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Expert Consensus of Multidisciplinary Diagnosis and Treatment for Paroxysmal Nocturnal Hemoglobinuria(2024)
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摘要:
阵发性睡眠性血红蛋白尿症(paroxysmal nocturnal hemoglobinuria, PNH)是一种由于磷脂酰肌醇聚糖A基因突变引起细胞膜上锚链蛋白糖基磷脂酰肌醇(glycosylphosphatidylinositol, GPI)表达异常所致的后天获得性克隆性造血干细胞疾病, 临床常表现为血管内溶血、反复血栓形成及骨髓衰竭, 也可出现肾功能异常、肺动脉高压、吞咽困难、胸痛、腹痛、勃起功能障碍等多系统受累的症状。由于PNH为罕见病, 且临床表现异质性强, 常需进行多学科协作诊疗。北京协和医院依托罕见病诊疗平台, 邀请多学科临床专家, 在PNH诊疗方面达成了统一意见, 并形成《阵发性睡眠性血红蛋白尿症多学科诊疗专家共识(2024)》, 以期促进PNH诊疗的标准化、规范化。
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关键词:
- 阵发性睡眠性血红蛋白尿症 /
- 多学科诊疗 /
- 多系统受累 /
- 共识
Abstract:Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal hematopoietic stem cell disease caused by abnormal expression of glycosylphosphatidylinositol (GPI) on the cell membrane due to mutations in the phosphatidylinositol glycan class A(PIGA) gene. It is commonly characterized by intravascular hemolysis, repeated thrombosis, and bone marrow failure, as well as multiple systemic involvement symptoms such as renal dysfunction, pulmonary hypertension, swallowing difficulties, chest pain, abdominal pain, and erectile dysfunction. Due to the rarity of PNH and its strong heterogeneity in clinical manifestations, multidisciplinary collaboration is often required for diagnosis and treatment. Peking Union Medical College Hospital, relying on the rare disease diagnosis and treatment platform, has invited multidisciplinary clinical experts to form a unified opinion on the diagnosis and treatment of PNH, and formulated the Expert Consensus of Multidisciplinary Diagnosis and Treatment for Paroxysmal Nocturnal Hemoglobinuria (2024), with the hope of promoting the standardization of PNH diagnosis and treatment.
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骨成熟度的评估对于生长发育异常患儿的诊断、治疗及随访具有重要作用[1]。目前临床主要通过拍摄左手及腕部X线片评估骨龄以了解骨成熟度，但其具有辐射风险，且存在来源人群陈旧、一致性低、复杂费时等问题[2-3]。而超声可清晰显示发育期低回声骺软骨及其内强回声的次级骨化中心并进行相应测量，且无辐射，可用于动态随诊[4]。基于发育过程中长骨关节端的大体及微观特点[5-6]，本研究结合长骨关节端声像表现，初步探索采用超声骺软骨厚度(ultrasonic epiphysis cartilage thickness, UECT)定量评估骺软骨发育情况并分析其与骨龄的相关性，以期为骨成熟度评估提供新思路。
