A Meta-analysis of the Risk of Secondary Infection of Tocilizumab in the Treatment of COVID-19
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摘要:
目的 通过Meta分析评估托珠单抗(tocilizumab,TCZ)治疗新型冠状病毒感染(corona virus disease 2019,COVID-19)导致的继发感染风险,为托珠单抗在COVID-19患者中应用的安全性提供循证依据。 方法 在The Cochrane Library、PubMed、Web of Science、中国知网、中国生物医学文献数据库以及万方数据库中检索了2019年12月19日至2022年12月30日期间使用托珠单抗治疗COVID-19患者的相关研究,筛选并提取文献中发生继发感染的数据,利用RevMan 5.4.1进行Meta分析。 结果 共筛选了 1691 篇参考文献,纳入18项研究,涉及3933 名患者。托珠单抗+标准治疗组继发感染发生率为19.14%(331/1729 ),标准治疗组继发感染发生率为12.11%(267/2204 )。Meta分析结果显示,托珠单抗+标准治疗组继发感染发生率高于标准治疗组[RR = 1.35,95%CI (1.05,1.74),P = 0.02]。亚组分析显示,使用不同剂量的托珠单抗发生继发感染的风险不同。托珠单抗给药剂量为400~800 mg/d的亚组继发感染发生率明显高于标准治疗组,差异具有统计学意义[RR = 1.48,95%CI (1.19,1.84),P =0.0004 ];≤400 mg/d继发感染发生率也显著高于标准治疗组,差异具有统计学意义[RR = 1.87,95%CI (1.28,2.72),P = 0.001];托珠单抗给药剂量为6~8 mg/kg亚组与标准治疗组比较差异无统计学意义。结论 与标准治疗相比,托珠单抗可能增加COVID-19患者发生继发感染的风险,临床给药前应仔细评估使用托珠单抗治疗的利益和风险。但是,目前仍需要更多大样本、高质量的研究来进一步评估。 Abstract:Objective Meta-analysis was conducted to assess the risk of secondary infection caused by tocilizumab (TCZ) in the treatment of Corona Virus Disease 2019 (COVID-19), in order to provide an evidence-based basis for the safety of tocilizumab in patients with COVID-19. Methods Cochrane Library, PubMed, Web of Science, CNKI, SinoMed and Wanfang databases were searched in computer to collect randomized controlled trial and cohort study of treating COVID-19 with tocilizumab from December 19, 2019 to December 30, 2022. A meta-analysis of the results of each study was performed using RevMan 5.4.1 software. Results A total of 1691 references were screened and eighteen studies involving3933 patients were included. The incidence of secondary infection in the tocilizumab with the standard treatment group and standard treatment group was 19.14% (331/1729 ) and 12.11% (267/2204 ), respectively. Meta-analysis showed that the tocilizumab + standard treatment group had a higher incidence of secondary infection than the standard treatment group [RR = 1.35, 95%CI (1.05, 1.74), P = 0.02]. The results of the subgroup analysis showed that the risk of secondary infection with different doses of tocilizumab was different. The incidence of secondary infection was significantly higher in the subgroup with doses of 400~800 mg/d tocilizumab than in the standard care