2023, Vol. 43
2. 苏州大学苏州医学院放射医学与防护学院 省部共建放射医学与辐射防护国家重点实验室, 苏州 215123
2. State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Soochow University, Suzhou 215123, China
2019年末，一种快速传播的新型冠状病毒爆发，并迅速肆虐全球[1]。虽然新型冠状病毒肺炎(COVID-19)患者大多为无症状或轻症，但也有部分患者快速进展为重型/危重型，常表现为急性呼吸窘迫综合征或多器官功能衰竭[2-3]。严重的呼吸系统感染引起细胞因子风暴、过度的宿主免疫反应以及病毒直接损伤可引起弥漫性肺泡损伤和微血管血栓等病理生理变化，进而引起呼吸功能损害，呼吸衰竭是COVID-19患者最常见的死亡原因[4-5]。重症监护室(ICU)治疗可改善重型/危重型患者的生存[6]，但死亡率仍高达30%~40%[7-9]，依赖机械通气的危重型COVID-19患者死亡率高达80%[10]。临床迫切需要寻求新的治疗手段降低患者死亡率。
20世纪初，人们尝试使用低剂量放疗(LDRT)治疗炎性疾病，0.5~1.5 Gy的LDRT能快速缓解细菌性肺炎、病毒性肺炎、间质性肺炎和非典型肺炎等患者呼吸系统症状，提高生存率[11-14]。此后，抗生素的发展取代了LDRT。疫情期间，重型/危重型COVID-19患者现有治疗方法疗效有限，临床迫切需要寻求新的治疗手段。尽管LDRT的抗炎作用机制尚未完全清楚，但国外多个临床试验均显示LDRT治疗重型/危重型COVID-19肺部感染是可行和有效的，该方法得到了美国食品和药品管理局(FDA)的批准。本文对LDRT治疗重型/危重型COVID-19的放射生物学机制及前瞻性临床试验结果进行综述，以期更好地认识其临床获益和不良反应。
一、COVID-19的发生进展机制和临床表现COVID-19通过病毒表面核衣壳蛋白、刺突糖蛋白、膜蛋白、包膜蛋白等病原相关分子模式(PAMP)与血管紧张素转换酶2(ACE2)蛋白等模式识别受体(PRRs)结合进入细胞内[15]。进入细胞后的病毒在多种促炎干扰素调节因子和核因子κB (NF-κB)的作用下进行复制，诱导Ⅰ型和Ⅲ型干扰素及干扰素刺激基因上调，促使趋化因子分泌介导的白细胞转运和归巢[16]。COVID-19临床快速恶化的直接病理生理原因是各种因子的释放导致的炎症风暴，炎症风暴引起正常组织损伤并推动病毒的免疫逃逸。COVID-19患者中白介素(IL)-1β、IL-6、肿瘤坏死因子α(TNF-α) 和C基序趋化因子配体10(CXCL-10)显著升高，其中IL-6是抗病毒通路JAK/STAT的主要激活剂，被认为是最重要的预后预测因子[17-18]。COVID-19感染者的尸检报告显示，肺泡上皮细胞损伤、Ⅱ型肺细胞增生和成纤维细胞实变[19]。另外，严重的T细胞减少和广泛的细胞因子激活也可能是COVID-19患者的死亡原因[20]。重型/危重型COVID-19患者大多以呼吸系统症状为主，主要表现为需氧量增加(氧饱和度 < 93%)、急性呼吸窘迫综合征、呼吸衰竭和败血症等。检验常发现IL-6、C反应蛋白、D-二聚体和铁蛋白等指标升高。影像学表现为肺实质50%以上炎症浸润，形成所谓“白肺”。
二、LDRT治疗COVID-19的放射生物学基础LDRT与炎症反应之间存在多层次的相互关系，动物实验表明，LDRT主要通过作用于内皮细胞、白细胞、巨噬细胞创造一个抗炎环境，调节细胞因子、趋化因子和生长因子的分泌，从而快速逆转炎症症状，促进疾病好转[21-22]。LDRT可抑制炎性细胞因子(如IL-6、TNF-α等)的产生，降低“炎症风暴”带来的危害[23]。LDRT (< 1 Gy) 可抑制诱导型一氧化氮合酶(iNOS)的表达，从而减少NO生成，从而减轻炎症反应和细胞损伤 [24-25]。0.5~1.0 Gy之间的LDRT导致趋化因子CCL20释放减少，而CCL20的减少可阻止白细胞向损伤部位趋化[26]。LDRT对巨噬细胞也有显著作用，研究显示，0.5~0.7 Gy的LDRT可降低活化巨噬细胞NF-κB的转录调控，使NF-κB的上游p38 MAPK和下游AKT蛋白减少，导致促炎细胞因子IL-1β分泌减少[27]。LDRT对淋巴细胞的作用尚存在争议，高剂量放疗对淋巴细胞具有杀伤作用，从而导致外周血淋巴细胞减少，然而Hildebrandt等[25]对胰岛细胞癌小鼠实施LDRT后发现，LDRT增加了CD8+T细胞的肿瘤浸润。另外，LDRT可调节COVID-19病毒突刺蛋白和宿主的ACE2相互作用，降低ACE2的表达和活性，从而降低病毒导致的肺损伤[28]。这些机制都充分表明，LDRT治疗炎症渗出为主要表现的重型/危重型COVID-19患者具有理论上的可行性。