1. 资料与方法
1.1 研究对象
本研究为前瞻性观察性研究，以2023年3—6月就读于济宁市某体校的青少年为研究对象，记录年龄、身高等信息。纳入标准：(1)年龄为7~18岁；(2)外形及营养状况良好。排除标准：(1)患有可能导致生长发育异常的慢性肝肾疾病、骨骼系统疾病、内分泌遗传综合征等；(2)超声或骨龄X线图像质量差、无法识别；(3)手和腕部及膝关节组成骨存在近期骨折史。
本研究已通过北京协和医院伦理审查委员会审批(审批号：K4393)，研究对象或其亲属均签署知情同意书。
1.2 研究方法
1.2.1 X线检查
于1周内行X线骨龄检查，并由1名具有15年阅读骨龄片经验的内分泌科医师使用Greulich-Pyle(GP)图谱法评估骨龄。
1.2.2 超声检查
分别由具有20年及8年超声工作经验的2名医师针对非优势侧手、腕部及膝关节7个组成部位进行超声检查(GE Logiq E20彩色多普勒超声诊断仪)，探头选用L6-24靴型探头及L2-9线阵探头。首先使患者手背朝上，采用L6-24靴型探头顺序扫查第三掌骨头部背侧正中矢状面、尺骨茎突冠状面、桡骨茎突冠状面。随后使患者采取俯卧位，暴露膝关节背侧，采用L2-9线阵探头扫查股骨内上髁冠状面、股骨外上髁冠状面、胫骨背侧正中矢状面、胫骨内侧髁冠状面。所有切面均清晰显示干骺端、次级骨化中心及骺软骨。
1.2.3 UECT测量
首先沿骨干强回声带外缘内侧作骨干方向延长线，其与骨干强回声带外缘产生交点，随后根据次级骨化中心所示强回声带的形状选择相应测量方法：(1)若呈从骨干向关节端下降的抛物线形，则以次级骨化中心骨干端外缘顶点与前述骨干外缘交点的距离作为UECT；(2)若呈半圆形，作与前述骨干方向延长线的平行线，其中与次级骨化中心强回声带相切的切点与前述骨干外缘交点距离为UECT(图 1、2)。对于单个研究对象的多部位UECT联合分析，则将各部位UECT之和作为总UECT并分析其与骨龄的相关性。
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图 1 次级骨化中心呈从骨干向关节端下降的抛物线形(A)和半圆形(B)强回声带(UECT勾画示意图)Dia(diaphysis)：骨干；Soc(secondary ossification center)：次级骨化中心；UECT(ultrasonic epiphyseal cartilage thickness)：超声骺软骨厚度Figure 1. The schematic diagram depicts the way to measure UECT when secondary ossification center shows a parabolic strong echo zone descending from the diaphysis to the joint end (A) and a semicircular strong echo band(B)![]()
图 2 次级骨化中心呈从骨干向关节端下降的抛物线形(A~G)和半圆形(a~g)强回声带(7个部位UECT超声图示)A.第三掌骨头部背侧正中矢状面；B.尺骨茎突冠状面；C.桡骨茎突冠状面；D.股骨内上髁冠状面；E.股骨外上髁冠状面；F.胫骨背侧正中矢状面；G.胫骨内侧髁冠状面Figure 2. Ultrasound diagram of UECT at 7 sites when the secondary ossification center shows a parabolic strong echo zone descending from the diaphysis to the joint end(A-G) and a semicircular strong echo band(a-g)A.dorsal median sagittal plane of the third metacarpal head(MCP3); B.coronal plane of ulnar styloid process(Ulna); C.coronal plane of radial styloid process(Radius); D.coronal plane of medial epicondyle of femur(FM); E.coronal plane of lateral epicondyle of femur(FL); F.median sagittal plane of dorsal tibia(TD); G.coronal plane of medial condyle of tibia(TM)
UECT: 同图 11.2.4 重复测量信度检验
以组内相关系数(intraclass correlation coefficient, ICC)评估UECT测量的信度与可重复性。研究按照性别与骨龄采用分层抽样法随机抽取50人超声图像，由另一操作者再次测量UECT值，计算ICC并评估一致性。