group [RR = 1.48, 95%CI (1.19, 1.84), P =0.0004 ]. The incidence of secondary infection in subgroups with doses of ≤400 mg/d tocilizumab was also significantly higher than that in the standard treatment group [RR = 1.87, 95%CI (1.28, 2.72), P = 0.001]. However, there was no statistical significance between the subgroup 6~8 mg/kg tocilizumab and the standard treatment group.Conclusions Tocilizumab may increase the risk of secondary infection in patients with COVID-19 compared with standard treatment, and the benefits and risks of tocilizumab should be carefully evaluated before clinical administration. Moreover, large and high-quality studies are needed for further evaluation. -
Key words:
- Tocilizumab /
- COVID-19 /
- Secondary infection /
- Meta-analysis
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疼痛是生理、心理、感觉、情感、认知、行为和社会等综合因素相互作用的体验,主要分为急性疼痛和慢性疼痛[1]。慢性疼痛持续时间长且不易根治,患者常伴有抑郁和焦虑等消极情绪,严重影响生活质量。文献报道[2-3],失眠在慢性疼痛患者中高发,而睡眠质量较差又会导致患者心境忧郁、紧张、易激惹和精力不足,易产生或加重患者心身症状,使睡眠质量更差,导致恶性循环[4]。同时,与原发性失眠症相比,继发于慢性疼痛的失眠在临床表现及程度也较为相似,疼痛的严重程度与睡眠障碍之间也存在相关性[5]。调查2019年1至6月玉溪市某综合医院疼痛科慢性疼痛者中失眠情况及影响因素,为相关工作策略的制定提供参考。
1. 对象与方法
1.1 研究对象
选取2019年1月至6月于玉溪市人民医院疼痛科就诊患者。纳入标准:(1)首次因慢性疼痛到本科就诊者;(2)符合国际疼痛学会的慢性疼痛诊断标准[6],即疼痛时间 > 3月,视觉模拟评分(visual analog scale,VAS)≥ 3分或日本尼普洛知觉痛觉定量分析装置NIPRO Painvision判定为疼痛,每天或几乎每天疼痛者;(3)年龄 ≥ 18岁;(4)能够理解所填调查量表者;(5)知情并同意参与。排除标准:(1)急性疼痛者;(2)年龄 < 18岁;(3)无法阅读、理解调查量表内容者;(4)拒绝参与本研究者。
1.2 研究工具及方法
采用自设问卷调查病人的基本人口学特征、疼痛持续时间、疼痛类型等。分别采用日本尼普洛知觉痛觉定量分析装置NIPRO Painvision(PS-2100)和VAS评价患者的疼痛程度。VAS为一条10 cm长的直线,两端分别表示无痛(0分)和剧痛(10分),由患者划出自己的疼痛程度,测量所画线长度即VAS得分,其中0分为无疼痛,1~3分为轻度疼痛,4~6分为中度疼痛,7~10分为重度疼痛。使用Painvision的“疼痛度”评价是根据最小感知电流值以及疼痛对应电流值这2种电流测量、评价疼痛程度的方法,与传统疼痛评价使用的VAS相比,有望导出更为客观的指标,有报告称疼痛度的许多结果与VAS明显相关。综合两种疼痛程度评价方法,得出最终疼痛程度评分,相对单一评价方法更为科学合理。
贝克抑郁自评问卷(beck depression inventory,BDI)[7]评价患者的目前或近1周抑郁状况,BDI共21个项目,以0~3分计分,统计总分:0~13分为无抑郁,14~19分为轻度抑郁,20~28分为中度抑郁,≥29分为重度抑郁。贝克焦虑自评问卷(beck anxiety inventory,BAI)[7]评价患者的目前或近1周焦虑状况,BAI 共21个项目,以0~3分计分,统计总分:0~14分为无焦虑,15~25分为轻度焦虑,26~35为中度焦虑,≥36分为重度焦虑。阿森斯失眠量表(athens insomnia scale,AIS)[8]评价患者的目前或近1周睡眠质量,AIS共8个项目,每个项目分数0~3分,AIS评分≥6分为失眠。三种问卷中文版均具有良好的信度和效度。
1.3 质量控制
调查开始前对调查员进行培训,根据纳入标准确定研究对象并按照知情同意的原则获取同意,所有入选对象均在统一指导语下填写调查问卷,尽可能地保证资料收集的准确性与完整性。在规定时间内完成问卷,视力不佳者由调查人员协助完成调查问卷,问卷当场收回,检查调查表格的质量,发现漏项时,重新询问并补充。在资料分析前,对数据的编码与录入工作进行了查错、补漏及逻辑检查,对有明显逻辑错误以及超过20%漏项的问卷予以剔除。剔除后,共计431例患者问卷纳入研究。
