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北京大学学报（医学版） ›› 2022, Vol. 54 ›› Issue (5): 1013-1020. doi: 10.19723/j.issn.1671-167X.2022.05.031

• 论著 • 上一篇    下一篇

异基因造血干细胞移植后晚发重症肺炎患者治疗与预后转归的关系

曹乐清,周婧睿,陈育红,陈欢,韩伟,陈瑶,张圆圆,闫晨华,程翼飞,莫晓冬,付海霞,韩婷婷,吕萌,孔军,孙于谦,王昱,许兰平,张晓辉,黄晓军*()   

  1. 北京大学人民医院血液科, 北京大学血液病研究所, 国家血液系统疾病临床医学研究中心, 造血干细胞移植治疗血液病北京市重点实验室, 北京 100044
  • 收稿日期:2022-04-19 出版日期:2022-10-18 发布日期:2022-10-14
  • 通讯作者: 黄晓军 E-mail:huangxiaojun@bjmu.edu.cn
  • 作者简介:黄晓军, 博士生导师, 教授, 北京大学人民医院血液科主任, 北京大学血液病研究所所长, 国家血液系统疾病临床医学研究中心主任。国家基金委创新群体、科技部、教育部创新团队带头人, 国家重点学科、国家临床重点专科负责人; 现任亚太血液联盟常委会主任, 第四、五届中国医师协会血液科医师分会会长, 中华骨髓库专家委员会主任委员, 中国病理生理学会实验血液学专业委员会主任委员, 中国医疗保健国际交流促进会血液学分会主任委员, 国际白血病比较研究组织(International Association for Comparative Research on Leukemia and Related Disease, IACRLR)全球委员会委员。曾任第九届中华医学会血液学分会主任委员、美国血液学会国际常委会委员。
    主持国家重点研发计划、863项目、国家自然科学基金重点项目、国家杰出青年科学基金等国家级课题; 以通信或第一作者发表SCI论文400余篇, 入选2014—2021年中国高被引学者榜单(医学); 移植领域的相关成果被美国、英国骨髓移植协会、美国国家癌症研究所等共46项国际指南或共识引用; 获国家科技进步二等奖2项、省部级一等奖4项、何梁何利科学技术与进步奖、谈家桢生命科学临床医学奖、转化医学杰出贡献奖及光华工程科技奖等。
    任British Journal of Haematology、Journal of Hematology and Oncology、Chinese Medical Journal副主编, Annals of Hematology高级编委, Blood、Bone Marrow Transplantation及Blood Reviews编委
  • 基金资助:
    国家自然科学基金(81621001)

Relationship between treatment and prognosis in patients with late-onset severe pneumonia after allogeneic hematopoietic stem cell transplantation

Le-qing CAO,Jing-rui ZHOU,Yu-hong CHEN,Huan CHEN,Wei HAN,Yao CHEN,Yuan-yuan ZHANG,Chen-hua YAN,Yi-fei CHENG,Xiao-dong MO,Hai-xia FU,Ting-ting HAN,Meng LV,Jun KONG,Yu-qian SUN,Yu WANG,Lan-ping XU,Xiao-hui ZHANG,Xiao-jun HUANG*()   

  1. Department of Hematology, Peking University People's Hospital; Peking University Institute of Hematology; National Clinical Research Center for Hematologic Disease; Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing 100044, China
  • Received:2022-04-19 Online:2022-10-18 Published:2022-10-14
  • Contact: Xiao-jun HUANG E-mail:huangxiaojun@bjmu.edu.cn
  • Supported by:
    the National Natural Science Foundation of China(81621001)

