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Chinese Expert Consensus on Clinical Application of Human Papilloma Virus Vaccine
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摘要: 人乳头瘤病毒(human papilloma virus，HPV)疫苗接种是预防HPV感染及相关疾病的有效方法，是防控HPV感染相关疾病的一级预防措施。低龄人群接种效果优于高龄人群，性暴露前接种免疫效果最佳。HPV疫苗不仅适用于普通人群，同样推荐用于高危、特殊人群。对于具有遗传易感、高危生活方式和HIV感染的适龄女性优先推荐接种HPV疫苗。适龄女性无论是否存在HPV感染、细胞学是否异常均可接种HPV疫苗。近期有妊娠计划、妊娠期或哺乳期女性不宜接种HPV疫苗。接种HPV疫苗后仍应进行子宫颈癌筛查。Abstract: Human papilloma virus (HPV) vaccination is a primary preventive measure and an effective method to prevent HPV infection and the related diseases. Its effect in young women is better, and the immune efficacy of vaccination for teenagers before sexual exposure is the best. HPV vaccine is not only suitable for the general population, but also recommended for high-risk and special groups. HPV vaccination should be recommended for women at the appropriate age with genetic susceptibility, high-risk lifestyle, or HIV infection. No matter whether they have HPV infection or abnormal cytology, women of appropriate ages can be vaccinated. Women with a pregnancy plan in the near future and pregnant or lactating women should not be vaccinated. Recommendation of cervical cancer screening should be carried out after HPV vaccination.
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Keywords:
- human papilloma virus /
- vaccine /
- clinical application /
- high risk /
- special population
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肺动脉高压(pulmonary hypertension, PH)是以肺动脉压力升高为主要特征的一种异常血流动力学状态和病理生理综合征，其病因复杂、病情进展迅速，如诊断不及时或未予以有效干预，患者远期预后较差[1]。多种病因和不同发病机制导致的PH患者肺血管结构和功能改变，可引起右心室后负荷持续升高而累及右心室[2]。右心功能与PH患者的预后密切相关，失代偿性右心衰竭是世界卫生组织PH临床分类中的第一大类即动脉性肺动脉高压(pulmonary arterial hypertension, PAH)患者死亡的首要原因[3]，因此，国际指南建议临床使用右心导管、超声心动图等工具常规监测PH患者的右心功能[4]，以早期识别可能发生的右心衰竭。
