia after haematopoietic stem cell transplantation. J Antimicrob Chemother 2008; 61: 411–6. 6） Clancy CJ, Nguyen MH: Finding the “missing 50%” of invasive candidiasis: how nonculture diagnostics will improve understanding of disease spectrum and transform patient care. Clin Infect Dis 2013; 56: 1284–92. 33） Shibata W, Niki M, Sato K, Fujimoto H, Yamada K, Watanabe T, et al: Detection of Rhizopus-specific antigen in human and murine serum and bronchoalveolar lavage. Med Mycol 2020; 58: 958–64. 36） Freifeld AG, Bow EJ, Sepkowitz KA, Boeckh MJ, Ito JI, Mullen CA, et al: Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis 2011; 52: e56-93. 1） Donnelly JP, Chen SC, Kauffman CA, Steinbach WJ, Baddley JW, Verweij PE, et al: Revision and update of the consensus definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium. Clin Infect Dis 2020; 71: 1367–76. 32） Millon L, Caillot D, Berceanu A, Bretagne S, Lanternier F, Morio F, et al: Evaluation of serum Mucorales polymerase chain reaction (PCR) for the diagnosis of Mucormycoses: The MODIMUCOR Prospective Trial. Clin Infect Dis 2022; 75: 777–85. 20）Duarte RF, Sánchez-Ortega I, Cuesta I, Arnan M, Patiño B, Fernández de Sevilla A, et al: Serum galactomannan-based early detection of invasive aspergillosis in hematology patients receiving effective antimold prophylaxis. Clin Infect Dis 2014; 59: 1696–702. 7） Neofytos D, Horn D, Anaissie E, Steinbach W, Olyaei A, Fishman J, et al: Epidemiology and outcome of invasive fungal infection in adult hematopoietic stem cell transplant recipients: analysis of Multicenter Prospective Antifungal Therapy (PATH) Alliance registry. Clin Infect Dis 2009; 48: 265–73. 10） Greene RE, Schlamm HT, Oestmann JW, Stark P, Durand C, Lortholary O, et al: Imaging findings in acute invasive pulmonary aspergillosis: clinical significance of the halo sign. Clin Infect Dis 2007; 44: 373–9. 21） Kimura SI, Kanda Y, Oyake T, Yamaguchi H, Fujiwara SI, Okamoto A, et al: Fungal biomarker monitoring and CT scans for early detection of invasive fungal disease in neutropenic hematological patients. J Infect 2022; 84: 80–6. 26） White SK, Walker BS, Hanson KE, Schmidt RL: Diagnostic accuracy of β-d-glucan (fungitell) testing among patients with hematologic malignancies or solid organ tumors: a systematic review and meta-analysis. Am J Clin Pathol 2019; 151: 275–85. 8） Morrell M, Fraser VJ, Kollef MH: Delaying the empiric treatment of Candida bloodstream infection until positive blood culture results are obtained: a potential risk factor for hospital mortality. Antimicrob Agents Chemother 2005; 49: 3640–5. 30） Mercier T, Guldentops E, Lagrou K, Maertens J: Prospective evaluation of the turbidimetric β-D-glucan assay and 2 lateral flow assays on serum in invasive aspergillosis. Clin Infect Dis 2021; 72: 1577–84. 17） Mattei D, Rapezzi D, Mordini N, Cuda F, Lo Nigro C, Musso M, et al: False-positive Aspergillus galactomannan enzyme-linked immunosorbent assay results in vivo during amoxicillin-clavulanic acid treatment. J Clin Microbiol 2004; 42: 5362–3. 13） Leeflang MM, Debets-Ossenkopp YJ, Wang J, Visser CE, Scholten RJ, Hooft L, et al: Galactomannan detection for invasive aspergillosis in immunocompromised patients. Cochrane Database Syst Rev 2015; 2015: CD007394. 27） Sunamura EI, Iwasaki M, Shiina S, Kitahara SI, Yotani T, Manabe M, et al: A novel enzyme immunoassay for the measurement of plasma (1→3)-β-D-glucan levels. J Immunol Methods 2020; 487: 112872. 35） Ceesay MM, Desai SR, Berry L, Cleverley J, Kibbler CC, Pomplun S, et al: A comprehensive diagnostic approach using galactomannan, targeted β-d-glucan, baseline computerized tomography and biopsy yields a significant burden of invasive fungal disease in at risk haematology patients. Br J Haematol 2015; 168: 219–29. 38） Cordonnier C, Pautas C, Maury S, Vekhoff A, Farhat H, Suarez F, et al: Empirical versus preemptive antifungal therapy for high-risk, febrile, neutropenic patients: a randomized, controlled trial. Clin Infect Dis 2009; 48: 1042–51. 22） Koo S, Bryar JM, Baden LR, Marty FM: Prognostic features of galactomannan antigenemia in galactomannan-positive invasive aspergillosis. J Clin Microbiol 2010; 48: 1255–60. 29） Mengoli C, Cruciani M, Barnes RA, Loeffler J, Donnelly JP: Use of PCR for diagnosis of invasive aspergillosis: systematic review and meta-analysis. Lancet Infect Dis 2009; 9: 89–96. 