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1999年4月26日,河南省封丘县发生了一起因非法倒卖60Co治疗机和放射源导致7人受到照射(简称受照)的严重放射事故,其中3人诊断为中、重度骨髓型急性放射病(acute radiation sickness,ARS),经救治,7例患者均康复出院。参照国家相关标准复出院。参照国家相关标准[1],卫生部核事故医学应急中心第一临床部于患者受照半年后开始进行系统的医学随访,至2019年(即受照后20年)累计完成11次。国内已发表的放射事故随访的研究多侧重于患者造血系统损伤的远后恢复情况,甚少对造血系统各项指标的变化规律及影响因素进行探讨,本研究对其随访结果进行分析。
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1999年4月26日,“天”将非法收购的两根放射性活度为21.4 TBq(577 Ci)的60Co治疗机源棒放在妻儿房间,导致3人受照[1]。患者“梅”(母亲)、“天”(父亲)和“旺”(儿子)受照时分别为38岁、37岁、8岁。3例患者的个人资料、体模模拟测量的物理剂量、染色体畸变(双+环)估算的生物剂量、估算的全身平均剂量、受照方式及最终临床诊断见表1[2-4]。经卫生部核事故医学应急中心第一临床部的积极救治,3例患者均在受照后91 d临床治愈出院。
患者 性别 年龄(岁) 物理剂量(Gy) 生物剂量(Gy) 全身平均剂量(Gy) 受照方式 临床诊断 “梅” 女 38 5.60 5.09 6.10 不均匀照射 重度骨髓型ARS “天” 男 37 2.60 2.61 2.40 均匀照射 中度骨髓型ARS “旺” 男 8 3.30 2.49 3.40 不均匀照射 中度骨髓型ARS 注:ARS为急性放射病 表 1 3例中、重度骨髓型ARS患者1999年受到照射的情况及临床诊断
Table 1. Radiation exposure and clinical diagnosis of 3 patients with moderate or severe bone marrow form of acute radiation sickness in 1999
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3例患者受照后第1年,每半年随访1次;受照后第2~3年,每年随访1次;受照后第4~15年,每2年随访1次;受照第15年以后,每5年随访1次。
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外周血象检查:采用全自动血细胞分析仪分析外周血WBC、血小板(platelet,PLT)计数、RBC计数及血红蛋白(hemoglobin,Hb)水平、中性粒细胞(neutrophilicgranulocyte,NEUT)百分比和淋巴细胞(lymphocyte,LYM)百分比。
骨髓穿刺检查:髂后上棘穿刺取骨髓,行骨髓涂片检查及造血祖细胞培养。红细胞集落生成单位(colony-forming unit-erythroid,CFU-E)和爆式红细胞集落生成单位( burst-forming unit-erythrocytic,BFU-E)采用体外单层琼脂培养法;粒细胞-单核细胞集落生成单位(colony forming unit-granulocyte-monocyte,CFU-GM)采用半固体琼脂培养法。
造血刺激因子检查:促红细胞生成素(erythropoietin,EPO)和粒细胞-巨噬细胞集落刺激因子(granulocyte-macrophage colony-stimulating factor,GM-CSF)采用甲基纤维素半固体培养法测定。
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3例患者于1999年4月受照后,累计随访11次,分别为1999年11月、2000年5月、2001年6月、2002年5月、2004年5月、2006年9月、2008年10月、2010年4月、2012年2月、2014年4月及2019年9月。“旺”进入青春期后,因其父母拒绝,未参加受照后第9年(2008年)和第11年(2010年)的随访。
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3例患者随访期间外周血象的检查结果见表2。其中2012年的数据来源于文献[5]。随访期间,3例患者的WBC基本在正常范围内;受照后半年,LYM百分比均偏低,NEUT百分比均偏高。“梅”在随访期间多次出现NEUT百分比升高,“旺”多次出现LYM百分比和NEUT百分比异常。
患者 年份 白细胞计数
(×109个/L)血红蛋白
(g/L)血小板计数
(×109个/L)中性粒细胞百分比
(%)淋巴细胞百分比
(%)红细胞计数
