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Frontiers of Medicine

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Front. Med.    2019, Vol. 13 Issue (3) : 365-377    https://doi.org/10.1007/s11684-018-0641-0
RESEARCH ARTICLE
Clinical risk score for invasive fungal diseases in patients with hematological malignancies undergoing chemotherapy: China Assessment of Antifungal Therapy in Hematological Diseases (CAESAR) study
Ling Wang1, Ying Wang1, Jiong Hu1(), Yuqian Sun2, He Huang3, Jing Chen4, Jianyong Li5, Jun Ma6, Juan Li7, Yingmin Liang8, Jianmin Wang9, Yan Li10, Kang Yu11, Jianda Hu12, Jie Jin3, Chun Wang13, Depei Wu14, Yang Xiao15, Xiaojun Huang2()
1. Blood & Marrow Transplantation Center, Department of Hematology, Collaborative Innovation Center of Hematology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
2. Peking University Institute of Hematology, Peking University, People’s Hospital, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing 100044, China
3. Department of Hematology, The First Affiliated Hospital of Medical School of Zhejiang University, Hangzhou 310003, China
4. Department of Hematology-Oncology, Shanghai Children’s Medical Center, Shanghai 200127, China
5. Department of Hematology, Jiangsu Province Hospital, Nanjing 210029, China
6. Harbin Hematologic Tumor Institution, Harbin 150010, China
7. Department of Hematology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China
8. Department of Hematology, Tangdu Hospital, Fourth Military Medical University, Xi’an 710032, China
9. Department of Hematology, Changhai Hospital of the Second Military Medical University, Shanghai 200082, China
10. Department of Hematology, The First Affiliated Hospital of China Medical University, Shenyang 110001, China
11. Department of Hematology, The First Affiliated Hospital of Wenzhou Medical College, Wenzhou 325000, China
12. Department of Hematology, Fujian Medical University Union Hospital, Fuzhou 350001, China
13. Department of Hematology, The First People’s Hospital of Shanghai, Shanghai 200080, China
14. Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
15. Department of Hematology, The General Hospital of Guangzhou Military Command of PLA, Guangzhou 510010, China
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Abstract

Invasive fungal disease (IFD) is a major infectious complication in patients with hematological malignancies. In this study, we examined 4889 courses of chemotherapy in patients with hematological diseases to establish a training dataset (n=3500) by simple random sampling to develop a weighted risk score for proven or probable IFD through multivariate regression, which included the following variables: male patients, induction chemotherapy for newly diagnosed or relapsed disease, neutropenia, neutropenia longer than 10 days, hypoalbuminemia, central-venous catheter, and history of IFD. The patients were classified into three groups, which had low (0–10, ~1.2%), intermediate (11–15, 6.4%), and high risk (>15, 17.5%) of IFD. In the validation set (n=1389), the IFD incidences of the groups were ~1.4%, 5.0%, and 21.4%. In addition, we demonstrated that anti-fungal prophylaxis offered no benefits in low-risk patients, whereas benefits were documented in intermediate (2.1% vs. 6.6%, P=0.007) and high-risk patients (8.4% vs. 23.3%, P=0.007). To make the risk score applicable for clinical settings, a pre-chemo risk score that deleted all unpredictable factors before chemotherapy was established, and it confirmed that anti-fungal prophylaxis was beneficial in patients with intermediate and high risk of IFD. In conclusion, an objective, weighted risk score for IFD was developed, and it may be useful in guiding antifungal prophylaxis.
