Clinical risk score for invasive fungal diseases in patients with hematological malignancies undergoing chemotherapy: China Assessment of Antifungal Therapy in Hematological Diseases (CAESAR) study

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

References

[1] Pagano L, Akova M, Dimopoulos G, Herbrecht R, Drgona L, Blijlevens N. Risk assessment and prognostic factors for mould-related diseases in immunocompromised patients. J Antimicrob Chemother 2011; 66(Suppl 1): i5–i14

[2] Lewis RE, Cahyame-Zuniga L, Leventakos K, Chamilos G, Ben-Ami R, Tamboli P, Tarrand J, Bodey GP, Luna M, Kontoyiannis DP. Epidemiology and sites of involvement of invasive fungal infections in patients with haematological malignancies: a 20-year autopsy study. Mycoses 2013; 56(6): 638–645

[3] Cornely OA, Maertens J, Winston DJ, Perfect J, Ullmann AJ, Walsh TJ, Helfgott D, Holowiecki J, Stockelberg D, Goh YT, Petrini M, Hardalo C, Suresh R, Angulo-Gonzalez D. Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med 2007; 356(4): 348–359

[4] Rijnders BJ, Cornelissen JJ, Slobbe L, Becker MJ, Doorduijn JK, Hop WC, Ruijgrok EJ, Löwenberg B, Vulto A, Lugtenburg PJ, de Marie S. Aerosolized liposomal amphotericin B for the prevention of invasive pulmonary aspergillosis during prolonged neutropenia: a randomized, placebo-controlled trial. Clin Infect Dis 2008; 46(9): 1401–1408

[5] Wingard JR, Carter SL, Walsh TJ, Kurtzberg J, Small TN, Baden LR, Gersten ID, Mendizabal AM, Leather HL, Confer DL, Maziarz RT, Stadtmauer EA, Bolaños-Meade J, Brown J, Dipersio JF, Boeckh M, Marr KA; Blood and Marrow Transplant Clinical Trials Network. Randomized, double-blind trial of fluconazole versus voriconazole for prevention of invasive fungal infection after allogeneic hematopoietic cell transplantation. Blood 2010; 116(24): 5111–5118

[6] Rogers TR, Slavin MA, Donnelly JP. Antifungal prophylaxis during treatment for haematological malignancies: are we there yet? Br J Haematol 2011; 153(6): 681–697

[7] Mousset S, Buchheidt D, Heinz W, Ruhnke M, Cornely OA, Egerer G, Krüger W, Link H, Neumann S, Ostermann H, Panse J, Penack O, Rieger C, Schmidt-Hieber M, Silling G, Südhoff T, Ullmann AJ, Wolf HH, Maschmeyer G, Böhme A. Treatment of invasive fungal infections in cancer patients-updated recommendations of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO). Ann Hematol 2014; 93(1): 13–32

[8] Patterson TF, Thompson GR 3rd, Denning DW, Fishman JA, Hadley S, Herbrecht R, Kontoyiannis DP, Marr KA, Morrison VA, Nguyen MH, Segal BH, Steinbach WJ, Stevens DA, Walsh TJ, Wingard JR, Young JA, Bennett JE. Practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the infectious diseases society of America. Clin Infect Dis 2016; 63(4): e1–e60

[9] Nucci M, Garnica M, Gloria AB, Lehugeur DS, Dias VC, Palma LC, Cappellano P, Fertrin KY, Carlesse F, Simões B, Bergamasco MD, Cunha CA, Seber A, Ribeiro MP, Queiroz-Telles F, Lee ML, Chauffaille ML, Silla L, de Souza CA, Colombo AL. Invasive fungal diseases in haematopoietic cell transplant recipients and in patients with acute myeloid leukaemia or myelodysplasia in Brazil. Clin Microbiol Infect 2013; 19(8): 745–751

[10] Pagano L, Caira M, Candoni A, Offidani M, Martino B, Specchia G, Pastore D, Stanzani M, Cattaneo C, Fanci R, Caramatti C, Rossini F, Luppi M, Potenza L, Ferrara F, Mitra ME, Fadda RM, Invernizzi R, Aloisi T, Picardi M, Bonini A, Vacca A, Chierichini A, Melillo L, de Waure C, Fianchi L, Riva M, Leone G, Aversa F, Nosari A. Invasive aspergillosis in patients with acute myeloid leukemia: a SEIFEM-2008 registry study. Haematologica 2010; 95(4): 644–650

[11] Gerson SL, Talbot GH, Hurwitz S, Strom BL, Lusk EJ, Cassileth PA. Prolonged granulocytopenia: the major risk factor for invasive pulmonary aspergillosis in patients with acute leukemia. Ann Intern Med 1984; 100(3): 345–351