(×1012个/L)“梅” 1999 5.30 108↓ 80↓ 75.0↑ 18.0↓ 4.36 2000 4.80 108↓ 91↓ 66.0 29.0 - 2001 4.10 126 112 76.0↑ 22.0 3.90 2002 4.80 115 102 70.0 28.0 3.62 2004 4.70 85↓ 130 72.0↑ 25.0 3.51 2006 6.40 116 247 71.0↑ 27.0 4.31 2008 5.50 114 204 68.7 22.2 4.43 2010 5.30 115 183 58.1 37.2 4.53 2012 6.50 114 263 - - - 2014 6.67 109↓ 225 67.8 26.8 4.50 2019 4.93 119 228 66.0 29.3 4.84 “天” 1999 6.70 148 136 71.0↑ 21.0 4.27 2000 5.60 140 128 65.0 24.0 - 2001 8.40 136 150 61.0 33.0 - 2002 5.30 145 128 56.0 44.0↑ 5.10 2004 8.80 147 145 66.0 32.0 4.98 2006 8.80 164↑ 138 64.0 32.0 5.31 2008 9.70 173↑ 190 56.3 35.1 5.45 2010 10.10↑ 158 192 62.5 32.5 5.24 2012 9.50 154 215 - - - 2014 5.95 147 204 59.1 25.5 4.94 2019 8.11 140 235 64.1 30.2 4.92 “旺” 1999 7.30 114↓ 91↓ 69.0 19.0↓ 4.55 2000 7.05 128 149 53.0 38.0 - 2001 5.80 130 152 48.0↓ 43.0↑ - 2002 5.20 120 132 49.0↓ 49.0↑ 4.13 2004 6.50 132 185 72.0↑ 25.0 5.08 2006 6.60 151 208 74.0↑ 20.0 5.13 2012 7.40 163↑ 192 - - - 2014 6.67 109↓ 255 67.8 26.8 4.50 2019 8.24 161↑ 218 72.3↑ 22.1 5.61 参考值 - 4.00~10.00(成人) 110~150(女性) 100~300 50.0~70.0 20.0~40.0 3.50~5.00(女性) 5.00~12.00(儿童) 120~160(男性) 4.00~5.50(男性) 注:参考值来源于《临床检验基础》(第5版)[6],其中仅白细胞计数单独给出儿童的参考值,“旺”开始接受随访时年龄8岁,各项指标已接近成人,其他指标均参考成人参考值。↑表示高于参考值,↓表示低于参考值,-表示无此项数据 表 2 3例中、重度骨髓型急性放射病患者受到照射后20年随访期间外周血象的检查结果
Table 2. Peripheral hemogram results of 3 patients with moderate or severe bone marrow form of acute radiation sickness during 20-year follow-up after irradiation
“梅”的PLT计数在受照后半年及第1年轻度下降,分别为80×109个/L和91×109个/L;“旺”的PLT计数在受照后半年轻度下降,为91×109个/L;“天”的PLT计数在随访期间正常。
“梅”的Hb水平多次轻度降低,受照后第5年中度降低,为85 g /L;“天”受照后第9年Hb水平异常升高;随访期间“天”和“旺”的 Hb水平数次轻度升高或降低。
3例患者RBC计数均在正常范围内。
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3例患者分别于受照后半年和第1、2、3、5、7年共进行6次骨髓穿刺涂片检查,结果均为骨髓增生活跃或增生明显活跃(表3)。“天”于2012年确诊为(胃黏膜)弥漫大B细胞淋巴瘤,其后2年累计进行了24个周期(共计3个方案,具体不详)全身静脉化疗(未行放疗),期间出现Ⅳ度骨髓抑制,给予造血刺激因子及升白药物治疗后情况改善。末次化疗后2个月,“天”参加2014年(即受照后第15年)随访,行骨髓穿刺涂片检查,结果为骨髓增生活跃。
患者 年份 骨髓穿刺涂片 CFU-E
(个/2×104BMMNC)BFU-E
(个/2×104BMMNC)CFU-GM
(个/1×105BMMNC)EPO
(mIU/mL)GM-CSF
(pg/mL)“梅” 1999 增生活跃 144↑ 65↑ 182↑ 11.50 <1.00↓ 2000 增生活跃 33↑ 0↓ 5↓ 6.87 14.30↑ 2001 增生活跃 0↓ 0↓ 0↓ 7.77 5.01 2002 增生活跃 - - - 8.90 - 2004 增生明显活跃 1↓ 2↓ 9↓ - - 2006 增生活跃 12↑ 3↓ 13↓ - - “天” 1999 增生明显活跃 170↑ 86↑ 171↑ 12.40↑ <1.00↓ 2000 增生活跃 140↑ 45↑ 26 5.30↓ 5.16 2001 增生明显活跃 0↓ 0↓ 0↓ 6.35 5.41 2002 增生活跃 - - - 10.30 - 2004 增生明显活跃 8↑ 8↓ 33↑ - - 2006 增生活跃 13↑ 4↓ 18 - - “旺” 1999 增生明显活跃 145↑ 65↑ 182↑ 7.80 <1.00↓ 2000 增生活跃 0↓ 0↓ 0↓ 10.30 7.06 2001 增生明显活跃 0↓ 0↓ 0↓ 6.27 5.95 2002 增生活跃 - - - 7.99 - 2004 增生明显活跃 3↓ 5↓ 22 - - 2006 增生活跃 15↑ 5↓ 19 - - 参考值 - 增生活跃或