37） Maertens J, Theunissen K, Verhoef G, Verschakelen J, Lagrou K, Verbeken E, et al: Galactomannan and computed tomography-based preemptive antifungal therapy in neutropenic patients at high risk for invasive fungal infection: a prospective feasibility study. Clin Infect Dis 2005; 41: 1242–50. 24） White SK, Schmidt RL, Walker BS, Hanson KE: (1→3)-β-D-glucan testing for the detection of invasive fungal infections in immunocompromised or critically ill people. Cochrane Database Syst Rev 2020; 7: CD009833. 40） Kanda Y, Kimura SI, Iino M, Fukuda T, Sakaida E, Oyake T, et al: D-index-guided early antifungal therapy versus empiric antifungal therapy for persistent febrile neutropenia: a randomized controlled noninferiority trial. J Clin Oncol 2020; 38: 815–22. |
| References_xml | – reference: 13） Leeflang MM, Debets-Ossenkopp YJ, Wang J, Visser CE, Scholten RJ, Hooft L, et al: Galactomannan detection for invasive aspergillosis in immunocompromised patients. Cochrane Database Syst Rev 2015; 2015: CD007394. – reference: 20）Duarte RF, Sánchez-Ortega I, Cuesta I, Arnan M, Patiño B, Fernández de Sevilla A, et al: Serum galactomannan-based early detection of invasive aspergillosis in hematology patients receiving effective antimold prophylaxis. Clin Infect Dis 2014; 59: 1696–702. – reference: 17） Mattei D, Rapezzi D, Mordini N, Cuda F, Lo Nigro C, Musso M, et al: False-positive Aspergillus galactomannan enzyme-linked immunosorbent assay results in vivo during amoxicillin-clavulanic acid treatment. J Clin Microbiol 2004; 42: 5362–3. – reference: 7） Neofytos D, Horn D, Anaissie E, Steinbach W, Olyaei A, Fishman J, et al: Epidemiology and outcome of invasive fungal infection in adult hematopoietic stem cell transplant recipients: analysis of Multicenter Prospective Antifungal Therapy (PATH) Alliance registry. Clin Infect Dis 2009; 48: 265–73. – reference: 1） Donnelly JP, Chen SC, Kauffman CA, Steinbach WJ, Baddley JW, Verweij PE, et al: Revision and update of the consensus definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium. Clin Infect Dis 2020; 71: 1367–76. – reference: 16） Kappe R, Schulze-Berge A: New cause for false-positive results with the Pastorex Aspergillus antigen latex agglutination test. J Clin Microbiol 1993; 31: 2489–90. – reference: 21） Kimura SI, Kanda Y, Oyake T, Yamaguchi H, Fujiwara SI, Okamoto A, et al: Fungal biomarker monitoring and CT scans for early detection of invasive fungal disease in neutropenic hematological patients. J Infect 2022; 84: 80–6. – reference: 24） White SK, Schmidt RL, Walker BS, Hanson KE: (1→3)-β-D-glucan testing for the detection of invasive fungal infections in immunocompromised or critically ill people. Cochrane Database Syst Rev 2020; 7: CD009833. – reference: 15） Marr KA, Balajee SA, McLaughlin L, Tabouret M, Bentsen C, Walsh TJ: Detection of galactomannan antigenemia by enzyme immunoassay for the diagnosis of invasive aspergillosis: variables that affect performance. J Infect Dis 2004; 190: 641–9. – reference: 23） Lamoth F, Akan H, Andes D, Cruciani M, Marchetti O, Ostrosky-Zeichner L, et al: Assessment of the role of 1,3-β-d-glucan testing for the diagnosis of invasive fungal infections in adults. Clin Infect Dis 2021; 72 (Suppl 2): S102–8. – reference: 14） Kimura SI, Fujita H, Handa H, Hiramoto N, Hosono N, Minamiguchi H, et al: Real-world management of infection during chemotherapy for acute leukemia in Japan: from the results of a nationwide questionnaire-based survey by the Japan Adult Leukemia Study Group. Int J Hematol 2020; 112: 409–17. – reference: 9） Garey KW, Rege M, Pai MP, Mingo DE, Suda KJ, Turpin RS, et al: Time to initiation of fluconazole therapy impacts mortality in patients with candidemia: a multi-institutional study. Clin Infect Dis 2006; 43: 25–31. – reference: 4) Yu VL, Muder RR, Poorsattar A: Significance of isolation of Aspergillus from the respiratory tract in diagnosis of invasive pulmonary aspergillosis: results from a three-year prospective study. Am J Med 1986; 81: 249–54. – reference: 11） Chamilos G, Lewis RE, Kontoyiannis DP: Delaying amphotericin B-based frontline therapy significantly increases mortality among patients with hematologic malignancy who have zygomycosis. Clin Infect Dis 2008; 47: 503–9. – reference: 8） Morrell M, Fraser VJ, Kollef MH: Delaying the empiric