心室-动脉耦合属于生理学概念，是指心室功能与大动脉功能之间的相互匹配和适应关系，其中左心室-主动脉耦合已在高血压、左心功能不全和休克患者中得到较为充分的研究[5-6]；而在PH患者中，研究者关注的重点是右心室与肺动脉的耦合关系，特别是右心室收缩功能对升高的后负荷的适应能力。大量研究表明，右心室-肺动脉耦合是衡量右心室功能的关键指标，对PH患者的预后起决定性作用[7]。近年来，右心室-肺动脉耦合的有创评估已在PH的基础实验中得到了广泛研究，其无创替代指标也在PH的早期筛查、鉴别诊断和预后评估中引发了持续关注。本研究旨在对现有右心室-肺动脉耦合评估方法进行总结，并重点分析基于超声的右心室-肺动脉耦合无创评估的临床意义，以期为PH的临床诊疗提供参考。
1. 右心室-肺动脉耦合的原理
生理情况下，肺循环主要由低阻力、高顺应性的血管构成，肌壁较薄的右心室在较低的后负荷下将足量的血液泵入肺动脉。PH早期，肺血管发生重构，以致右心室后负荷轻度增加并通过代偿性心肌肥厚增加收缩力，以维持正常的心输出量而不发生扩张(等长调节)[7]；随PH进展，肺血管阻力和肺动脉压力进行性升高，长期处于超负荷状态的右心室无法继续相应地增加收缩力，即右心室与肺循环失耦合。为延缓心输出量的下降，右心室扩张(异长调节)并导致一系列功能障碍，最终进入右心功能失代偿阶段[3](图 1)。除累及右心功能外，扩张的右心室可通过室间隔在舒张末期向左移位而影响左心室充盈，导致左心室射血分数下降和功能障碍[8]。由此可见，右心室-肺动脉耦合是心肺循环维持正常生理功能的关键因素。
右心室-肺动脉失耦合现象在PH患者中普遍存在，是PH进展为失代偿性右心衰竭并导致不良预后的重要环节[9]，合理规范的靶向药物治疗可通过扩张肺血管而降低右心后负荷，改善右心重构与功能障碍，促使右心室与肺循环恢复正常耦合，从而提高患者的生存率。既往PH相关研究倾向于将右心室和肺动脉视为两个孤立的单元分别进行评估，而忽略了二者在生理功能上的密切联系。右心室-肺动脉耦合则强调以整体性视角理解PH的病理生理机制，该理念逐渐被临床认可。
2. 右心室-肺动脉耦合的有创评估
心室-动脉耦合的定量评估最早始于20世纪70年代。Suga等[10]使用电导导管记录了心室在心动周期中不同时刻的压力和容积，并分别将其作为Y轴和X轴绘制压力-容积环，通过压力与容积之间的关系定量评估非负荷依赖的心室收缩功能参数心室收缩末期弹性(end systolic elastance, Ees)，以及心室后负荷参数动脉弹性(arterial elastance, Ea)。在计算Ees时，需在至少2个压力-容积环的收缩末期处取值，通过线性回归法获取收缩末期压力-容积关系的斜率，而Ea则需通过收缩末期压力与每搏输出量的比值进行计算，Ees与Ea的比值(Ees/Ea)即为心室-动脉耦合参数，可视为校正了后负荷的心室收缩能力[9]。研究表明，生理状况下Ees/Ea在1.5~2.0时提示右心室-肺动脉耦合良好，此条件下右心可在最低耗能下实现最优的心输出量；而PH患者的Ees/Ea普遍降低，此现象与肺血管重构导致的后负荷升高及右心功能障碍有关[11-13]。
目前，电导导管压力-容积环法仍是评价心室-动脉耦合状况的金标准，该项技术已广泛应用于PH的基础研究，如通过动物模型探索急慢性PH的病理生理特点[14-15]、比较不同靶向药物对右心室-肺动脉耦合的影响等[16]。鉴于导管操作的技术难度以及侵入性，该技术未在临床得到推广。此外，在右心室形态不规则的情况下，采用电导导管估计的心室容积可能存在较大误差。针对上述问题，多种评估右心室-肺动脉耦合的替代方法被陆续提出，如使用“单次心搏法”降低操作风险[17]，联合心脏磁共振提高右心室容积的测量精度[18]，在导管的基础上使用超声实现“半无创”评估右心室-肺动脉耦合等[19-20]，但该方法由于费用昂贵、患者接受度低等问题仍未得到广泛应用。在临床上，尽管右心室-肺动脉耦合与PH预后的相关性已得到公认，但目前并无证据支持需常规对PH患者进行有创Ees/Ea评估。