1.3 样本量估算
采用G*power 3.1.9.7软件分析纳入的样本量，参数选择效应量f2=0.15、α=0.05，β=0.80，计算所需最小样本量为55例。
1.4 统计学处理
采用R Studio 4.3.0软件进行统计学分析。正态性分析采用Shapiro-Wilk检验，年龄、骨龄及身高均不符合正态分布，以中位数(四分位数)表示。组间比较采用秩和检验。计数资料以频数(百分数)表示，组间比较采用卡方检验。采用Spearman法分析UECT与骨龄的相关性，高低分级参考前述研究[7]，|r|为0.5~0.7表示中度相关；|r|为0.7~0.9表示高度相关；|r|为0.9~1.0表示非常高度相关。采用SPSS 24.0软件进行ICC分析，计算参数选择single measurement、2-way random effects、absolute agreement，ICC≥0.75为一致性较好，ICC＜0.4为一致性较差。以P＜0.05为差异具有统计学意义。
2. 结果
2.1 一般资料
共纳入141名青少年，其中男性80名，女性61名。中位年龄为13(12，14)岁。男性身高显著高于女性(表 1)。男性中位骨龄15(13，17)岁，女性中位骨龄16(14，17)岁。男女骨龄与年龄差值＞1岁者分别占比60%、67%。男女年龄、身高及骨龄分布见图 3。
表 1 男性与女性一般资料比较Table 1. General information between male and female项目 男性(n=80) 女性(n=61) P值 年龄[M(P25, P75)，岁] 13(12, 14) 13(12, 14) 0.52 骨龄[M(P25, P75)，岁] 15(13, 17) 16(14, 17) 0.40 骨龄-年龄＞1岁[n(%)] 48(60) 41(67) 0.48 身高[M(P25, P75)，cm] 175.3 (167.8, 181.4) 167.1 (161.4, 173.2) ＜0.001 ![]()
图 3 141名青少年年龄、身高及骨龄分布A.年龄；B.身高；C.骨龄Figure 3. Age, height and bone age distribution of 141 adolescentsA.age; B.height; C.bone age2.2 发育过程长骨关节端的声像表现
利用超声观察不同骨龄阶段研究对象的长骨关节端，其声像表现存在以下规律：生长发育初期，次级骨化中心首先在低回声骨骺中央萌出，声像图显示为小半圆形强回声带。次级骨化中心进一步扩展增大，但仍然保持半圆形的形状。随着骨成熟度提高，次级骨化中心所示强回声带呈从骨干向关节端下降的似抛物线形，强回声带的骨干端从低于骨干外缘逐渐上升至与其平齐。生长晚期至终止时，次级骨化中心与骨干不断接近，最终形成一条完整、平滑的强回声带，关节面被覆薄层低回声关节软骨(图 4)。
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图 4 不同骨龄男性青少年长骨关节端声像图(以尺骨茎突、桡骨茎突、股骨外上髁、胫骨内上髁为例)Figure 4. Sonograms of the joint ends of different long bones in male adolescents of different bone ages (taking the ulnar styloid process, radial styloid process, femoral lateral epicondyle, and tibial medial epicondyle as examples)2.3 UECT与骨龄相关性
男、女7个部位的UECT均随骨龄增长而减小，至骨龄18岁时测量值趋近于0(表 2、3)。各部位UECT与骨龄均呈负相关，男性单部位UECT与骨龄均呈高度负相关(|r|≥0.83)，而女性单部位UECT与骨龄呈中高度负相关(0.65≤|r|≤0.75)(表 4)。
表 2 不同骨龄男性青少年7个部位的UECT测值[M(P25, P75)，mm]Table 2. Measured values of UECT at 7 sites in male adolescents of different bone ages[M(P25, P75), mm]骨龄(岁) MCP3 Ulna Radius FM FL TD TM 8(n=1) 1.4 4.2 5.4 5.0 2.6 3.0 4.7 9(n=1) 1.4 3.0 4.8 5.7 3.7 3.4 3.5 11(n=6) 1.7(1.3, 2.2) 3.2(2.7, 3.5) 4.2(4.0, 4.9) 3.5(2.4, 4.2) 2.5(2.2, 2.7) 3.6(2.8, 4.1) 4.0(3.5, 4.8) 12(n=3) 1.3(1.2, 1.9) 4.4(3.6, 5.2) 4.9(3.7, 5.5) 2.4(2.15, 3) 