增生明显活跃5~6 16~19 14~29 5.80~12.30 4.85~9.32 注:参考值来源于中国医学科学院血液学研究所血液病医院实验室的参考值。↑表示高于参考值,↓表示低于参考值,-表示无此项数据。CFU-E为红细胞集落生成单位;BMMNC为骨髓单核细胞;BFU-E为爆式红细胞集落生成单位;CFU-GM为粒细胞-单核细胞集落生成单位;EPO为促红细胞生成素;GM-CSF为粒细胞-巨噬细胞集落刺激因子 表 3 3例中、重度骨髓型急性放射病患者受到照射后随访期间骨髓穿刺涂片、骨髓祖细胞及造血刺激因子的检查结果
Table 3. Results of bone marrow biospy smeas,bone marrow progenitor cell culture and hematopoietic stimulating factors in 3 patients with moderate or severe bone marrow form acute radiation sickness during follow-up after irradiation
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3例患者受照后半年和第1、2、5、7年进行了骨髓祖细胞培养,结果见表3。3例患者受照后半年的CFU-E、BFU-E和CFU-GM均异常升高;受照后第2年,上述3项指标均降为0;其后缓慢回升,至受照后第7年,CFU-E均高于正常范围,CFU-GM基本恢复,BFU-E仍显著减低。
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前3年的随访中,3例患者均进行了EPO和GM-CSF检查,结果见表3。“天”受照后半年和第1年EPO轻度异常,“梅”和“旺”EPO均在正常范围内。受照后半年,3例患者GM-CSF均<1.00 pg/mL;“梅”受照后第 1 年 GM-CSF 异常升高, 为14.30 pg/mL,受照后第2年恢复正常;“天”和“旺”受照后第1~2年,GM-CSF均正常。
河南“4.26” 60Co辐射事故3例中、重度骨髓型急性放射病患者造血系统改变20年比较分析
A comparative analysis of hematopoietic system in three cases with moderate or severe bone marrow form of acute radiation sickness for 20 years after the “4.26” 60Co radiation accident in Henan
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摘要:
目的 观察3例骨髓型急性放射病(ARS)患者造血系统的远后效应,探究急性外照射后造血系统的远后变化规律及其影响因素。 方法 对1999年河南“4.26”60Co辐射事故中2例中度骨髓型ARS患者(“天“和”旺”,均为男性,年龄分别为37岁和8岁)和1例重度骨髓型ARS患者(“梅”,女性,38岁)进行临床随访,随访时间截至2019年,共随访11次。依据《外照射急性放射病的远期效应医学随访规范》,于患者受照后半年开始定期采集3例患者的外周血和骨髓进行外周血象、骨髓穿刺涂片、骨髓祖细胞培养及造血刺激因子等检查。(1)外周血象检查:使用全自动血细胞分析仪分析外周血白细胞、血小板(PLT)、红细胞计数和血红蛋白(Hb)水平,以及中性粒细胞(NEUT)百分比和淋巴细胞(LYM)百分比。(2)骨髓穿刺检查:行骨髓穿刺涂片及造血祖细胞培养,检测红细胞集落生成单位(CFU-E)、爆式红细胞集落生成单位(BFU-E)、粒细胞-单核细胞集落生成单位(CFU-GM)。(3)造血刺激因子检查:检测促红细胞生成素(EPO)和粒细胞-巨噬细胞集落刺激因子(GM-CSF)。 结果 20年随访期间,3例患者的白细胞计数基本在正常范围内。受到照射后半年,LYM百分比均偏低,NEUT百分比均偏高。“梅”在随访期间多次出现NEUT百分比升高,“旺”多次出现LYM百分比和NEUT百分比异常。“梅”在受到照射后半年及第1年的随访中PLT计数轻度下降,分别为80×109个/L和91×109个/L;“旺”受到照射后半年,PLT计数轻度下降,为91×109个/L;“天”的PLT计数正常。“梅”的Hb水平多次轻度降低,受到照射后第5年中度下降,为85 g/L;“天”受到照射后第9年Hb水平异常升高;随访期间“天”和“旺”的Hb水平数次轻度升高或降低。3例患者随访期间的6次骨髓穿刺涂片检查的结果均为骨髓增生活跃或增生明显活跃。3例患者受到照射后半年的CFU-E、BFU-E和CFU-GM均异常升高;第2年,上述3项指标均降为0;其后缓慢回升,至第7年,CFU-E均高于正常值,CFU-GM基本恢复,BFU-E仍显著减低。在前3年的随访中,“天”的半年和1年EPO轻度异常,“梅”和“旺”EPO均在正常范围。受到照射后半年,3例患者的 GM-CSF均<1.00 pg/mL;“梅”第1年的GM-CSF异常升高,为14.3 pg/mL,第2年恢复正常;“天”和“旺”第1~2年的 GM-CSF均正常。 结论 急性照射对造血系统的损伤具有剂量依赖性和长期性;造血刺激因子对骨髓造血功能的恢复具有长期影响;反映骨髓造血功能恢复情况的各指标间可缺乏一致性改变,随访中需要综合评估。 