3. 右心室-肺动脉耦合的无创评估
近年来，基于超声心动图的右心室-肺动脉耦合无创评估是心内科研究的热点之一。从原理来看，右心室-肺动脉耦合的无创评估工具必须能同时评价右心室的收缩功能和后负荷。作为PH筛查、风险评估和随访管理中最重要的工具之一，超声心动图不仅可提供关于血流动力学和右心功能的大量信息，且具有安全、经济、可床旁进行等优点，因此由传统二维超声心动图、二维斑点追踪超声心动图和三维超声心动图等衍生的右心室-肺动脉耦合指标具有在临床推广应用的巨大潜力。
超声衍生的右心室-肺动脉耦合指标绝大多数是传统超声参数以比值的形式进行的组合，这些比值通过模拟Ees/Ea的原理进而估测右心室与肺动脉之间的耦合关系，其中比值的分子多为可反映右心室收缩功能的参数，如三尖瓣环收缩期位移(tricuspid annular plane systolic excursion, TAPSE)、三尖瓣环收缩期峰值运动速度、右心室面积变化分数等，分母则主要为与右心室后负荷相关的参数，如收缩期肺动脉压力(pulmonary artery systolic pressure, PASP)、肺动脉血流加速时间等[21-22]。此外，有研究者将肺动脉脉搏波传导时间(收缩压的脉搏波由肺动脉瓣传导至肺静脉的时间)，作为右心室-肺动脉耦合的评估指标[23]。Tello等[20]在一项纳入52例PAH和慢性血栓栓塞性PH患者的研究中比较了多个超声组合指标与金标准电导导管“单次心搏法”测定的Ees/Ea的相关性，并以Ees/Ea=0.805为界值，通过受试者操作特征曲线下面积(area under the curve, AUC)评估各指标对右心室与肺循环失耦合的区分度，发现TAPSE/PASP是金标准Ees/Ea最为理想的无创替代指标(AUC=0.816，P＜0.05)。TAPSE/PASP等无创指标为右心室-肺动脉耦合的床旁评估和动态监测提供了极大便利，未来有望成为PH风险评估和危险分层的常规参数。
由于右心室几何形状不规则且心肌力学功能模式较复杂，使用传统二维超声心动图评估右心室形态和功能的准确性受到限制，而使用二维超声斑点追踪成像技术测量的右心室应变和应变率，以及使用三维超声心动图测量的右心室射血分数(right ventricular ejection fraction，RVEF)和每搏输出量等参数则无需依赖右心室几何学假设，可更为精准地反映右心室收缩功能，在右心室-肺动脉耦合的无创评估中受到广泛关注[24-25]。Iacoviello等[26]在315例慢性心力衰竭(heart failure, HF)患者中采用右心室整体纵向应变、右心室游离壁应变与PASP的比值分别评估右心室-肺动脉耦合，发现此2个指标均与HF患者随访中全因死亡风险显著相关。Nochioka等[27]对社区动脉粥样硬化风险队列中的728名参与者进行三维超声心动图检查，发现RVEF/PASP降低不仅提示严重的心功能障碍，其与患者全因死亡风险升高的关系更为密切。虽然上述指标与右心室-肺动脉耦合的相关性可能更强，但由于检测手段的普及程度不及传统二维超声，目前尚缺乏在PH人群中的相关研究，此类无创超声指标代替Ees/Ea的可行性仍有待探索。
4. TAPSE/PASP在PH中的应用
在PH人群中，TAPSE/PASP是当前研究最为深入的无创性右心室-肺动脉耦合参数。2013年，Guazzi等[28]最早提出可通过TAPSE/PASP评估右心室-肺动脉耦合并预测HF患者临床结局，随后TAPSE/PASP的应用范围逐渐扩大至各个临床分类的PH、高血压、急性肺栓塞以及瓣膜手术患者中[29-32]。通过对2个临床常见的超声指标PASP、TAPSE进行整合，TAPSE/PASP可同时反映右心室收缩功能和后负荷变化情况，从而将右心与肺循环作为一个整体进行分析，其评估结果相比单一指标更优，在PH早期筛查、鉴别诊断及风险评估中均体现出良好的应用价值[28, 30]。
4.1 TAPSE/PASP与PH的早期筛查