1.4 统计学处理
所有的调查问卷数据,用Epidata 3.1 软件建立数据库,双录入并进行一致性检验,SPSS 24.0完成统计分析。偏态分布资料用中位数M(P25~P75)。分类资料采用频数(百分比)描述。采用Logistic回归模型分析慢性疼痛者中失眠的影响因素,变量筛选法为逐步向前法(LR),入选标准α = 0.05,剔除标准为β = 0.10。P < 0.05为差异有统计学意义。
2. 结果
2.1 基本情况
431例研究对象中,男女比约为1.95∶1;年龄最小18岁,最大99岁,年龄中位数为65(53~73)岁。以汉族、文化程度为初中及以上、已婚、非农、轻度焦虑、轻度抑郁、中度疼痛、> 1个疼痛部位、慢性肌肉骨骼疼痛和疼痛病程为1~2.9 a为主,占比分别为:79.12%、54.75%、51.04%、53.13%、61.95%、65.66%、58.24%、56.15%、30.86%和69.14%,见表1。
表 1 431例慢性疼痛患者的基本情况及失眠的单因素分析Table 1. The basic characteristics and univariate analysis contributing to insomnia among 431 patients with chronic pain因素 n 失眠人数 单因素 P n 率(%) OR(95% CI) 性别 男 279 130 46.59 1.000 女 152 96 63.16 1.965(1.311~2.946) 0.001 年龄(岁) 18~ 71 27 38.03 1.000 30~ 85 28 32.94 0.801(0.414~1.547) 0.508 40~ 44 13 29.55 0.683(0.305~1.529) 0.354 50~ 142 84 59.15 2.360(1.316~4.324) 0.004 ≥60 89 74 83.15 8.040(3.862~16.736) < 0.001 民族 其他民族 90 36 40.00 1.000 汉族 341 190 55.72 1.887(1.176~3.028) 0.008 文化程度 小学及以下 195 88 45.13 1.000 初中及以上 236 138 58.47 1.712(1.168~2.511) 0.006 婚姻状况 未婚 103 41 39.81 1.000 已婚 220 109 49.55 1.485(0.924~2.388) 0.103 离异或丧偶 108 76 70.37 3.591(2.029~6.358) < 0.001 职业 农民 202 121 59.90 1.000 非农 229 105 45.85 0.567(0.386~0.831) 0.004 焦虑程度 无 51 12 23.53 1.000 轻度 267 124 46.44 2.818(1.413~5.620) 0.003 中度 86 69 80.23 13.191(5.713~30.458) < 0.001 重度 27 21 77.78 11.375(3.732~34.667) < 0.001 抑郁程度 无 51 12 23.53 1.000 轻度 283 129 45.58 2.722(1.368~5.417) 0.004 中度 86 76 88.37 24.700(9.807~62.212) < 0.001 重度 11 9 81.82 14.625(2.772~77.163) 0.002 疼痛程度 轻度 11 2 18.18 1.000 中度 251 99 39.44 2.931(0.620~13.850) 0.175 重度 169 125 73.96 12.784(2.659~61.462) 0.001 疼痛部位数(个) 1 189 58 30.69 1.000 > 1 242 168 69.42 5.128(3.394~7.749) < 0.001 疼痛类型 慢性创伤和术后疼痛 95 27 28.42 1.000 慢性肌肉骨骼疼痛 133 50 37.59 1.517(0.860~2.676) 0.150 慢性内脏/头/面部神经疼痛 104 60 57.69 3.434(1.901~6.206) < 0.001 慢性神经病理性疼痛 70 63 90.00 22.667(9.223~55.705) < 0.001 癌性相关疼痛 29 26 89.66 21.827(6.096~78.155) < 0.001 疼痛病程(a) < 1 38 17 44.74 1.000 1~ 298 148 49.66 1.219(0.618~2.402) 0.568 3~ 34 19 55.88 1.565(0.617~3.971) 0.346 ≥5 61 42 68.85 2.731(1.181~6.314) 0.019 2.2 不同特征慢性疼痛患者的失眠率
431例慢性疼痛病人中,226例最近1周失眠,失眠率为52.44%(95%CI 47.72%~57.15%),女性、年龄 ≥ 60岁、汉族、文化程度为初中及以上、离异或丧偶、农民、中度焦虑、中度抑郁、重度疼痛、> 1个疼痛部位、慢性神经病理性疼痛类型和疼痛病程 ≥ 5 a的慢性疼痛病人失眠率最高,见表1。
2.3 慢性疼痛患者失眠的多因素分析