[12] Georgiadou SP, Lewis RE, Best L, Torres HA, Champlin RE, Kontoyiannis DP. The impact of prior invasive mold infections in leukemia patients who undergo allo-SCT in the era of triazole-based secondary prophylaxis. Bone Marrow Transplant 2013; 48(1): 141–143

[13] Caira M, Candoni A, Verga L, Busca A, Delia M, Nosari A, Caramatti C, Castagnola C, Cattaneo C, Fanci R, Chierichini A, Melillo L, Mitra ME, Picardi M, Potenza L, Salutari P, Vianelli N, Facchini L, Cesarini M, De Paolis MR, Di Blasi R, Farina F, Venditti A, Ferrari A, Garzia M, Gasbarrino C, Invernizzi R, Lessi F, Manna A, Martino B, Nadali G, Offidani M, Paris L, Pavone V, Rossi G, Spadea A, Specchia G, Trecarichi EM, Vacca A, Cesaro S, Perriello V, Aversa F, Tumbarello M, Pagano L; SEIFEM Group (Sorveglianza Epidemiologica Infezioni Fungine in Emopatie Maligne). Pre-chemotherapy risk factors for invasive fungal diseases: prospective analysis of 1,192 patients with newly diagnosed acute myeloid leukemia (SEIFEM 2010-a multicenter study). Haematologica 2015; 100(2): 284–292

[14] Garnica M, da Cunha MO, Portugal R, Maiolino A, Colombo AL, Nucci M. Risk factors for invasive fusariosis in patients with acute myeloid leukemia and in hematopoietic cell transplant recipients. Clin Infect Dis 2015; 60(6): 875–880

[15] Wald A, Leisenring W, van Burik JA, Bowden RA. Epidemiology of Aspergillus infections in a large cohort of patients undergoing bone marrow transplantation. J Infect Dis 1997; 175(6): 1459–1466

[16] Grow WB, Moreb JS, Roque D, Manion K, Leather H, Reddy V, Khan SA, Finiewicz KJ, Nguyen H, Clancy CJ, Mehta PS, Wingard JR. Late onset of invasive aspergillus infection in bone marrow transplant patients at a university hospital. Bone Marrow Transplant 2002; 29(1): 15–19

[17] Garcia-Vidal C, Upton A, Kirby KA, Marr KA. Epidemiology of invasive mold infections in allogeneic stem cell transplant recipients: biological risk factors for infection according to time after transplantation. Clin Infect Dis 2008; 47(8): 1041–1050

[18] Thursky KA, Worth LJ, Seymour JF, Miles Prince H, Slavin MA. Spectrum of infection, risk and recommendations for prophylaxis and screening among patients with lymphoproliferative disorders treated with alemtuzumab. Br J Haematol 2006; 132(1): 3–12

[19] de Boer MG, Jolink H, Halkes CJ, van der Heiden PL, Kremer D, Falkenburg JH, van de Vosse E, van Dissel JT. Influence of polymorphisms in innate immunity genes on susceptibility to invasive aspergillosis after stem cell transplantation. PLoS One 2011; 6(4): e18403

[20] Zaas AK, Liao G, Chien JW, Weinberg C, Shore D, Giles SS, Marr KA, Usuka J, Burch LH, Perera L, Perfect JR, Peltz G, Schwartz DA. Plasminogen alleles influence susceptibility to invasive aspergillosis. PLoS Genet 2008; 4(6): e1000101

[21] Cristina ML, Sartini M, Spagnolo AM. Health care-acquired aspergillosis and air conditioning systems. J Prev Med Hyg 2009; 50(1): 3–8

[22] Weber DJ, Peppercorn A, Miller MB, Sickbert-Benett E, Rutala WA. Preventing healthcare-associated Aspergillus infections: review of recent CDC/HICPAC recommendations. Med Mycol 2009; 47(s1 Suppl 1): S199–S209

[23] Sun Y, Huang H, Chen J, Li J, Ma J, Li J, Liang Y, Wang J, Li Y, Yu K, Hu J, Jin J, Wang C, Wu D, Xiao Y, Huang X. Invasive fungal infection in patients receiving chemotherapy for hematological malignancy: a multicenter, prospective, observational study in China. Tumour Biol 2015; 36(2): 757–767

[24] Nivoix Y, Velten M, Letscher-Bru V, Moghaddam A, Natarajan-Amé S, Fohrer C, Lioure B, Bilger K, Lutun P, Marcellin L, Launoy A, Freys G, Bergerat JP, Herbrecht R. Factors associated with overall and attributable mortality in invasive aspergillosis. Clin Infect Dis 2008; 47(9): 1176–1184

[25] Neofytos D, Horn D, Anaissie E, Steinbach W, Olyaei A, Fishman J, Pfaller M, Chang C, Webster K, Marr K. 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(3): 265–273