Keywords invasive fungal diseases      hematological malignancies      chemotherapy      risk score      prophylaxis     
Corresponding Author(s): Jiong Hu,Xiaojun Huang   
Just Accepted Date: 09 November 2018   Online First Date: 13 December 2018    Issue Date: 05 June 2019
 Cite this article:   
Ling Wang,Ying Wang,Jiong Hu, et al. Clinical risk score for invasive fungal diseases in patients with hematological malignancies undergoing chemotherapy: China Assessment of Antifungal Therapy in Hematological Diseases (CAESAR) study[J]. Front. Med., 2019, 13(3): 365-377.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-018-0641-0
https://academic.hep.com.cn/fmd/EN/Y2019/V13/I3/365
Factors Training set Validation set P value
Sex Male 2072 (59.2%) 818 (58.9%) 0.8566
Female 1428 (40.8%) 571 (41.1%)
Age Mean (S.D) 40.69 (20.665) 40.93 (20.691) 0.7239
Median 43.0 43.0
Min, Max 1.0, 90.0 1.0, 89.0
Eastern Cooperative Oncology Group score 0 1555 (44.4%) 601 (43.3%) 0.9975
1 1379 (39.4%) 587 (42.3%)
2 399 (11.4%) 144 (10.4%)
3 124 (3.5%) 44 (3.2%)
4 43 (1.2%) 13 (0.9%)
Diabetes Yes 211 (6.0%) 77 (5.5%) 0.5449
No 3289 (94.0%) 1312 (94.5%)
Previous IFD Yes 191 (5.5%) 74 (5.3%) 0.8888
No 3309 (94.5%) 1315 (94.7%)
Disease* ALL 703 (20.1%) 262 (18.9%) 0.5101
CLL 68 (1.9%) 28 (2.0%)
MM 324 (9.3%) 119 (8.6%)
AML 961 (27.5%) 397 (28.6%)
CML 33 (0.9%) 8 (0.6%)
NHL 943 (26.9%) 403 (29.0%)
MDS 59 (1.7%) 22 (1.6%)
AHL 15 (0.4%) 6 (0.4%)
HPS 2 (0.1%) 0
LCH 6 (0.2%) 1 (0.1%)
Plasma cell disease other than MM 19 (0.5%) 8 (0.6%)
Others 367 (10.5%) 135 (9.7%)
Disease status** Newly-diagnosed 664 (19.0%) 286 (20.6%) 0.6838
CR1 1547 (44.2%) 635 (45.7%)
CR2 119 (3.4%) 44 (3.2%)
CR3 42 (1.2%) 12 (0.9%)
CR4 0 1 (0.1%)
PR 599 (17.1%) 220 (15.8%)
NR 190 (5.4%) 72 (5.2%)
AP 14 (0.4%) 6 (0.4%)
BP 7 (0.2%) 1 (0.1%)
CP 0 1 (0.1%)
Hematological relapse 248 (7.1%) 91 (6.6%)
PD 15 (0.4%) 4 (0.3%)
Non evaluable 51 (1.5%) 16 (1.2%)
Other 4 (0.1%) 0
Type of chemotherapy Induction 701 (20.0%) 289 (20.8%) 0.1389
Consolidation 1783 (50.9%) 727 (52.3%)
Re-induction 687 (19.6%) 262 (18.9%)
Chemo-relapse/refractory disease 329 (9.4%) 111 (8.0%)
Nadir ANC***(×109/L) ≥1.5 1964 (56.1%) 748 (53.9%) 0.1870
1.0≤and<1.5 81 (2.3%) 37 (2.7%)
0.5≤and<1.0 260 (7.4%) 102 (7.3%)
0.1≤and<0.5 430 (12.3%) 187 (13.5%)
<0.1 765 (21.9%) 315 (22.7%)
Duration of Neutropenia ≤10 days 641 (19.5%) 278 (21.4%) 0.2933
11−14 days 144 (4.4%) 48 (3.7%)
>14 days 205 (6.2%) 89 (6.8%)
Corticosteroid Yes 1864 (53.3%) 760 (54.7%) 0.3733
No 1636 (46.7%) 629 (45.3%)
Broad-stream Antibiotics for 7 days Yes 358 (10.2%) 144 (10.4%) 0.8756
No 3141 (89.8%) 1245 (89.6%)
EBV viremia Yes 28 (0.8%) 12 (0.9%) 0.2566
No 876 (25.0%) 317 (22.8%)
NA 2595 (74.2%) 1060 (76.3%)
CMV viremia Yes 16 (0.5%) 6 (0.4%) 0.0529
No 892 (25.5%) 309 (22.2%)
NA 2591 (74.0%) 1074 (77.3%)
Liver function Abnormal 222 (6.3%) 80 (5.8%) 0.4692
