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Invasive aspergillosis in allogeneic stem cell transplant recipients: changes in epidemiology and risk factors

Kieren A. Marr, Rachel A. Carter, Michael Boeckh, Paul Martin and Lawrence Corey

Article Figures & Data

Figures

  • Fig. 1.

    One-year cumulative incidence of proven or probable IA among allogeneic graft recipients through the 1990s.

    Data for years 1990 through 1992 were abstracted from a previously published study.2 Diagnoses established after second transplantation, relapsed malignancy, or death are not included.

  • Fig. 2.

    Probability of developing proven or probable IA according to time after transplantation for 187 case patients between 1993 and 1998.

  • Fig. 3.

    Probability of developing proven or probable IA among patients alive at day 40 in 2 cohorts.

    The first cohort underwent HSC transplantation between 1987 and 1992 and the second between 1993 and 1998 (overallP = .001).

  • Fig. 4.

    Probability of developing proven or probable IA late after onset of acute GVHD, diagnosis of CMV disease, or receipt of corticosteroids.

    Panel A shows probabilities for patients with acute GVHD (aGVHD) grade 1 or 2 and those with aGVHD grade 3 or 4. Panel B shows CMV disease, and panel C shows probability according to dose of corticosteroids administered.

  • Fig. 5.

    Probability of survival one year after diagnosis of proven or probable IA early, late, and very late after receipt of HSCT.

Tables

  • Table 1.

    Characteristics and outcomes of the cohort of patients who received allogeneic HSCTs at FHCRC, 1993-1998 (n = 1682)

    No. (%)
    Median recipient age, y (range)37 (0-68)
    Male sex1013 (60.2)
    Underlying diagnosis
     CML, chronic phase404 (24.0)
     Hematologic malignancy, first remission166 (9.9)
     Hematologic malignancy, other729 (43.3)
     Other383 (22.8)
    Donor and stem cell source
     MR BM566 (33.7)
     MR PBSCs192 (11.4)
     MM/UR BM882 (52.4)
     MM/UR PBSCs29 (1.7)
     Cord blood13 (0.8)
     T cell–depleted/CD34-selected70 (4.2)
    CMV serostatus*
     D−/R−571 (34.2)
     D+/R−252 (15.1)
     D−/R+366 (21.9)
     D+/R+483 (28.9)
    CMV disease166 (9.9)
    GVHD, acute grade higher than 11207 (77.2)
    GVHD, clinically extensive696 (59.0)
    Respiratory virus infection280 (16.7)
    Delayed neutrophil engraftment973 (57.9)
    Delayed lymphocyte engraftment1123 (66.8)
    Delayed monocyte engraftment1162 (69.1)
    Secondary neutropenia170 (10.1)
    • Only patients who received myeloablative conditioning regimens between January 1, 1993, and December 31, 1998, were included in the cohort. Cohort does not include patients who developed IA prior to HSC transplantation. Characteristics and outcome variables shown are those that were examined in risk factor models.

    • BM indicates bone marrow; PBSCs, peripheral blood stem cells; MM, mismatched; and UR, unrelated.

    • * CMV serostatus was not available for 10 patient-donor pairs.

  • Table 2.

    Risk factors for proven or probable IA among case (n = 187) and control (n = 1495) patients who received allogeneic HSCTs at FHCRC, 1993-1998

    Controls, no. (%)Cases, no. (%)HR95% CI
    Recipient-related factors
     Age, y
      Younger than 19239 (16.0)23 (12.3)1.0
      19-40634 (42.4)67 (35.8)1.5NS
      Older than 40622 (41.6)97 (51.9)2.41.5-3.82-153
     Underlying disease
      CML, chronic phase367 (24.6)37 (19.8)1.0
      Hematologic malignancy, first remission151 (10.1)15 (8.0)1.1NS
      Hematologic malignancy, other650 (43.5)79 (42.3)1.61.1-2.42-155
      Other* 327 (21.9)56 (30.0)2.11.4-3.22-153
    Transplant-related factors (donor and stem cell source)
     MR BM509 (34.1)57 (30.5)1.0
     MR PBSCs175 (11.7)17 (9.1)0.7NS
     MM/UR BM779 (52.1)103 (55.1)1.1NS
     MM/UR PBSCs22 (1.5)7 (3.7)2.81.1-7.02-155
     Cord blood10 (0.7)3 (1.6)5.11.5-17.22-155
     T cell–depleted/CD34-selected54 (3.6)16 (8.6)2.21.2-4.12-155
    Transplant complications
     Neutropenia 3.02.0-4.62-153
     GVHD, acute,
      Grades 0-11.0
      Grades 2-42.21.4-3.42-153
      Missing2.1NS
     GVHD, chronic (clinically extensive), 2.21.3-3.72-155
     CMV disease 7.04.5-10.82-153
     Respiratory virus infection 2.11.4-3.12-153
    • Hazard ratios (HRs) and 95% confidence intervals (CIs) are shown for all significant variables.

    • —indicates data not applicable; NS, not significant in the multivariable model.

    • * The most common “other” diagnoses are aplastic anemia, myelodysplastic syndrome, and multiple myeloma.

    • Factors entered into the model as time-dependent covariates.