[26] Marr KA, Seidel K, Slavin MA, Bowden RA, Schoch HG, Flowers ME, Corey L, Boeckh M. Prolonged fluconazole prophylaxis is associated with persistent protection against candidiasis-related death in allogeneic marrow transplant recipients: long-term follow-up of a randomized, placebo-controlled trial. Blood 2000; 96(6): 2055–2061

[27] Goodman JL, Winston DJ, Greenfield RA, Chandrasekar PH, Fox B, Kaizer H, Shadduck RK, Shea TC, Stiff P, Friedman DJ, Powderly WG, Silber JL, Horowitz H, Lichtin A, Wolff SN, Mangan KF, Silver SM, Weisdorf D, Ho WG, Gilbert G, Buell D. A controlled trial of fluconazole to prevent fungal infections in patients undergoing bone marrow transplantation. N Engl J Med 1992; 326(13): 845–851

[28] Robenshtok E, Gafter-Gvili A, Goldberg E, Weinberger M, Yeshurun M, Leibovici L, Paul M. Antifungal prophylaxis in cancer patients after chemotherapy or hematopoietic stem-cell transplantation: systematic review and meta-analysis. J Clin Oncol 2007; 25(34): 5471–5489

[29] Bow EJ, Laverdière M, Lussier N, Rotstein C, Cheang MS, Ioannou S. Antifungal prophylaxis for severely neutropenic chemotherapy recipients: a meta analysis of randomized-controlled clinical trials. Cancer 2002; 94(12): 3230–3246

[30] Glasmacher A, Prentice A, Gorschlüter M, Engelhart S, Hahn C, Djulbegovic B, Schmidt-Wolf IG. Itraconazole prevents invasive fungal infections in neutropenic patients treated for hematologic malignancies: evidence from a meta-analysis of 3,597 patients. J Clin Oncol 2003; 21(24): 4615–4626

[31] De Pauw BE, Donnelly JP. Prophylaxis and aspergillosis—has the principle been proven? N Engl J Med 2007; 356(4): 409–411

[32] Pagano L, Caira M, Nosari A, Cattaneo C, Fanci R, Bonini A, Vianelli N, Garzia MG, Mancinelli M, Tosti ME, Tumbarello M, Viale P, Aversa F, Rossi G; HEMA e-Chart Group. The use and efficacy of empirical versus pre-emptive therapy in the management of fungal infections: the HEMA e-Chart Project. Haematologica 2011; 96(9): 1366–1370

[33] Groll AH, Castagnola E, Cesaro S, Dalle JH, Engelhard D, Hope W, Roilides E, Styczynski J, Warris A, Lehrnbecher T; Fourth European Conference on Infections in Leukaemia; Infectious Diseases Working Party of the European Group for Blood Marrow Transplantation (EBMT-IDWP); Infectious Diseases Group of the European Organisation for Research and Treatment of Cancer (EORTC-IDG); International Immunocompromised Host Society (ICHS); European Leukaemia Net (ELN). Fourth European Conference on Infections in Leukaemia (ECIL-4): guidelines for diagnosis, prevention, and treatment of invasive fungal diseases in paediatric patients with cancer or allogeneic haemopoietic stem-cell transplantation. Lancet Oncol 2014; 15(8): e327–e340

[34] Stanzani M, Lewis RE, Fiacchini M, Ricci P, Tumietto F, Viale P, Ambretti S, Baccarani M, Cavo M, Vianelli N. A risk prediction score for invasive mold disease in patients with hematological malignancies. PLoS One 2013; 8(9): e75531

[35] Pechlivanoglou P, De Vries R, Daenen SM, Postma MJ. Cost benefit and cost effectiveness of antifungal prophylaxis in immunocompromised patients treated for haematological malignancies: reviewing the available evidence. Pharmacoeconomics 2011; 29(9): 737–751

[36] Cornet M, Levy V, Fleury L, Lortholary J, Barquins S, Coureul MH, Deliere E, Zittoun R, Brücker G, Bouvet A. Efficacy of prevention by high-efficiency particulate air filtration or laminar airflow against Aspergillus airborne contamination during hospital renovation. Infect Control Hosp Epidemiol 1999; 20(7): 508–513

[37] Berthelot P, Loulergue P, Raberin H, Turco M, Mounier C, Tran Manh Sung R, Lucht F, Pozzetto B, Guyotat D. Efficacy of environmental measures to decrease the risk of hospital-acquired aspergillosis in patients hospitalised in haematology wards. Clin Microbiol Infect 2006; 12(8): 738–744