Abstract:Objective To observe the late effects of hematopoietic system damage in patients with a bone marrow form of acute radiation sickness (ARS) and to explore the rules and influencing factors of distant posterior changes in the hematopoietic system after acute irradiation. Methods Clinical follow-up was conducted on two patients with moderate bone marrow form of ARS ("Tian" and "Wang", both male, aged 37 and 8 years, respectively) and one patient with severe bone marrow form of ARS ("Mei", female, 38 years old) during the "4.26" 60Co radiation accident in Henan Province in 1999. The follow-up period was until 2019 with a total of 11 times. According to the Standard in Medical Follow-up of the Long-Term Effects of Acute Radiation Sickness by External Irradiation, the peripheral blood and bone marrow of 3 patients were collected regularly for peripheral hemogram, bone marrow smear, bone marrow progenitor cell culture, and hematopoietic stimulating factor examination from half a year after irradiation until 2019. (1) Peripheral hemogram examination: automatic blood cell analyzer was used to analyze white blood cell (WBC), platelet (PLT), and red blood cell counts; hemoglobin (Hb) level; and neutrophil (NEUT) and lymphocyte (LYM) percentages in peripheral blood. (2) Bone marrow aspiration examination: bone marrow smear and hematopoietic progenitor cell culture were performed to detect colony-forming unit-erythroid (CFU-E), burst-forming unit-erythrocytic(BFU-E), colony forming unit-granulocyte–monocyte (CFU-GM). (3)Hematopoietic stimulating factor examination: erythropoietin (EPO) and granulocyte-macrophage colony-stimulating factor (GM-CSF) were detected. Results During the 20-year follow-up, the WBC counts of all three patients were within the normal range. The percentages of LYM were low, and those of NEUT were high half a year after irradiation. During the follow-up period, "Mei" repeatedly had increased NEUT percentage, and "Wang" repeatedly showed abnormal LYM and NEUT percentages. The PLT counts of "Mei" decreased slightly to 80×109/L and 91×109/L respectively in half a year and the first year after irradiation. A half year after irradiation, the PLT count of "Wang" decreased slightly to 91×109/L, whereas that of "Tian" was normal. The Hb level of "Mei" decreased slightly several times and moderately