Colalillo等[33]对51例疑似PAH的系统性硬化患者同时采用DETECT流程(一种在系统性硬化患者中早期筛查PAH的评分工具)和TAPSE/PASP进行早期筛查，并对DETECT流程筛选出的患者进行右心导管检查测定肺动脉压力，发现以0.60 mm/mm Hg为界值时，TAPSE/PASP诊断PAH的阳性预测值为62.5%，可作为DETECT流程的有效补充。Gall等[34]在PH新定义的背景下比较了不同超声指标筛查PH的效能，并提出在超声测量的三尖瓣反流压差≤46 mm Hg(1 mm Hg=0.013 kPa)人群中，TAPSE与三尖瓣反流压差的比值可更精确地识别右心导管测量的肺动脉平均压＞20 mm Hg患者。上述研究均支持TAPSE/PASP等超声参数可用于识别临床前阶段和疾病早期PH患者的结论，进而指导临床有针对性地开展右心导管检查。
4.2 TAPSE/PASP与PH的鉴别诊断
混合性毛细血管前和后性PH的TAPSE/PASP普遍更低，死亡风险增高。Gorter等[35]研究发现，TAPSE/PASP有助于孤立性毛细血管后性PH与混合性毛细血管前和后性PH的鉴别诊断；TAPSE/PASP以0.36 mm/mm Hg为临界值时，识别混合性毛细血管前和后性PH的灵敏度、特异度分别为86%和79%，AUC达0.86，具有较好的区分度。
4.3 TAPSE/PASP与PH的预后评估
Guazzi等[36]在一项纳入459例HF患者(多数为左心疾病所致的PH患者)的研究中发现，TAPSE/PASP与心肺运动试验测定的峰值摄氧量呈正相关(r=0.34，P＜0.001)，与二氧化碳通气当量斜率呈负相关(r=-0.48，P＜0.001)；TAPSE/PASP较低(＜0.40 mm/mm Hg)患者的运动耐量下降、通气效率受损，更易出现振荡呼吸，随访4年后发现此类人群发生心血管不良事件的风险增高。随后，Guazzi等[37]对219例射血分数保留的HF患者(多数为左心疾病所致的PH患者)进行右心导管检查，发现HF患者TAPSE/PASP降低不仅与血流动力学恶化有关，且提示更高的因心血管原因再住院和死亡风险。Tello等[38]以290例PAH患者为研究对象分析了TAPSE/PASP与心肺功能及预后的相关性，结果显示TAPSE/PASP较低患者(＜0.19 mm/mm Hg)的病情更重，且具有更差的世界卫生组织心功能分级；此外，较低的TAPSE/PASP值与血流动力学参数，特别是与肺血管阻力增高和肺动脉顺应性降低显著相关，并可反映超声心动图测定的三尖瓣反流、右心房和右心室扩张严重程度；多因素Cox回归模型校正混杂因素后发现，TAPSE/PASP与PAH患者全因死亡独立相关(HR=4.13, 95%CI：2.02~8.48, P＜0.001)。Guo等[39]在一项前瞻性研究中对112例系统性红斑狼疮相关PAH患者进行了中位数为18个月的随访，发现TAPSE/PASP和6 min步行距离是此类PAH患者临床病情恶化及全因死亡的独立预测因子，当TAPSE/PASP＜0.184 mm/mm Hg和/或6 min步行距离＜395 m时，提示PAH患者预后不佳。上述研究表明，TAPSE/PASP是对PH患者进行病情评估和风险分层的一个重要参数，未来有望更广泛地用于指导治疗和疗效评估。
4.4 TAPSE/PASP的局限性
TAPSE/PASP具有便捷、安全性高、实用性强等优点，临床应用前景广阔，但其准确性受到超声固有局限性的影响。首先，虽然在生理状态下TAPSE所代表的纵向收缩能力是右心室泵血功能的主要成分，但PH患者右心室结构和功能发生变化时，室壁运动的横向及前后向成分对整体射血分数的贡献率也可能随之改变，此时TAPSE无法准确反映右心室的整体收缩能力。其次，超声对PASP的测量受多种因素的影响，在声窗欠佳、频谱质量差、三尖瓣反流信号无法测定时[40]，由三尖瓣反流速度估测的PASP存在高估或低估的可能，不能代替右心导管的测量结果。最后，右心室后负荷由固定性负荷和搏动性负荷两部分组成，而PASP仅可反映固定性负荷[41]，造成对右心室后负荷评估的准确性降低。鉴于上述局限性，TAPSE/PASP在PH中应用的临床意义仍有待进一步考证。
5. 小结与展望