[38] Thio CL, Smith D, Merz WG, Streifel AJ, Bova G, Gay L, Miller CB, Perl TM. Refinements of environmental assessment during an outbreak investigation of invasive aspergillosis in a leukemia and bone marrow transplant unit. Infect Control Hosp Epidemiol 2000; 21(1): 18–23

[39] Kagen SL, Kurup VP, Sohnle PG, Fink JN. Marijuana smoking and fungal sensitization. J Allergy Clin Immunol 1983; 71(4): 389–393

[40] Szyper-Kravitz M, Lang R, Manor Y, Lahav M. Early invasive pulmonary aspergillosis in a leukemia patient linked to aspergillus contaminated marijuana smoking. Leuk Lymphoma 2001; 42(6): 1433–1437

Acknowledgements

Jiong Hu and Xiaojun Huang contributed to the conception and design of the study. Ling Wang, Ying Wang and Jiong Hu interpreted the data and drafted the paper. Yuqian Sun, He Huang, Jing Chen, Jianyong Li, Jun Ma, Juan Li, Yingming Liang, Jianmin Wang, Yan Li, Kang Yu, Jianda Hu, Jie Jin, Chun Wang, Depei Wu, and Yang Xiao were involved in the development of the methodology and participated in the analysis. All authors contributed in the writing, review, and revision of the article and final approval for submission.

The authors would like to thank the patients and investigators at each study site, without whom this study would not have been possible. The CAESAR study group investigators not listed as authors were as follows: Zhixiang Shen, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai; Waiyi Zou, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou; Jun Yang, and Yu Cai, The First People’s Hospital of Shanghai, Shanghai; Yonghua Li, The General Hospital of Guangzhou Military Command of PLA, Guangzhou; Yongping Song and Yuewen Fu, Henan Tumor Hospital affiliated to Zhengzhou University, Zhengzhou; Xudong Hu and Xingzhou Ren, The First Affiliated Hospital of Wenzhou Medical College, Wenzhou; Huisheng Ai and Jianhui Qiao, Chinese PLA 307 Hospital, Beijing; Xianmin Song, Changhai Hospital of the Second Military Medical University, Shanghai; Hai Bai and Chunbang Wang, The General Hospital of Lanzhou Military Area, Lanzhou; Yongmin Tang and Heping Shen, Children’s Hospital of Zhejiang University Medical School, Hangzhou; Xiaoyan Zhang, Jiangsu Province Hospital, Nanjing; Xin Du and Chengwei Luo, Guangdong General Hospital, Guangzhou; Jian Ouyang and Yong Xu, Nanjing Drum Tower Hospital, Nanjing; Huo Tan and Runhui Zheng, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou; Ting Liu and Juan Xu, West China Hospital, Sichuan University, Chengdu; Jin Zhou and Liming Li, The First Hospital of Harbin Medical University, Harbin; Zhuogang Liu, Shengjing Hospital of China Medical University, Shenyang; Ping Zou and Yong You, Wuhan Union Hospital, Huazhong University of Science and Technology, Wuhan; Lin Liu and Li Wang, The First Affiliated Hospital of Chongqing Medical University, Chongqing; Ran Gao, The First Affiliated Hospital of China Medical University, Shenyang; Zhanxiang Liu, Chinese PLA General Hospital (301 Hospital), Beijing; Mangju Wang, The First Hospital of Peking University, Beijing; Guopan Yu, Nanfang Hospital, Nanfang Medical University, Guangzhou; Jun Wang, The First Affiliated Hospital of Soochow University, Suzhou; Guixin Zhang, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences, Tianjin; Xia Qin, Shanghai Children’s Medical Center, Shanghai; Liya Ma and Wangzhuo Xie, The First Affiliated Hospital of Medical School of Zhejiang University, Hangzhou, China.

This work was supported by Merck Sharp & Dohme (China), who sponsored the study. The support for the manuscript development was provided by Merck & Co., Inc. (Whitehouse Station, NJ). The authors are grateful for the contribution made by Bo-Jing Cai (Merck.co.,) in the data management and statistical analysis.

Compliance with ethics guidelines

Ling Wang, Ying Wang, Jiong Hu, Yuqian Sun, He Huang, Jing Chen, Jianyong Li, Jun Ma, Juan Li, Yingmin Liang, Jianmin Wang, Yan Li, Kang Yu, Jiandu Hu, Jie Jin, Chun Wang, Depei Wu, Yang Xiao, and Xiaojun Huang declare no conflicts of interest. This observational study was conducted in accordance with the Declaration of Helsinki, International Conference on Harmonization Good Clinical Practice and nationally mandated ethical requirements. The study protocol and informed consent document were reviewed and approved by the ethics committee of Peking University People’s Hospital. All participating institutions obtained ethical approval separately before the initiation of the study. All study participants provided informed consent.

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