decreased to 85 g/L in the fifth year after irradiation. The Hb level of "Tian" increased abnormally in the ninth year after irradiation, and the Hb levels of "Tian" and "Wang" increased or decreased slightly several times during the follow-up period. The results of the six bone marrow biopsy smears of all three patients showed active or remarkably active myelodysplastic during the follow-up period. The CFU-E, BFU-E, and CFU-GM levels of the three patients increased abnormally half a year after irradiation, decreased to 0 in the second year, and then recovered slowly in the seventh year. The CFU-Es of the three patients were higher than the normal range, the CFU-GMs almost recovered, and the BFU-Es still decreased considerably. In the first three years of follow-up, the EPOs of "Tian" were slightly abnormal in half a year and the first year, whereas those of "Mei" and "Wang" were within the normal range. Half a year after irradiation, the GM-CSF levels of the three patients were all less than 1.00 pg/mL. The GM-CSF level of "Mei" increased abnormally to 14.3 pg/mL in the first year and returned to normal in the second year. "Tian" and "Wang" had normal GM-CSF levels in the first and second years. Conclusions Hematopoietic system damage by acute irradiation is dose dependent and long term. Hematopoietic stimulating factor has a long-term effect on the recovery of bone marrow hematopoietic function. No consistent change was observed among the indexes that reflect the recovery of bone marrow hematopoietic function, which needs comprehensive evaluation during medical follow-up. -
表 1 3例中、重度骨髓型ARS患者1999年受到照射的情况及临床诊断
Table 1. Radiation exposure and clinical diagnosis of 3 patients with moderate or severe bone marrow form of acute radiation sickness in 1999
患者 性别 年龄(岁) 物理剂量(Gy) 生物剂量(Gy) 全身平均剂量(Gy) 受照方式 临床诊断 “梅” 女 38 5.60 5.09 6.10 不均匀照射 重度骨髓型ARS “天” 男 37 2.60 2.61 2.40 均匀照射 中度骨髓型ARS “旺” 男 8 3.30 2.49 3.40 不均匀照射 中度骨髓型ARS 注:ARS为急性放射病 表 2 3例中、重度骨髓型急性放射病患者受到照射后20年随访期间外周血象的检查结果
Table 2. Peripheral hemogram results of 3 patients with moderate or severe bone marrow form of acute radiation sickness during 20-year follow-up after irradiation
患者 年份 白细胞计数
(×109个/L)血红蛋白
(g/L)血小板计数
(×109个/L)中性粒细胞百分比
(%)淋巴细胞百分比
(%)红细胞计数