3.1(2.7, 3.8) 1.6(1.5, 2.1) 4.5(4.5, 4.8) 12.5(n=1) 1.0 2.6 3.1 2.1 2.4 2.3 2.8 13(n=11) 1.4(0.9, 1.5) 2.5(2.1, 2.9) 3.0(2.6, 3.3) 2.0(1.3, 2.6) 2.9(2.3, 3.0) 1.8(1.7, 2.0) 3.0(2.6, 3.2) 13.5(n=2) 1.5(1.2, 1.9) 3.0(2.9, 3.0) 3.1(3.0, 3.2) 1.9(1.9, 1.9) 1.7(1.6, 1.9) 3.0(2.4, 3.5) 2.7(2.5, 2.8) 14(n=7) 0.8(0.7, 0.9) 2.0(1.5, 2.1) 2.2(1.9, 2.9) 1.8(1.4, 2.0) 2.0(1.3, 2.3) 1.6(1.2, 2.2) 2.1(2.0, 3.3) 15(n=11) 0.6(0.6, 0.7) 1.9(1.5, 2.2) 2.2(1.6, 2.3) 1.5(1.1, 1.9) 1.7(0.9, 2.7) 1.2(0.7, 1.8) 2.2(1.3, 2.5) 16(n=4) 0.4(0.2, 0.4) 1.1(0.9, 1.4) 1.2(0.8, 1.7) 0.8(0.6, 1.0) 1.2(1.0, 1.3) 0.7(0.5, 0.8) 1.3(1.1, 1.4) 17(n=19) 0.1(0, 0.4) 1.3(0.7, 1.7) 1.3(1.1, 1.5) 0(0, 0.8) 0.9(0.6, 1.4) 0(0, 0.7) 0.6(0, 1.3) 18(n=14) 0(0, 0) 0.6(0.4, 1.0) 0.6(0.4, 0.9) 0(0, 0) 0(0, 0.4) 0(0, 0) 0(0, 0) 表 3 不同骨龄女性青少年7个部位的UECT测值[M(P25, P75)，mm]Table 3. Measured values of UECT at 7 sites in female adolescents of different bone ages [M(P25, P75), mm]骨龄(岁) MCP3 Ulna Radius FM FL TD TM 7(n=1) 1.7 4.7 6.4 3.1 3.8 1.5 2.3 8(n=1) 2.0 5.4 4.9 1.8 4.0 3.8 3.0 11(n=2) 1.1(1.0, 1.2) 2.4(2.0, 2.7) 3.4(2.6, 4.3) 2.5(2.2, 2.7) 2.2(1.7, 2.6) 1.9(1.8, 1.9) 1.7(1.4, 1.9) 11.5(n=1) 0.7 1.5 2.6 2.9 1.9 1.4 2.4 12(n=2) 0.9(0.8, 0.9) 1.9(1.9, 2.0) 2.1(2.0, 2.3) 1.5(1.4, 1.6) 1.7(1.7, 1.8) 0.9(0.9, 1.0) 4.4(4.0, 4.7) 13(n=7) 0.5(0.4, 0.6) 1.7(1.1, 1.8) 1.7(1.5, 1.9) 1.3(1.1, 2.0) 1.1(1.0, 1.3) 1.1(0.8, 1.4) 1.9(1.0, 2.7) 14(n=3) 0.3(0.3, 0.7) 1.3(1.3, 1.8) 1.3(1.2, 1.8) 1.4(0.7, 2.1) 1.0(1.0, 1.3) 0.6(0.3, 0.7) 1.3(1.2, 1.3) 15(n=4) 0.5(0.3, 0.5) 1.9(1.5, 2.1) 1.6(1.5, 1.7) 1.1(0.6, 1.6) 0.9(0.7, 1.4) 0.9(0.6, 1.3) 0.8(0.3, 1.5) 16(n=13) 0(0, 0) 0.9(0.9, 1.1) 0.8(0.6, 1.2) 0(0, 0.6) 0.9(0.5, 1.5) 0(0, 0) 0(0, 0.5) 17(n=19) 0(0, 0.2) 0.8(0.6, 1.1) 1.1(1.0, 1.4) 0(0, 0.7) 0.5(0, 1.0) 0(0, 0.2) 0(0, 0.2) 18(n=8) 0(0, 0) 0.4(0.2, 0.7) 0.6(0.4, 0.8) 0(0, 0) 0(0, 0.1) 0(0, 0) 0(0, 0) 表 4 单部位UECT与骨龄的相关系数(r)Table 4. Correlation coefficient between single-site UECT and bone age性别 MCP3 Ulna Radius FM FL TM TD 男 -0.84 -0.85 -0.90 -0.83 -0.80 -0.87 -0.86 女 -0.74 -0.71 -0.69 -0.67 -0.65 -0.75 -0.71 MCP3、Ulna、Radius、FM、FL、TD、TM：同图 2 男、女7个部位UECT总和与骨龄的负相关性均达到较高水平(男：|r|=0.93；女：|r|=0.80)(表 5), 单独选取手和腕部3个部位或膝关节4个部位时，女性UECT总和与骨龄高度负相关(|r|≥0.76)，而男性则表现出非常高度负相关性(|r|≥0.90)(表 6)。