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摘要：

目的: 探讨接受异基因造血干细胞移植(allogeneic stem cell transplantation, allo-SCT)后出现晚发重症肺炎(late-onset severe pneumonia, LOSP)患者的药物治疗情况与肺炎预后转归的关系。方法: 回顾性分析2016年1月至2021年8月在北京大学人民医院接受allo-SCT后出现LOSP的82例患者的治疗药物启用时间, 尤其是抗病毒药物和激素类药物的启用时间与肺炎预后转归的关系。采用Mann-Whitney U检验、χ2检验进行单因素分析, Logistic回归进行多因素分析; χ2检验若涉及多组(n＞2), 其检验水准采用Bonferroni校正。结果: 在82例患者中, LOSP的中位发病时间为移植后220 d(93~813 d), 患者60 d的生存率为58.5%(48/82), 其中好转患者对应的中位好转时间为18 d(7~44 d), 死亡患者的中位死亡时间为22 d(2~53 d)。多因素分析结果显示, 抗病毒药物启用距离LOSP发病的时间(＜10 d vs. ≥10 d, P=0.012)和激素启用距离抗病毒药物的时间(＜10 d vs. ≥10 d, P=0.027)是影响LOSP患者60 d生存情况的因素。根据上述多因素分析结果进一步将患者分为4组: A组(抗病毒＜10 d且激素≥10 d)、B组(抗病毒＜10 d且激素＜10 d)、C组(抗病毒≥10 d且激素≥10 d)和D组(抗病毒≥10 d且激素＜10 d), 其60 d生存率分别为91.7%、56.8%、50.0%和21.4%。结论: 在接受allo-SCT后出现LOSP的患者中, 抗病毒药物及激素类药物的启用时间与肺炎预后相关, 早期加用抗病毒药物且在其后晚加用激素类药物的患者生存率最高, 提示对于病因不明确的LOSP患者需高度怀疑病毒感染继发过度免疫反应的可能。

关键词: 异基因造血干细胞移植, 肺炎, 抗病毒药, 糖皮质激素类, 预后

Abstract:

Objective: To explore the relationship between drug treatment and outcomes in patients with late-onset severe pneumonia (LOSP) after allogeneic stem cell transplantation (allo-SCT). Methods: We retrospectively analyzed the effects of the initiation time of treatment drugs, especially antiviral drugs and glucocorticoids on the clinical outcomes in 82 patients between January 2016 and August 2021 who developed LOSP after allo-SCT in Peking University People's Hospital. Univariate analysis was performed by Mann-Whitney U test and χ2 test, and multivariate analysis was performed by Logistic regression. When multiple groups (n>2) were involved in the χ2 test, Bonferroni correction was used for the level of significance test. Results: Of all 82 patients in this study, the median onset time of LOSP was 220 d (93-813 d) after transplantation, and the 60-day survival rate was 58.5% (48/82). The median improvement time of the survival patients was 18 d (7-44 d), while the median death time of the died patients was 22 d (2-53 d). Multivariate analysis showed that the initiation time of antiviral drugs from the onset of LOSP (< 10 d vs. ≥10 d, P=0.012), and the initiation time of glucocorticoids from antiviral drugs (< 10 d vs. ≥10 d, P=0.027) were the factors affecting the final outcome of the patients with LOSP at the end of 60 d. According to the above results, LOSP patients were divided into four subgroups: group A (antiviral drugs < 10 d, glucocorticoids ≥10 d), group B (antiviral drugs < 10 d, glucocorticoids < 10 d), group C (antiviral drugs ≥10 d, glucocorticoids ≥10 d) and group D (antiviral drugs ≥10 d, glucocorticoids < 10 d), the 60-day survival rates were 91.7%, 56.8%, 50.0% and 21.4%, respectively. Conclusion: Our study demonstrated that in patients who developed LOSP after allo-SCT, the initiation time of antiviral drugs and glucocorticoids were associated with the prognosis of LOSP, and the survival rate was highest in patients who received antiviral drugs early and glucocorticoids later. It suggested that for patients with LOSP of unknown etiology should be highly suspicious of the possibility of a secondary hyperimmune response to viral infection.

Key words: Allogeneic hematopoietic stem cell transplantation, Pneumonia, Antiviral agents, Glucocorticoids, Prognosis

中图分类号: 

  • R733

表1

异基因造血干细胞移植术后LOSP患者临床特征的比较"