    • The GVHD variable “missing” signifies patients who did not have data entered into the computerized system (n = 118). Acute and chronic GVHD were independently graded, as previously described.17 18

    • F2-153 P ≤ .001.

    • F2-155 P ≤ .05.

  • Table 3.

    Risk factors for early IA (up to 40 days after transplantation) and late IA (days 41-180 after transplantation)

    Early IA (n = 57)Late IA (n = 99)
    Cases, no. (%)HR95% CICases, no. (%)HR95% CI
    Recipient-related factors
     Age, y
      Younger than 195 (8.8)1.012 (12.1)
      19-4021 (36.8)3.81.3-11.23-155 34 (34.3)NSNS
      Older than 4031 (54.4)5.92.0-17.43-154 53 (53.5)
     Underlying disease3-150
      CML, chronic phase3 (5.3)1.024 (24.2)1.0
      Hematologic malignancy, first remission5 (8.8)4.41.0-18.83-155 6 (6.1)NS
      Hematologic malignancy, other31 (54.4)6.92.1-23.13-155 37 (37.4)NS
      Aplastic anemia2 (3.5)8.31.4-50.63-155 2 (2.0)NS
      Myelodysplastic syndrome9 (15.8)6.01.6-22.43-155 13 (13.1)NS
      Multiple myeloma2 (3.5)NS13 (13.1)4.52.3-9.13-154
     CMV serostatus3-151
      D−/R−14 (24.6)20 (20.2)1.0
      D+/R−5 (8.8)NSNS17 (17.2)2.01.0-3.73-155
      D−/R+17 (29.8)30 (30.3)2.01.1-3.73-155
      D+/R+21 (36.8)32 (32.3)NS
    Transplant-related factors (donor and stem cell source)
     MR BM17 (29.8)1.031 (31.3)
     MR PBSCs2 (3.5)0.20.05-0.93-155 12 (12.1)
     MM/UR BM32 (56.1)NS53 (53.5)NSNS
     MM/UR PBSCs3 (5.3)NS3 (3.0)
     Cord blood3 (5.3)13.53.3-55.53-154 0
     T cell–depleted/CD34-selected6 (10.5)NS9 (9.1)3.41.7-7.03-154
    Transplant complications
     Neutropenia3-152 2.61.4-4.83-155
     Lymphopenia3-152 2.01.1-3.83-155
     GVHD, acute3-152,3-153
      Grades 0-11.0
      Grades 2-410.62.6-43.43-154
      Missing10.62.2-52.13-155
     GVHD, chronic (clinically extensive)3-152,3-153 NS
     CMV disease3-152 26.39.6-72.03-154 10.25.4-19.53-154
     Respiratory virus infection3-152 NS2.11.1-3.83-155
    • Calculated on the basis of 1625 evaluable control patients and 57 cases during the early period and 1526 evaluable control patients and 99 cases during the late period. Hazard ratios (HRs) and 95% confidence intervals (CIs) are shown for all significant variables. —indicates data not applicable; NS indicates not significant in the multivariable model.

    • F3-150 Only underlying diseases associated with significant risks are shown.

    • F3-151 CMV serostatus was not available for 10 patient-donor pairs.

    • F3-152 Factors entered into the model as time-dependent covariates.

    • F3-153 The GVHD variable “missing” signifies patients who did not have data entered into the computerized system (n = 113). Acute and chronic GVHD were independently graded, as previously described.17 18 GVHD variables were not entered into the model for early IA.

    • F3-155 P ≤ .05.

    • F3-154 P ≤ .001.

  • Table 4.

    Risk factors for IA between days 40 and 100 after transplantation (analysis of corticosteroid therapy)

    Controls (n = 1552), no. (%)Cases (n = 73), no. (%)HR95% CI
    Recipient-related factors
     Age, y
      Younger than 19249 (16.0)8 (11.0)1.0
      19-40659 (42.5)21 (28.8)NS
      Older than 40644 (41.5)44 (60.3)3.31.5-7.1
     CMV serostatus4-150
      D−/R−542 (35.2)15 (20.6)1.0
      D+/R−234 (15.2)13 (17.8)2.21.0-4.6
      D−/R+330 (21.4)19 (26.0)NS
      D+/R+436 (28.3)26 (35.6)NS
    Transplant-related factors (stem cells) cell-depleted/CD34-selected56 (3.6)8 (11.0)2.81.2-6.1
    Transplant complications
     Neutropenia4-151 2.31.1-5.0
     CMV disease4-151 15.47.5-31.74-153
     Respiratory virus infection4-151 2.81.3-5.7
     Corticosteroids, maximum dose, mg/kg/d4-151
      01.0
      Less than 1.9NS
      2.0-3.08.02.9-22.54-153
      More than 3.015.45.2-45.74-153
    • Calculated on the basis of 1552 evaluable control patients and 73 cases. Hazard ratios (HRs) and 95% confidence intervals (CIs) are shown for all significant variables.

    • —indicates data not applicable; NS, not significant in the multivariable model.

    • F4-150 Either donor or recipient serostatus was not available for 10 patients.

    • F4-151 Factors entered into the model as time-dependent covariates.

    • P ≤ .05.

    • F4-153 P ≤ .001.