表 5 7个部位UECT总和与骨龄及年龄的相关系数(r)Table 5. Correlation between the sum of UECT at 7 sites and bone age or chronological age性别 骨龄 年龄 男 -0.93 -0.79 女 -0.80 -0.64 表 6 多部位UECT总和与骨龄的相关系数Table 6. Correlation coefficient between UECT sum of different sites and bone age性别 FL+TM+TD FM+TM+TD knee joint hand and wrist all 男 -0.91 -0.92 -0.93 -0.90 -0.93 女 -0.80 -0.76 -0.79 -0.77 -0.80 FL、FM、TM、TD：同图 2；knee joint：膝关节4个部位UECT总和；hand and wrist：手和腕部3个部位UECT总和；all：7个部位UECT总和 2.4 不同操作者测量UECT的可重复性
7个部位UECT测量的一致性分析均具有显著统计学意义(P均＜0.001)，ICC值均≥0.75提示各部位UECT测量一致性均较好(表 7)。
表 7 UECT测量的一致性分析Table 7. Consistency analysis of UECT measurements部位 ICC 95% CI MCP3 0.91 0.79~0.96 Ulna 0.95 0.84~0.98 Radius 0.91 0.78~0.97 FM 0.98 0.95~0.99 FL 0.93 0.83~0.97 TD 0.93 0.83~0.97 TM 0.95 0.89~0.98 MCP3、Ulna、Radius、FM、FL、TD、TM：同图 2；ICC(intraclass correlation coefficient): 组内相关系数 3. 讨论
本研究显示，UECT与骨龄呈中至高度负相关，提示UECT可一定程度上反映发育过程中骺软骨的变化，具有较好的可重复性，可用于骨成熟度水平定量评估。声像图显示发育过程中长骨次级骨化中心形态变化及其与骨干的位置关系改变，与大体及微观研究结果相符[5-6]。与其他利用骨骺生长发育过程中声像改变划分阶段推测法医学年龄的研究不同[8-9]，本研究以UECT连续定量评估骨成熟度，而Torenek等[10]根据手和腕部的所有指骨和桡骨远端骨骺以及第一掌骨头部的籽骨共13个部位的声像表现构建半定量评估系统，结果发现除第一、二指骨近节指骨外，超声与X线的评分结果无统计学差异(P＜0.05)。本研究发现，UECT与骨龄相关性在不同性别中存在差异，男性单个及多个部位均表现为高度负相关，而女性多为中度负相关，分析原因可能是大骨龄女性比例较高(16~18岁骨龄的女性占比67%)，且女性的发育起点和终点均早于男性，使女性UECT值多数较低，未来可通过控制研究群体的分布开展进一步研究。
多项研究通过测量发育过程中长骨关节端结构进行骨成熟度评估，Castriota-Scanderbeg等[11-12]研究发现，无骨龄提前或延后的研究对象股骨头软骨超声测量厚度与年龄、骨龄、身高等均高度相关，但对于发育异常对象而言，该方法与放射学评估的一致性较低。本研究显示，男女UECT与骨龄均呈负相关性，且明显高于其与年龄的相关性(表 5)，说明UECT可反映研究对象的发育提前特点。
另有多个研究聚焦于骨关节端的次级骨化中心研究。Sherif等[13]利用超声测量正常儿童的根骨体积并以此作为标准准确预测了验证组健康儿童的年龄，但从出生后第5年开始根骨的体积增长率仅为12%左右，因此其应用范围较有限，也缺乏在发育异常患儿中的验证。Windschall等[14]利用超声测量早产儿与足月儿的股骨远端及胫骨近端次级骨化中心大小并评估其与胎龄的相关性，发现存在中度相关(R2=0.35~0.50)。Wan等[15-17]将骨化中心最大直径与无回声骨骺最大直径比值定义为骨化率，发现桡骨茎突冠状面、尺骨茎突冠状面、股骨内上髁冠状面三者的骨化率总和与骨龄呈正相关(r=0.97)，对异常骨龄具有非常高的诊断性与特异性(灵敏度≥93%，特异度≥98%)。骨化率反映了骺软骨骨化不断扩大并最终发育成骨关节末端的过程，而UECT则反映骨化中心不断接近骨干端至最后愈合的过程。前者是比值型指标，受身高影响可能更小，但关节端的骺软骨与发育成熟后保留于骨表面的薄层关节软骨均表现为同质性的低回声[18]，常难以获得准确的骨骺最大直径。有研究采用手和腕部以及膝关节X线片测量数个长骨次级骨化中心以及骨干的横径比来评估骨成熟度，结果均表现为高度相关[19-20]，而本研究声像图显示，发育成熟过程中长骨的次级骨化中心往往先上升至与骨干外缘同一高度，随后表现为二者间骺软骨不断变薄至消失，因此前述方法可能对生长发育晚期的变化描述有限。