Normal 3278 (93.7%) 1309 (94.2%)
Renal function Abnormal 88 (2.5%) 41 (3.0%) 0.3754
Normal 3412 (97.5%) 1348 (97.0%)
Central venous catheter Yes 1584 (45.3%) 650 (46.8%) 0.3397
No 1916 (54.7%) 739 (53.2%)
Respiratory support No 3481 (99.5%) 1381 (99.4%) 0.8809
Non-invasive 12 (0.3%) 6 (0.4%)
Invasive 6 (0.2%) 2 (0.1%)
Hypoalbuminemia Yes 544 (15.5%) 211 (15.2%) 0.7924
No 2956 (84.5%) 1178 (84.8%)
Parenteral nutrition Yes 75 (2.1%) 36 (2.6%) 0.3396
No 3423 (97.9%) 1353 (97.4%)
ICU Yes 7 (0.2%) 1 (0.1%) 0.4538
No 3491 (99.8%) 1388 (99.9%)
Anti-fungal Prophylaxis Yes 571 (16.3%) 256 (18.4%) 0.0758
No 2929 (83.7%) 1133 (81.6%)
Tab.1  Patients’ characteristics in training and validation dataset
Risk factor Variables Coefficient Weight of score Standard error Walds P value OR 95%CI of OR
Intercept -6.66 0.44 225.76 − −
Hypoalbuminemia Yes vs. No 1.49 5 0.27 30.06 0.00 4.45 2.6088−7.5827
Chemotherapy (Re) Induction vs. consolidation 1.05 4 0.34 9.66 0.00 2.85 1.4731−5.5308
Neutropenia ANC<0.5×109/L,≤10 days vs.≥0.5×109/L 1.18 4 0.34 11.71 0.00 3.25 1.6549−6.3871
Neutropenia ANC<0.5×109/L , 11−14 days vs.≥0.5×109/L 1.86 6 0.41 20.28 0.00 6.43 2.8604−14.449
Neutropenia ANC<0.5×109/L,>14 days vs.≥0.5×109/L 1.86 6 0.36 26.67 0.00 6.42 3.1686−12.991
Central-venous catheter Yes vs. No 0.57 2 0.28 4.22 0.04 1.77 1.0267−3.0625
Sex Male vs. Female 0.61 2 0.28 4.58 0.03 1.83 1.0523−3.1874
History of IFD Yes vs. No 1.24 4 0.38 10.80 0.00 3.47 1.6517−7.2811
Tab.2  Risk factor analysis by multivariate analysis (stepwise) in the training dataset
Factors Variables Scores
Sex Male 2
Female 0
Hypoalbuminemia Yes 5
No 0
Chemotherapy Induction/re-induction 4
Consolidation 0
Neutropenia ANC<0.5×109/L 4
No 0
Duration of neutropenia ANC<0.5×109/L,>10 days 2
No 0
Central-venous catheter Yes 2
No 0
History of IFD Yes 4
No 0
Tab.3  Risk scores for proven and probable IFD
Risk score Chemotherapy courses (n) IFD episodes (n) / incidence (%)
Training dataset
0−5 1446 4 (0.3%)
6−10* 1432 17 (1.2%)
11−15** 502 32 (6.4%)
>15*** 120 21 (17.5%)
Validation dataset
0−5 560 2 (0.4%)
6−10# 587 8 (1.4%)
11−15## 200 10 (5.0%)
>15### 42 9 (21.4%)
Tab.4  Distribution of risk scores versus the cumulative incidence of proven or probable IFD in the training and validation datasets
Fig.1  Receiver-operator curve (ROC) analysis of the risk score in the training and validation datasets. (Left) ROC analysis plot of the true positives plotted as a function of false positives (100 specificity) at different cut-offs of the risk score in the training set. The dotted line represents a reference line without discrimination for IFD (aROC= 0.5). (Right) ROC analysis plot of the true positives plotted as a function of false positives (100 specificity) at different cut-offs of the risk score in the validation set. The dotted line represents a reference line without discrimination for IFD (aROC= 0.5).