三、LDRT治疗重型/危重型COVID-19的临床应用1. LDRT治疗重型/危重型COVID-19肺部感染的临床疗效和不良反应：全球已注册了60余个LDRT治疗COVID-19的前瞻性临床试验，已有11个报道了研究结果，LDRT治疗病例数为3~50例，大多采用二维照射技术进行全肺0.5~1.5 Gy照射。其中，10个试验结果显示，LDRT对治疗重型/危重型COVID-19肺部感染可带来不同程度的临床获益，主要表现为供氧量下降、缺氧症状改善、插管率下降、长期住院率下降、炎症指标改善、肺部炎症范围缩小、临床康复时间缩短、康复率上升、生存率提高等。但NCT04598581试验得出了阴性结果，该研究入组了22名ICU住院的机械通气患者(LDRT组、假RT组各11人)，LDRT组进行1.0 Gy全肺照射，结果显示LDRT组患者生存率无明显改善[29]，见表 1。所有临床研究均未观察到急性放射性不良反应，晚期放射性不良反应有待进一步观察。
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表 1 低剂量放疗治疗重型/危重型COVID-19的临床研究 Table 1 Clinical studies of low-dose radiation therapy for severe/critical COVID-19 |
2. LDRT治疗重型/危重型COVID-19肺部感染的剂量选择和干预时机：美国食品药品管理局(FDA)批准LDRT治疗COVID-19肺部感染的剂量为0.5 Gy，但0.5 Gy是否为最佳剂量尚存在争议，已报道的11个临床试验中仅3个临床试验采用的是0.5 Gy剂量。2020年3月，Ghadimi-Moghadam等[39]推荐治疗COVID-19的剂量为0.25 Gy，然而大多临床试验未采用这个剂量。Lumniczky等[40]研究认为，剂量 < 1.0 Gy具有抗炎作用，而>1.0 Gy有促炎作用并导致纤维化。Arruda等[41]基于虚拟病例模型研究认为，< 1.0 Gy的剂量(特别是 < 0.5 Gy的剂量)不仅可以提高低剂量放射治疗的治疗效果，而且可将可能的癌症风险降低到可接受的水平。Kirkby和Mackenzie[11]研究既往LDRT治疗肺炎的剂量分布，采用蒙特卡罗算法得出LDRT治疗肺炎的平均肺部剂量为0. 3~0.8 Gy。Bevelacqua等[42]分析了NCT04598581临床试验失败的原因，认为阴性结果可能是由于放疗剂量不在最佳剂量范围内引起，认为＜1.0 Gy才是合适的LDRT剂量，但其并未解释为何有些试验采用1.0或1.5 Gy剂量也能使患者临床获益。本院1例患者采用1.5 Gy全肺照射，逆转了患者病情恶化的趋势并顺利康复出院。因此，尽管LDRT的最佳剂量存在争议，现有临床研究显示，0.25~1.5 Gy都有可能取得疗效，但仍需通过进一步基础和临床研究确定最佳剂量范围。LDRT的主要机制是抑制COVID-19引起的炎症风暴，合适的时间窗是除剂量之外LDRT是否有效的又一关键因素。Bevelacqua等[42]认为，在患者病情严重到需要机械通气之前可能是LDRT的介入的最佳时机。
四、总结和展望一系列证据表明，COVID-19患者肺部状况恶化的直接原因是病毒感染引发的细胞因子风暴，这也是导致患者呼吸衰竭甚至死亡的主要原因。LDRT治疗重型/危重型COVID-19的可能机制是调节白细胞、巨噬细胞、成纤维细胞和内皮细胞的炎症特性，以及细胞因子/趋化因子和生长因子的分泌；抑制炎性细胞因子(如IL-6、TNF-α等)的产生[23]；调节COVID-19病毒突刺蛋白和宿主的ACE2相互作用，降低ACE2的表达和活性，从而降低病毒导致的肺损伤[28]。多数前瞻性临床试验结果表明，LDRT可能减弱免疫激活，治疗重型/危重型COVID-19疗效较高，且未观察到明显的不良反应，美国FDA也批准LDRT治疗COVID-19肺部感染。患者临床特征、放疗剂量以及放疗介入的时机均有可能对疗效产生影响，需要通过进一步临床试验进行优化。
利益冲突 所有作者宣称没有任何利益冲突, 未接受任何不当利益
作者贡献声明 刘佳负责文献整理和论文撰写；焦旸、殷华芳负责论文修订；何敏、蔡依玲负责部分文献收集；郭洪娟协助文献整理；王坚指导论文命题、思路、结构及论文修改
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