本研究局限性：(1)单中心研究；(2)研究对象多处于发育晚期，骨成熟度呈偏态分布；(3)对次级骨化中心的研究不足，可确定次级骨化中心形成似抛物线形及其骨干端与骨干外缘相平齐所对应的成熟度水平，进一步划分发育阶段；(4)缺乏与放射学方法评估骨龄的一致性评价。
综上所述，超声可观察描述长骨关节端的生长发育变化，UECT与骨龄表现出中至高度负相关，具有用于骨成熟度定量评估的潜在价值。
作者贡献：本共识由北京协和医院罕见病多学科协作组发起。张抒扬、韩冰组织建立共识制定小组，并进行共识讨论协调工作；专家组成员共同起草共识初稿并针对小组讨论意见予以修订。所有参与者均对共识终稿表示认同。利益冲突：所有参与共识制订的专家组成员均声明不存在利益冲突专家组成员 (按姓氏首字母排序) ：陈苗(北京协和医院血液内科)，陈丽萌(北京协和医院肾内科)，陈跃鑫(北京协和医院血管外科)，曹玮(北京协和医院感染内科)，杜顺达(北京协和医院肝脏外科)，郭潇潇(北京协和医院心内科)，韩冰(北京协和医院血液内科)，李景南(北京协和医院消化内科)，李宏军(北京协和医院泌尿外科)，李融融(北京协和医院营养科)，李方达(北京协和医院血管外科)，刘炜(北京协和医院放射科)，刘紫薇(北京协和医院血液内科)，刘鑫(北京协和医院药剂科)，倪俊(北京协和医院神经科)，宁聪(北京协和医院肝脏外科)，潘杰(北京协和医院放射介入组)，彭敏(北京协和医院呼吸与危重症医学科)，吴彤(北京高博博仁医院造血干细胞移植科)，王涛(北京协和医院皮肤科)，王健(北京协和医院放射介入组)，杨辰(北京协和医院血液内科)，乐偲(北京协和医院肾内科)，郑月宏(北京协和医院血管外科)，张波(北京协和医院药剂科)，张抒扬(北京协和医院心内科) -
表 1 PNH移植预处理方案
Table 1 Conditioning regimens of allogeneic hematopoietic stem cell transplantation for PNH
清髓预处理方案 减低强度预处理方案 Bu+Cy
Bu：3.2 mg/(kg·d)，连续4 d
Cy：60 mg/(kg·d)，连续2 d
TBI+Cy+ATG
TBI：分次照射，总剂量12~14 Gy
Cy：60 mg/(kg·d)，连续2 d
ATG(马来源)：总剂量60 mg/kgCy+ATG
Cy：50 mg/(kg·d), 连续4 d
ATG(马来源)：总剂量60~90 mg/kg
Cy+Flu+ATG
Cy：60 mg/(kg·d)，连续2 d
Flu：25 mg/(m2·d), 连续5 d
ATG(马来源)：总剂量160 mg/kg
或
Cy：50 mg/(kg·d), 连续2 d
Flu：30 mg/(m2·d), 连续6 d
ATG(兔来源)：总剂量12.5 mg/kg
Bu+Cy+ATG
Bu：3.2 mg/(kg·d)，连续2 d
Cy：50 mg/(kg·d), 连续4 d
ATG(兔来源)：总剂量10 mg/kg
Bu+Flu+ATG
Bu：3.2 mg/(kg·d), 连续3 d
Flu：30 mg/(m2·d), 连续5 d
ATG(兔来源)：总剂量8~10 mg/kgPNH(paroxysmal nocturnal hemoglobinuria)：阵发性睡眠性血红蛋白尿症；Bu(busulfan)：白消安；Cy(cyclophosphamide)：环磷酰胺；TBI(total body irradiation): 全身放疗；ATG(anti-thymocyte globulin)：抗胸腺细胞免疫球蛋白；Flu(fludarabine)：氟达拉滨 
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附录1 GRADE证据等级
附录1 GRADE quality of the evidence
证据等级 定义 高 非常确信估计的效应值接近真实效应值，进一步研究也不可能改变该估计效应值的可信度 中 估计的效应值和真实效应值存在不相同的可能性，进一步研究有可能改变该估计效应值的可信度 低 对估计效应值的确信程度有限，估计值与真实值可能大不相同，进一步研究极有可能改变该估计效应值的可信度 极低 对估计的效应值几乎没有信心，估计值与真实值很可能完全不同，对效应值的任何估计均极不确定
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附录2 GRADE推荐强度
附录2 GRADE strength of recommendations
推荐强度 定义 强推荐 有充分的证据支持其疗效，应当使用(基于高等级证据) 选择性推荐 有一定的证据支持，但不充分，在一定条件下可使用(基于中、低等级证据)
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