treatment of Candida bloodstream infection until positive blood culture results are obtained: a potential risk factor for hospital mortality. Antimicrob Agents Chemother 2005; 49: 3640–5. – reference: 10） Greene RE, Schlamm HT, Oestmann JW, Stark P, Durand C, Lortholary O, et al: Imaging findings in acute invasive pulmonary aspergillosis: clinical significance of the halo sign. Clin Infect Dis 2007; 44: 373–9. – reference: 12） Marchetti O, Lamoth F, Mikulska M, Viscoli C, Verweij P, Bretagne S: ECIL recommendations for the use of biological markers for the diagnosis of invasive fungal diseases in leukemic patients and hematopoietic SCT recipients. Bone Marrow Transplant 2012; 47: 846–54. – reference: 26） White SK, Walker BS, Hanson KE, Schmidt RL: Diagnostic accuracy of β-d-glucan (fungitell) testing among patients with hematologic malignancies or solid organ tumors: a systematic review and meta-analysis. Am J Clin Pathol 2019; 151: 275–85. – reference: 28） Jaijakul S, Vazquez JA, Swanson RN, Ostrosky-Zeichner L: (1,3)-β-D-glucan as a prognostic marker of treatment response in invasive candidiasis. Clin Infect Dis 2012; 55: 521–6. – reference: 27） Sunamura EI, Iwasaki M, Shiina S, Kitahara SI, Yotani T, Manabe M, et al: A novel enzyme immunoassay for the measurement of plasma (1→3)-β-D-glucan levels. J Immunol Methods 2020; 487: 112872. – reference: 22） Koo S, Bryar JM, Baden LR, Marty FM: Prognostic features of galactomannan antigenemia in galactomannan-positive invasive aspergillosis. J Clin Microbiol 2010; 48: 1255–60. – reference: 5） Maertens J, Maertens V, Theunissen K, Meersseman W, Meersseman P, Meers S, et al: Bronchoalveolar lavage fluid galactomannan for the diagnosis of invasive pulmonary aspergillosis in patients with hematologic diseases. Clin Infect Dis 2009; 49: 1688–93. – reference: 39） Maertens J, Lodewyck T, Donnelly JP, Chantepie S, Robin C, Blijlevens N, et al: Empiric vs preemptive antifungal strategy in high-risk neutropenic patients on fluconazole prophylaxis: a randomized trial of the European Organization for Research and Treatment of Cancer. Clin Infect Dis 2023; 76: 674–82. – reference: 18） Asano-Mori Y, Kanda Y, Oshima K, Kako S, Shinohara A, Nakasone H, et al: False-positive Aspergillus galactomannan antigenaemia after haematopoietic stem cell transplantation. J Antimicrob Chemother 2008; 61: 411–6. – reference: 30） Mercier T, Guldentops E, Lagrou K, Maertens J: Prospective evaluation of the turbidimetric β-D-glucan assay and 2 lateral flow assays on serum in invasive aspergillosis. Clin Infect Dis 2021; 72: 1577–84. – reference: 31） Mylonakis E, Clancy CJ, Ostrosky-Zeichner L, Garey KW, Alangaden GJ, Vazquez JA, et al: T2 magnetic resonance assay for the rapid diagnosis of candidemia in whole blood: a clinical trial. Clin Infect Dis 2015; 60: 892–9. – reference: 36） Freifeld AG, Bow EJ, Sepkowitz KA, Boeckh MJ, Ito JI, Mullen CA, et al: Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis 2011; 52: e56-93. – reference: 25） White PL, Price JS, Posso RB, Barnes RA: An evaluation of the performance of the Dynamiker® Fungus (1-3)-β-D-Glucan Assay to assist in the diagnosis of invasive aspergillosis, invasive candidiasis and Pneumocystis pneumonia. Med Mycol 2017; 55: 843–50. – reference: 6） Clancy CJ, Nguyen MH: Finding the “missing 50%” of invasive candidiasis: how nonculture diagnostics will improve understanding of disease spectrum and transform patient care. Clin Infect Dis 2013; 56: 1284–92. – reference: 32） Millon L, Caillot D, Berceanu A, Bretagne S, Lanternier F, Morio F, et al: Evaluation of serum Mucorales polymerase chain reaction (PCR) for the diagnosis of Mucormycoses: The MODIMUCOR Prospective Trial. Clin Infect Dis 2022; 75: 777–85. – reference: 29） Mengoli C, Cruciani M, Barnes RA, Loeffler J, Donnelly JP: Use of PCR for diagnosis of invasive aspergillosis: systematic review and meta-analysis. 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| Snippet | 侵襲性真菌感染症の診断において培養は基本かつ重要な検査であり，培養検査，病理組織学的な検査はその確定診断（proven... |
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| SubjectTerms | アスペルギルス カンジダ 侵襲性真菌感染症 培養 真菌バイオマーカー |
| Title | 血液領域の侵襲性真菌感染症診断における真菌バイオマーカーの基礎知識 |
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| ispartofPNX | 日本医真菌学会雑誌, 2024/07/31, Vol.65(3), pp.67-72 |
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