右心室-肺动脉耦合与PH患者的预后具有高度相关性，评估右心室-肺动脉耦合有助于揭示隐匿的右心功能障碍，从而进行早期干预，延缓病情进展并改善患者预后。尽管通过压力-容积环计算的Ees/Ea是诊断右心室-肺动脉耦合的金标准，但目前已获得的研究证据初步表明无创超声心动图检查在右心室-肺动脉耦合的评估中具有较大优势和潜力。超声指标TAPSE/PASP具有无创性的优势，在PH患者右心室-肺动脉耦合评估中受到广泛关注，有望成为PH筛查、鉴别诊断与预后评估的常规参数，辅助临床决策。相信随着更多无创性评估指标的发现，右心室-肺动脉耦合在PH临床诊疗中的应用有望得到多方面推广。未来需进一步验证新型无创指标与右心室-肺动脉耦合诊断金标准的相关性与一致性，并揭示右心室-肺动脉耦合受损的界值。目前PH中使用二维斑点追踪超声心动图和三维超声心动图评估右心室-肺动脉耦合的数据较少，有待更深入的探讨并进行综合性评价。此外，还应基于无创性指标在人群中展开不同PH治疗方案对右心室-肺动脉耦合优化效果的相关研究，以精准化指导临床治疗决策。
利益冲突： 无通信作者: 马丁1, dma@tjh.tjmu.edu.cn, 魏丽惠2, weilhpku@163.com, 谢幸3, xiex@zju.edu.cn, 孔北华4, kongbeihua@sdu.edu.cn -
表 1 我国国家药品监督管理局批准上市的HPV疫苗特点和接种程序
项目 国产双价HPV疫苗
(大肠杆菌)双价HPV吸附疫苗 四价HPV疫苗 九价HPV疫苗 全球上市时间 - 2007年 2006年 2014年 中国上市时间 2019年 2016年 2017年 2018年# 预防HPV型别 16/18 16/18 6/11/16/18 6/11/16/18/31/33/45/52/58 中国女性适宜接种年龄 9~45岁 9~45岁 9~45岁& 16~26岁 预防HPV感染相关
疾病(中国批准)子宫颈癌、CIN 1级、CIN 2/3级、AIS，HPV 16/18持续性感染 子宫颈癌、CIN 1级、CIN 2/3级、AIS 子宫颈癌、CIN 1级、
CIN 2/3级、AIS子宫颈癌、CIN 1级、CIN 2/3级、AIS，9种HPV相
关亚型感染表达系统 大肠杆菌 杆状病毒 酿酒酵母 酿酒酵母 免疫量 共接种3剂，每剂0.5 mL 共接种3剂，每剂0.5 mL 共接种3剂，每剂0.5 mL 共接种3剂，每剂0.5 mL 接种方法和部位 肌内注射，首选上臂三角肌 肌内注射，首选上臂三角肌 肌内注射，首选上臂三角肌 肌内注射，首选上臂三角肌 免疫程序(接种方案)* 第0、1、6个月，9~14岁
接种2剂第0、1、6个月 第0、2、6个月 第0、2、6个月 HPV：人乳头瘤病毒；CIN：子宫颈上皮内瘤变；AIS：原位腺癌；#2018年10月美国食品药品监督管理局批准九价HPV疫苗可用于9~45岁女性[38]； & 2020年11月国家药品监督管理局批准四价HPV疫苗应用于9~19岁女性; *1年内接种3剂为完成免疫接种 
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表 2 普通和特殊人群(女性)HPV疫苗接种的推荐级别*#
不同人群 推荐级别 普通人群 9~26岁女性 优先推荐 27~45岁女性 推荐 特殊人群 HPV感染/细胞学异常的适龄女性 推荐 妊娠期女性 不推荐 哺乳期女性 谨慎推荐 有HPV相关病变治疗史的适龄女性 推荐 有遗传易感和子宫颈癌发病高危因素的适龄女性* 优先推荐 免疫功能低下的适龄女性# HIV感染者 优先推荐 自身免疫性疾病患者：系统性红斑狼疮、风湿性关节炎、结缔组织病、干燥综合征、桥本甲状腺炎等 推荐 1型和2型糖尿病患者 推荐 肾衰竭接受血液透析者 与临床医生共同探讨 器官/骨髓移植术后长期服用免疫抑制剂者 与临床医生共同探讨 HPV：同表 1；HIV：人类免疫缺陷病毒；*建议首次性暴露前或尽早接种；#全身脏器功能差、病情不乐观、预期寿命有限者，不推荐
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