(×1012个/L)“梅” 1999 5.30 108↓ 80↓ 75.0↑ 18.0↓ 4.36 2000 4.80 108↓ 91↓ 66.0 29.0 - 2001 4.10 126 112 76.0↑ 22.0 3.90 2002 4.80 115 102 70.0 28.0 3.62 2004 4.70 85↓ 130 72.0↑ 25.0 3.51 2006 6.40 116 247 71.0↑ 27.0 4.31 2008 5.50 114 204 68.7 22.2 4.43 2010 5.30 115 183 58.1 37.2 4.53 2012 6.50 114 263 - - - 2014 6.67 109↓ 225 67.8 26.8 4.50 2019 4.93 119 228 66.0 29.3 4.84 “天” 1999 6.70 148 136 71.0↑ 21.0 4.27 2000 5.60 140 128 65.0 24.0 - 2001 8.40 136 150 61.0 33.0 - 2002 5.30 145 128 56.0 44.0↑ 5.10 2004 8.80 147 145 66.0 32.0 4.98 2006 8.80 164↑ 138 64.0 32.0 5.31 2008 9.70 173↑ 190 56.3 35.1 5.45 2010 10.10↑ 158 192 62.5 32.5 5.24 2012 9.50 154 215 - - - 2014 5.95 147 204 59.1 25.5 4.94 2019 8.11 140 235 64.1 30.2 4.92 “旺” 1999 7.30 114↓ 91↓ 69.0 19.0↓ 4.55 2000 7.05 128 149 53.0 38.0 - 2001 5.80 130 152 48.0↓ 43.0↑ - 2002 5.20 120 132 49.0↓ 49.0↑ 4.13 2004 6.50 132 185 72.0↑ 25.0 5.08 2006 6.60 151 208 74.0↑ 20.0 5.13 2012 7.40 163↑ 192 - - - 2014 6.67 109↓ 255 67.8 26.8 4.50 2019 8.24 161↑ 218 72.3↑ 22.1 5.61 参考值 - 4.00~10.00(成人) 110~150(女性) 100~300 50.0~70.0 20.0~40.0 3.50~5.00(女性) 5.00~12.00(儿童) 120~160(男性) 4.00~5.50(男性) 注:参考值来源于《临床检验基础》(第5版)[6],其中仅白细胞计数单独给出儿童的参考值,“旺”开始接受随访时年龄8岁,各项指标已接近成人,其他指标均参考成人参考值。↑表示高于参考值,↓表示低于参考值,-表示无此项数据 表 3 3例中、重度骨髓型急性放射病患者受到照射后随访期间骨髓穿刺涂片、骨髓祖细胞及造血刺激因子的检查结果
Table 3. Results of bone marrow biospy smeas,bone marrow progenitor cell culture and hematopoietic stimulating factors in 3 patients with moderate or severe bone marrow form acute radiation sickness during follow-up after irradiation
患者 年份 骨髓穿刺涂片 CFU-E
(个/2×104BMMNC)BFU-E
(个/2×104BMMNC)CFU-GM
(个/1×105BMMNC)EPO
(mIU/mL)GM-CSF
(pg/mL)“梅” 1999 增生活跃 144↑ 65↑ 182↑ 11.50 <1.00↓ 2000 增生活跃 33↑ 0↓ 5↓ 6.87 14.30↑ 2001 增生活跃 0↓ 0↓ 0↓ 7.77 5.01 2002 增生活跃 - - - 8.90 - 2004 增生明显活跃 1↓ 2↓ 9↓ - - 2006 增生活跃 12↑ 3↓ 13↓ - - “天” 1999 增生明显活跃 170↑ 86↑ 171↑ 12.40↑ <1.00↓ 2000 增生活跃 140↑ 45↑ 26 5.30↓ 5.16 2001 增生明显活跃 0↓ 0↓ 0↓ 6.35 5.41 2002 增生活跃 - - - 10.30 - 2004 增生明显活跃 8↑ 8↓ 33↑ - - 2006 增生活跃 13↑ 4↓ 18 - - “旺” 1999 增生明显活跃 145↑ 65↑ 182↑ 7.80 <1.00↓ 2000 增生活跃 0↓ 0↓ 0↓ 10.30 7.06 2001 增生明显活跃 0↓ 0↓ 0↓ 6.27 5.95 2002 增生活跃 - - - 7.99 - 2004 增生明显活跃 3↓ 5↓ 22 - - 2006 增生活跃 15↑ 5↓ 19 - - 参考值 - 增生活跃或
增生明显活跃5~6 16~19 14~29 5.80~12.30 4.85~9.32 注:参考值来源于中国医学科学院血液学研究所血液病医院实验室的参考值。↑表示高于参考值,↓表示低于参考值,-表示无此项数据。CFU-E为红细胞集落生成单位;BMMNC为骨髓单核细胞;BFU-E为爆式红细胞集落生成单位;CFU-GM为粒细胞-单核细胞集落生成单位;EPO为促红细胞生成素;GM-CSF为粒细胞-巨噬细胞集落刺激因子 -
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