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Mycology

Prospective Comparison of the Diagnostic Potential of Real-Time PCR, Double-Sandwich Enzyme-Linked Immunosorbent Assay for Galactomannan, and a (1→3)-β-d-Glucan Test in Weekly Screening for Invasive Aspergillosis in Patients with Hematological Disorders

Masahito Kawazu, Yoshinobu Kanda, Yasuhito Nannya, Katsunori Aoki, Mineo Kurokawa, Shigeru Chiba, Toru Motokura, Hisamaru Hirai, Seishi Ogawa
Masahito Kawazu
1Department of Hematology and Oncology
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Yoshinobu Kanda
1Department of Hematology and Oncology
2Department of Cell Therapy and Transplantation Medicine
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Yasuhito Nannya
1Department of Hematology and Oncology
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Katsunori Aoki
1Department of Hematology and Oncology
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Mineo Kurokawa
1Department of Hematology and Oncology
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Shigeru Chiba
1Department of Hematology and Oncology
2Department of Cell Therapy and Transplantation Medicine
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Toru Motokura
1Department of Hematology and Oncology
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Hisamaru Hirai
1Department of Hematology and Oncology
2Department of Cell Therapy and Transplantation Medicine
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Seishi Ogawa
1Department of Hematology and Oncology
3Department of Regeneration Medicine for Hematopoiesis, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan
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  • For correspondence: sogawa-tky@umin.ac.jp
DOI: 10.1128/JCM.42.6.2733-2741.2004
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  • FIG. 1.
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    FIG. 1.

    (A to C) ROC curves of the GM (A), PCR (B), and BDG (C) tests for screening for IA. Both methods I and II were used. The ROC curves obtained by estimate A/B are shown in red, and those obtained by estimate C are shown in blue. The ROC curves obtained by method II are indicated by solid lines, and those obtained by method I are indicated by dotted lines. (D) Combination of ROC curves of the GM test (method II) and those of the PCR and BDG tests (method I).

  • FIG. 2.
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    FIG. 2.

    Number of days from when GM assays become positive to the onset of treatment, using a threshold of 0.6 O.D.I. by method II (solid arrowheads) or 1.0 O.D.I. by method II (open arrowheads), or positive findings on CT. Open triangles indicate the date of positive culture, and solid triangles indicate when the histopathological diagnosis was made (Px, biopsy; Ax, autopsy). The values in parentheses indicate the number of days after the onset of treatment. For example, for episode 11, CT showed specific findings 50 days after the onset of treatment and the GM assay become positive 2 days before treatment. Episode numbers correspond to those in Table 2. Episodes whose GM assays did not reach the threshold are not shown. For episodes 2 and 9, a CT scan was not performed, and for episodes 7, 8, 10, 17, 19, 21, and 22, the CT findings were nonspecific and could not be used for decision-making. Each treatment was started at the discretion of the physician, taking into account various prices of clinical information, including CT findings and the results of GM assays. For Episode 8, IA was not suspected and no antifungal agent was administered. Therefore, the date of death was used instead of the date of treatment onset.

  • FIG. 3.
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    FIG. 3.

    Number of days before death that each test gave positive results. Solid triangles indicate the date when GM became positive, using a threshold of 0.6 O.D.I. by method II; open triangles indicate the date when PCR exceeded a cutoff value of 40 copies/ml; and shaded triangles indicate the date when the BDG test exceeded a cutoff value of 11 ng/ml, by method I. In episode 2, PCR never exceeded the cutoff value. Episode numbers correspond to those in Table 2.

Tables

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  • TABLE 1.

    Patient characteristics

    CharacteristicPatients with:Totalb
    Proven IAProbable IAPossible IFINo IA
    No. of episodes9213125149 (96)
    No. of deaths8141124
    No. of autopsies600814
    Age (yr)
        Mean4647434545
        Median4247404746
        Range19-6940-5318-6817-7417-74
    Sex (no. male/no. female)6/32/012/182/43102/47 (67/29)
    No. with diseasea
        AML3154857 (29)
        ALL1042631 (19)
        CML012811 (9)
        MDS3021116 (14)
        NHL2002830 (21)
        AA00022 (2)
        Other00022 (2)
    No. with allografts4264456
    Duration of episode (days)
        Mean12692785057
        Median13592573743
        Range36-23450-13435-17211-18111-234
    No. with host factor:
        Neutropenia71886102
        Fever6173751
        GVHD2251726
        Steroid2142835
        None1001819
    Duration of neutropenia (days)
        Mean6310421621
        Median3710181415
        Range0-2050-200-1620-1200-205
    No. of samples tested
        PCR154251469261,251
            Mean (per episode)17.112.511.27.48.4
            Median (per episode)1713966
            Range (per episode)7-326-194-243-263-32
        GM155241409141,233
            Mean (per episode)17.212.010.87.38.3
            Median (per episode)1812956
            Range (per episode)7-305-195-242-262-30
        BDG158241479141,243
            Mean (per episode)17.612.011.37.38.3
            Median (per episode)1912966
            Range (per episode)7-315-196-243-233-31
    • ↵ a AML, acute myelogenous leukemia; ALL, acute lymphocytic leukemia; CLL, chronic nyelogenous leukemia; MDS, myelodysplastic syndrome; NHL, non-Hodgkin lymphoma; AA, aplastic anemia.