Characteristics Total Outcomes at 60 d P value
Survival Death
Patients (male/female), n 82 (57/25) 48 (32/16) 34 (25/9) 0.506
Age/years, M (Range) 36 (12-66) 41 (12-66) 35 (17-64) 0.446
Diagnosis, n(%) 0.859
  AML 30 (36.6) 16 (33.3) 14 (41.2)
  ALL 34 (41.5) 21 (43.8) 13 (38.2)
  MDS 9 (11.0) 6 (12.5) 3 (8.8)
  Others 9 (11.0) 5 (10.4) 4 (11.8)
Transplant type, n(%) 0.599
  MSDT 17 (20.7) 9 (18.8) 8 (23.5)
  Haplo-SCT 65 (79.3) 39 (81.3) 26 (76.5)
Engraftment, n(%)
  Neutrophil 82 (100) 48 (100) 34 (100)
  Platelet 77 (93.9) 47 (97.9) 30 (88.2) 0.071
Time to engraftment/d, M (Range)
  Neutrophil 14 (10-23) 13 (10-23) 14 (11-23) 0.084
  Platelet 15 (8-180) 15 (8-180) 18 (9-117) 0.281
Early complications after transplantation, n(%)
  Cytomegalovirus viremia 55 (67.1) 32 (66.7) 23 (67.6) 0.926
  EBV infection 14 (17.1) 7 (14.6) 7 (20.6) 0.476
  Acute GVHD Ⅱ-Ⅳ 16 (19.5) 11 (22.9) 5 (14.7) 0.198
  Acute GVHD Ⅲ-Ⅳ 8 (9.8) 4 (8.3) 4 (11.8) 0.465
  Chronic GVHD 43 (52.4) 27 (56.1) 16 (47.1) 0.580
Time of LOSP post-transplantation/d, M (Range) 220 (93-813) 224 (98-811) 215 (96-813) 0.421
Season of LOSP, n(%) 0.042
  Spring (March to May) 14 (17.1) 10 (20.8) 4 (11.8)
  Summer (June to August) 19 (23.2) 6 (12.5) 13 (38.2)
  Autumn (September to November) 22 (26.8) 13 (27.1) 9 (26.5)
  Winter (December to February of the following year) 27 (32.9) 19 (39.6) 8 (23.5)
Pathogens detected during LOSP, n(%) 0.706
  Virus 31 (37.8) 19 (39.6) 12 (35.3)
  Bacteria 4 (4.9) 2 (4.2) 2 (5.9)
  Fungus 1 (1.2) 1 (2.1) 0
  Mixed organisms (virus+bacteria/fungus) 7 (8.5) 5 (10.4) 2 (5.9)
  Unidentified 39 (47.6) 21 (43.8) 18 (52.9)
Time from the start of intravenous antibacterial drugs to the onset of respiratory symptoms/d, M (Range) 0 (0-14) 0 (0-12) 0 (0-14) 0.545
Treatment with antiviral drugs, n(%) 80 (97.6) 47 (97.9) 33 (97.1) 0.804
Time from antiviral drug initiation to onset of LOSP/d, M (Range) 5 (0-27) 5 (0-20) 7 (0-22) 0.386
Time from antiviral drug initiation to onset of LOSP, n(%) 0.014
   < 10 d 60 (75.0) 40 (85.1) 20 (60.6)
  ≥ 10 d 20 (25.0) 7 (14.9) 13 (39.4)
Major antiviral drugs *, n(%) 0.501
  Ganciclovir 19 (23.8) 13 (27.7) 6 (18.2)
  Acyclovir 10 (12.5) 4 (8.5) 6 (18.2)
  Foscarnet sodium 38 (47.5) 23 (48.9) 15 (45.5)
  Combination 13 (16.3) 7 (14.9) 6 (18.2)
Glucocorticoid treatment during LOSP, n(%) 73 (89.0) 41 (85.4) 32 (94.1) 0.214
Time from LOSP onset to glucocorticoid use/d, M (Range) 10 (0-41) 13 (1-41) 10 (0-31) 0.084
Time from glucocorticoid initiation to antiviral drug/d, M (Range) 4 (0-35) 5 (0-35) 2 (0-14) 0.029
Time from glucocorticoid initiation to antiviral drug, n(%) 0.011
   < 10 d 58 (80.6) 28 (70.0) 30 (93.8)
  ≥ 10 d 14 (19.4) 12 (30.0) 2 (6.3)
Type of mechanical ventilation, n(%)
  Non-invasive mechanical ventilation 30 (36.6) 11 (22.9) 19 (55.9) 0.002
  Invasive mechanical ventilation 25 (30.5) 3 (6.3) 22 (64.7) ＜0.001

表2

影响异基因造血干细胞移植术后LOSP患者预后的单因素和多因素分析"

Characteristics Univariate analysis Multivariate analysis
χ2 value/Z value P value OR value 95%CI P value
Platelet engraftment (yes or no) 3.258 0.071
Engraftment time of neutrophil -1.728 0.084
Time from antiviral drug initiation to onset of LOSP (< 10 d vs. ≥ 10 d) 6.207 0.014 0.183 0.048-0.693 0.012
Time from glucocorticoid initiation to onset of LOSP (< 7 d vs. ≥ 7 d) 2.924 0.087
Time from glucocorticoid initiation to antiviral drug (< 10 d vs. ≥ 10 d) 6.402 0.011 6.503 1.235-34.238 0.027