Risk score Prophylaxis No of chemotherapy courses (n) IFD episode (n) / Incidence (%) P value
0−10 Yes 501 10 (2.0%) 0.004
No 3444 21 (0.6%)
11−15 Yes 243 5 (2.1%) 0.007
No 502 33 (6.6%)
>15 Yes 83 7 (8.4%) 0.007
No 116 27 (23.3%)
Tab.5  Impact of anti-fungal prophylaxis in patients with different risk score
Factors Variables Scores
Sex Male 2
Female 0
ECOG ≥3 3
<3 0
Chemotherapy Induction/re-induction 4
Consolidation 0
Neutropenia ANC<0.5×109/L 4
No 0
Duration of neutropenia ANC<0.5×109/L>10 days 3
No 0
History of IFD Yes 5
No 0
Tab.6  Pre-chemo risk scores for prediction of proven/probable IFD
Risk score Chemotherapy courses (n) IFI episodes (n) / incidence (%)
Training dataset
0−4 531 2 (0.4%)
5−9 * 2255 26 (1.2%)
10−15 ** 577 26 (4.5%)
>15 *** 137 20 (14.6%)
Validation dataset
0−4 218 0
5−9 # 894 12 (1.3%)
10−15 ## 216 10 (4.6%)
>15 ### 61 7 (11.5%)
Tab.7  Distribution of pre-chemo risk scores versus the cumulative incidence of proven/probable IFD in the training and validation datasets
Risk score Prophylaxis No of chemotherapy courses (n) IFD episode (n) / Incidence (%) P value
0−9 Yes 456 10 (2.2%) 0.01
No 3442 30 (0.9%)
10−15 Yes 284 6 (2.1%) 0.01
No 509 30 (5.9%)
>15 Yes 87 6 (6.9%) 0.02
No 111 21 (18.9%)
Tab.8  Impacts of anti-fungal prophylaxis in patients with different pre-chemo risk scores
Risk factors of IFD Prophylaxis No of chemotherapy courses (n) IFD episode (n) / incidence (%) P value
Hypoalbuminemia Yes Yes 127 4 (3.1%) 0.0348
No 417 38 (9.1%)
No Yes 444 11 (2.5%) 0.0050
No 2512 21 (0.8%)
Chemotherapy Induction/re-induction Yes 281 8 (2.8%) 0.7190
No 1436 50 (3.5%)
Consolidation Yes 290 7 (2.4%) 0.0085
No 1493 9 (0.6%)
Neutropenia Yes Yes 348 10 (2.87%) <0.001
No 642 38 (5.9%)
No Yes 156 4 (2.6%) 0.0293
No 2149 14 (0.7%)
Duration of neutropenia <10 days Yes 205 3 (1.5%) 0.2037
No 436 15 (3.4%)
11−14 days Yes 58 5 (8.6%) 0.7562
No 86 6 (7.0%)
>14 Yes 85 2 (2.4%) 0.0033
No 120 17 (14.2%)
Central-venous catheter Yes Yes 391 10 (2.6%) 0.7314
No 1193 37 (3.1%)
No Yes 180 5 (2.8%) 0.1022
No 1736 22 (1.3%)
History of IFD Yes Yes 93 5 (5.4%) 1.0000
No 98 6 (6.1%)
No Yes 478 10 (2.1%) 0.7177
No 2831 53 (1.9%)
Tab.9  Impacts of anti-fungal prophylaxis in patients with different IFD risk factors
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