    • ↵ b Values in parentheses are numbers of patients. Other values refer to numbers of episodes.

  • TABLE 2.

    Diagnosis of IA and its documentation

    Episode no.Patient characteristicsa:Host factorsClinical evidenceCulture and its sourceHistological evidenceMaximum value (method I/method II)
    Age (yr)SexIAPrimary diseaseStatus of primary diseaseOutcomePCR (copies/ml)GM (O.D.L)BDG (ng/ml)
    141FPAML M1Post-allo, RDDeadNFErosion of sinus walls A. flavus and A. fumigatus from pharyngeal mucosaBiopsy2,000/2003.8/3.619.7/4.7
    232MPMDS (RAEB-t)Post-allo, CRDeadGSDyspnea, pleural effusionAutopsy32/01.3/1.060.5/36.5
    358MPAML M1RDDeadNFHalo signAutopsy90/42.57.7/6.425/1.5
    438FPAML M2Post-allo, CRAliveNSCavity within area of consolidation A. fumigatus from broncheal lavage fluidBiopsy33.5/01.9/1.72.8/0
    551MPMacroglobulinemiaStable diseaseDeadNoneExtensive skull base destruction A. fumigatus from epidural abscessBiopsy0/01.2/0.837.4/7.1
    619MPMDS RARDDeadNFMultiple nodular lesions in the lung field, pleural effusionAutopsy3,500/1,0002.5/1.5155.5/59.2
    742MPMDS/AMLPost-allo, RDDeadNFGDyspnea, pleural effusionAutopsy24/92.4/0.60/0
    863FPATL acute typeRDDeadNFDyspnea, pleural effusionAutopsy50/12.51.9/0.72.4/0
    969MPALL PreBRDDeadNFNo specific clinical evidenceAutopsy100,000/5,0004.2/1.1171.7/12.6
    1053MPPAML M2Post-allo, CRDeadFGDyspnea, pleural effusion A. spergillus spp. from bronchoalveolar lavage fluidNAb5/05.3/0.74.5/2.2
    1140MPPCML CP1Post-allo, CRAliveNGSHalo sign A. fumigatus from sputumNA11.5/7.52.3/2.00/0
    1268MPPPMDS/AMLRDDeadNFMultiple nodular lesions in the lung field, intraparenchymal brain mass lesion, seizure, hemiparesisNA155/1002.2/1.518.3/16.6
    1324MPPPAML M4ECR, HDAraCAliveNFNodular skin lesion without any other explanation, multiple nodular lesions in the lung fieldNA20.5/04.5/0.30/0
    1461MPPPAML M4ECR, HDAraCAliveNHalo signNA1,000/90.2/0.13.5/2.9
    1530MPPPALL precursor BPost-allo, CRAliveNFGSNonspecific abnormal shadow in lung field, pleural effusionNA60/600.6/0.40/0
    1661MPPPAML M2RDDeadNFMultiple nodular lesions in the lung field, halo sign, cavity within area of consolidationNA84.5/01.1/0.72/0
    1768MPPPCML BCRDDeadNSDyspnea, pleural effusionNA165/00.3/0.20/0
    1825MPPPALL precursor BRDAliveNGCavity within area of consolidationNA400/00.7/0.63.2/0
    1932MPPPALL PreBPost-allo, CRDeadFGSDyspnea, pleural effusionNA27/10.7/0.53.7/2.4
    2018FPPPAML M2CR, HDAraCAliveNHalo signNA0/00.6/0.10/0
    2155MPPPMDS RAStable diseaseAliveFCough, dyspnea, pleural effusionNA19/40.8/0.30/0
    2228MPPPCML CP1Post-allo, CRAliveGCough, dyspnea, pleural effusionNA0/00.4/0.30/0
    2340MPPPCML CP1Post-allo, CRAliveGSCough, dyspnea, new infiltrate not fulfilling the major radiological criteria without an alternative diagnosisNA6/00.5/0.40/0
    2454MPPPALL precursor BPost-allo, CRAliveFDyspnea, new infiltrate not fulfilling the major radiological criteria without an alternative diagnosisNA10.5/00.5/0.30/0
    • ↵ a F, female; M, male; P, proven; PP, probable; PPP, possible; AML, acute myeloid leukemia; MDS, myelodysplastic syndrome; RA, refractory anemia; RAEB-t, RA with excess of blasts in transformation; ALL, acute lymphoblastic leukemia/lymphoma; CML, chronic myelogenous leukemia; CP, chronic phase; BC, blastic crisis; allo, allogencic hematopoietic stem cell transplantation; CR, complete remission; RD, refractory disease; HDAraC, high-dose cytrabine; N, neutropenia; F, persistent fever; G, GVHD, S, prolonged use of corticosteroid.

    • ↵ b NA, not available.

  • TABLE 3.