图1

移植后出现LOSP的患者加用抗病毒药物和糖皮质激素的情况及其预后转归"

表3

异基因造血干细胞移植术后LOSP患者各组间临床特征的比较"

Characteristics Time from antiviral drug initiation to onset of LOSP Time from glucocorticoid initiation to antiviral drug
< 10 d ≥ 10 d P value < 10 d ≥ 10 d P value
Patients (male/female), n 60 (40/20) 20 (15/5) 0.486 58 (43/15) 14 (8/6) 0.209
Age/years, M (Range) 41 (12-66) 32 (19-64) 0.100 36 (12-66) 45 (21-58) 0.385
Diagnosis, n(%) 0.816 0.305
  AML 24 (40.0) 6 (30.0) 20 (34.5) 8 (57.1)
  ALL 23 (38.3) 9 (45.0) 25 (43.1) 3 (21.4)
  MDS 7 (11.7) 2 (10.0) 5 (8.6) 2 (14.3)
  Others 6 (10.0) 3 (15.0) 8 (13.8) 1 (7.1)
Transplant type, n(%) > 0.999 0.524
  MSDT 12 (20.0) 4 (20.0) 12 (20.7) 4 (28.6)
  Haplo-SCT 48 (80.0) 16 (80.0) 46 (79.3) 10 (71.4)
Engraftment, n(%)
  Neutrophil 60 (100.0) 20 (100.0) 58 (100.0) 14 (100.0)
  Platelet 57 (95.0) 18 (90.0) 0.424 54 (93.1) 14 (100.0) 0.312
Time to engraftment/d, M (Range)
  Neutrophil 14 (10-23) 14 (11-23) 0.871 14 (11-23) 13 (10-23) 0.235
  Platelet 15 (8-180) 18 (10-46) 0.606 15 (9-180) 14 (8-38) 0.155
Early complications after transplantation, n(%)
  Cytomegalovirus viremia 40 (66.7) 14 (70.0) 0.783 40 (69.0) 7 (50.0) 0.181
  EBV infection 9 (15.0) 4 (20.0) 0.600 8 (13.8) 2 (14.3) 0.962
  Acute GVHD Ⅱ-Ⅳ 12 (20.0) 4 (20.0) > 0.999 9 (15.5) 5 (35.7) 0.087
  Acute GVHD Ⅲ-Ⅳ 4 (6.7) 4 (20.0) 0.085 5 (8.6) 3 (21.4) 0.171
  Chronic GVHD 29 (48.3) 13 (60.0) 0.285 30 (51.7) 9 (64.3) 0.335
Time of LOSP post-transplantation/d, M (Range) 222 (96-813) 222 (93-623) 0.537 215 (96-813) 233 (110-811) 0.490
Pathogens detected during LOSP, n(%) 0.530 0.841
  Virus 24 (40.0) 5 (25.0) 20 (34.5) 5 (35.7)
  Bacteria 3 (5.0) 2 (10.0) 4 (6.9) 0
  Fungus 1 (1.7) 0 1 (1.7) 0
  Mixed organisms (virus+bacteria/fungus) 6 (10.0) 1 (5.0) 5 (8.6) 1 (7.1)
  Unidentified 26 (43.3) 12 (60.0) 28 (48.3) 8 (57.1)
Time from the start of intravenous antibiotics to the onset of respiratory symptoms/d, M (Range) 0 (0-10) 0 (0-14) 0.552 0 (0-14) 0 (0-14) 0.364
Major antiviral drugs *, n(%) 0.423 0.314
  Ganciclovir 17 (28.3) 2 (10.0) 13 (22.4) 3 (21.4)
  Acyclovir 7 (11.7) 3 (15.0) 10 (17.2) 0
  Foscarnet sodium 27 (45.0) 11 (55.0) 25 (43.1) 9 (64.3)
  Combination 9 (15.0) 4 (20.0) 10 (17.2) 2 (14.3)
Type of mechanical ventilation, n(%)
  Non-invasive mechanical ventilation 24 (40.0) 6 (30.0) 0.424 25 (43.1) 4 (28.6) 0.320
  Invasive mechanical ventilation 16 (26.7) 9 (45.0) 0.126 23 (39.7) 1 (7.1) 0.021
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ISSN 1671-167X
CN 11-4691/R
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