    Statistics for some selected thresholds

    Method and thresholdSensitivity A/B (C)Specificity A/B (D)PPV A/B (D)NDV A/B (C)Efficacy A/B (C)
    Method I
        GM (O.D.I.)
            0.51.00 (0.88)0.34 (0.33)0.12 (0.11)1.00 (0.93)0.40 (0.43)
            0.61.00 (0.79)0.55 (0.54)0.16 (0.15)1.00 (0.93)0.59 (0.59)
            1.01.00 (0.58)0.86 (0.85)0.38 (0.34)1.00 (0.91)0.87 (0.81)
            1.50.82 (0.46)0.90 (0.89)0.41 (0.38)0.98 (0.90)0.89 (0.83)
        PCR (copies/ml)
            50.91 (0.88)0.43 (0.41)0.12 (0.11)0.98 (0.95)0.47 (0.30)
            100.82 (0.79)0.60 (0.55)0.15 (0.13)0.97 (0.94)0.62 (0.63)
            200.73 (0.67)0.78 (0.75)0.23 (0.19)0.97 (0.92)0.78 (0.77)
            400.45 (0.46)0.98 (0.93)0.63 (0.36)0.95 (0.90)0.93 (0.89)
        BDG (ng/ml)
            20.82 (0.58)0.77 (0.76)0.24 (0.21)0.98 (0.91)0.78 (0.74)
            30.64 (0.46)0.84 (0.82)0.26 (0.23)0.96 (0.89)0.82 (0.78)
            50.55 (0.29)0.92 (0.92)0.38 (0.35)0.96 (0.87)0.89 (0.82)
            110.55 (0.29)0.98 (0.97)0.67 (0.60)0.96 (0.88)0.94 (0.87)
    Method II
        GM (O.D.I.)
            0.51.00 (0.63)0.84 (0.83)0.35 (0.31)1.00 (0.92)0.85 (0.81)
            0.61.00 (0.58)0.93 (0.91)0.55 (0.48)1.00 (0.92)0.93 (0.87)
            1.00.64 (0.33)0.98 (0.97)0.70 (0.64)0.97 (0.88)0.95 (0.87)
            1.50.45 (0.25)0.98 (0.97)0.63 (0.56)0.95 (0.87)0.93 (0.86)
        PCR (copies/ml)
            50.64 (0.43)0.87 (0.86)0.30 (0.27)0.96 (0.89)0.85 (0.80)
            100.45 (0.30)0.94 (0.93)0.38 (0.33)0.95 (0.88)0.90 (0.84)
            200.36 (0.26)0.98 (0.97)0.67 (0.50)0.95 (0.88)0.93 (0.87)
            400.36 (0.26)1.00 (0.99)1.00 (0.67)0.95 (0.88)0.95 (0.89)
        BDG (ng/ml)
            20.64 (0.42)0.91 (0.90)0.39 (0.33)0.97 (0.89)0.89 (0.83)
            30.55 (0.29)0.95 (0.95)0.50 (0.66)0.96 (0.88)0.92 (0.85)
            50.55 (0.29)0.98 (0.97)0.67 (0.60)0.96 (0.88)0.94 (0.87)
            110.45 (0.25)0.99 (0.99)0.83 (0.71)0.95 (0.87)0.95 (0.87)
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Prospective Comparison of the Diagnostic Potential of Real-Time PCR, Double-Sandwich Enzyme-Linked Immunosorbent Assay for Galactomannan, and a (1→3)-β-d-Glucan Test in Weekly Screening for Invasive Aspergillosis in Patients with Hematological Disorders
Masahito Kawazu, Yoshinobu Kanda, Yasuhito Nannya, Katsunori Aoki, Mineo Kurokawa, Shigeru Chiba, Toru Motokura, Hisamaru Hirai, Seishi Ogawa
Journal of Clinical Microbiology Jun 2004, 42 (6) 2733-2741; DOI: 10.1128/JCM.42.6.2733-2741.2004

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Prospective Comparison of the Diagnostic Potential of Real-Time PCR, Double-Sandwich Enzyme-Linked Immunosorbent Assay for Galactomannan, and a (1→3)-β-d-Glucan Test in Weekly Screening for Invasive Aspergillosis in Patients with Hematological Disorders
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Prospective Comparison of the Diagnostic Potential of Real-Time PCR, Double-Sandwich Enzyme-Linked Immunosorbent Assay for Galactomannan, and a (1→3)-β-d-Glucan Test in Weekly Screening for Invasive Aspergillosis in Patients with Hematological Disorders
Masahito Kawazu, Yoshinobu Kanda, Yasuhito Nannya, Katsunori Aoki, Mineo Kurokawa, Shigeru Chiba, Toru Motokura, Hisamaru Hirai, Seishi Ogawa
Journal of Clinical Microbiology Jun 2004, 42 (6) 2733-2741; DOI: 10.1128/JCM.42.6.2733-2741.2004
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KEYWORDS

aspergillosis
enzyme-linked immunosorbent assay
hematologic diseases
Mannans
polymerase chain reaction
beta-Glucans

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