将单因素分析P < 0.05的因素纳入多因素Logistic回归模型,结果显示:女性失眠风险较男性的高;≥60岁的患者失眠风险较60岁以下者高,特别是18~30岁者(6.821倍);轻度、中度和重度抑郁患者较无抑郁病人者高;重度疼痛病人失眠风险较轻度疼痛患者高;疼痛部位>1个的病人失眠风险较仅有1个疼痛部位病人者高;慢性肌肉骨骼疼痛、慢性内脏/头/面部神经疼痛、慢性神经病理性疼痛和癌性相关疼痛病人的失眠风险较慢性创伤和术后疼痛者高;相较于疼痛病程 < 1a的患者,疼痛病程为1 a~和3 a~的患者失眠风险低,见 表2。
表 2 慢性疼痛病人失眠的多因素分析Table 2. The multivariate analysis contributing to insomnia among patients with chronic pain因素 β SE Wald χ2 OR(95% CI) P 性别 男 1.000 女 0.605 0.289 4.398 1.832(1.04~3.225) 0.036 年龄(岁) 18~ 1.000 30~ −0.120 0.433 0.076 0.887(0.379~2.075) 0.782 40~ −0.125 0.496 0.063 0.883(0.334~2.336) 0.802 50~ 0.359 0.410 0.764 1.432(0.640~3.201) 0.382 ≥60 1.920 0.539 12.676 6.821(2.37~19.627) < 0.001 抑郁程度 无 1.000 轻度 1.431 0.533 7.206 4.181(1.471~11.882) 0.007 中度 2.964 0.664 19.955 19.381(5.279~71.155) < 0.001 重度 3.077 1.047 8.634 21.688(2.786~168.85) 0.003 疼痛程度 轻度 1.000 中度 2.401 1.279 3.525 11.034(0.900~135.303) 0.060 重度 2.636 1.273 4.289 13.954(1.152~169.067) 0.038 疼痛部位数(个) 1 1.000 > 1 1.325 0.310 18.275 3.762(2.049~6.907) < 0.001 疼痛类型 慢性创伤和术后疼痛 1.000 慢性肌肉骨骼疼痛 0.766 0.369 4.301 2.150(1.043~4.433) 0.038 慢性内脏/头/面部神经疼痛 0.982 0.383 6.575 2.670(1.260~5.658) 0.010 慢性神经病理性疼痛 3.222 0.616 27.345 25.067(7.494~83.848) < 0.001 癌性相关疼痛 3.639 0.821 19.650 38.052(7.614~190.17) < 0.001 疼痛病程(a) < 1 1.000 1~ −1.110 0.455 5.949 0.330(0.135~0.804) 0.015 3~ −1.194 0.677 3.110 0.303(0.080~1.142) 0.078 ≥5 0.126 0.575 0.048 1.135(0.368~3.499) 0.826 3. 讨论
慢性疼痛患者所经历的睡眠障碍作为一种影响生活质量的重要因素,正引起研究人员越来越多的关注[5]。本次调查发现431例慢性疼痛病人的失眠率为52.44%,目前国内慢性疼痛病人的失眠率的相关调查较少,国外部分研究显示65%~89%的慢性疼痛患者在都存在着失眠问题[9-10],本次调查失眠率低于国外的该两项研究,不过一项在伦敦开展的调查显示慢性疼痛者失眠率为53%[11],与本调查研究结果相近。慢性疼痛及其引起的较高的失眠率问题不容忽视。
本次调查发现女性失眠风险是男性的1.832倍,可能原因为:女性对疼痛的敏感性较高、痛阈较低、耐受性较差;慢性疼痛诱发的负性情绪反应在女性病人表现得更为强烈,如女性患者在遭受到疼痛影响时,往往更容易情绪化,对疼痛的反应更加敏感[12]。此外,≥60岁的患者失眠风险是18~30岁的6.821倍,相较于普通人群,老年慢性疼痛者疼痛程度更重,生活行为受限等症状更明显,会严重的影响老年人的生活质量,且相关调查显示老年慢性疼痛患者较非慢性疼痛患者更易出现激惹、抑郁、焦虑等不良的心理状态,导致生活质量更低[13]。因此,老年人慢性疼痛问题及其相关联的焦虑、抑郁状态须加以关注。失眠风险随病人抑郁严重程度而增加,轻度、中度和重度抑郁病人分别是无抑郁病人的4.181、19.381和21.688倍,有研究表明,慢性疼痛与失眠以及焦虑、抑郁等有着紧密的联系,三者为循环因果关系;同时,睡眠障碍也是抑郁症状的一个外在表现,研究也发现最近一个月未发生睡眠障者较少出现抑郁状态[14]。提示通过改善睡眠也可以有效的降低抑郁状态发生率的可能性,对伴有睡眠障碍患者开展心理干预乃至药物的使用可能能够缓解睡眠障碍及减轻抑郁状态。
本研究发现疼痛部位 > 1个的患者失眠风险较高,中度疼痛和重度疼痛病人的失眠风险较轻度疼痛高,再次佐证了疼痛越严重,也就更易发生失眠情况,说明缓解疼痛引起的失眠,最有效的措施还是缓解、控制疼痛。相较于疼痛病程 < 1 a的病人,疼痛病程为1 a~和3 a~的患者失眠风险分别降低,疼痛史大于1 a者则表明患者已经饱受疼痛折磨,可能已经适应的疼痛,故对睡眠影响较小,因此,临床医生诊疗时必须详细询问其病史,了解其疼痛持续时间。
综上所述,本研究的调查发现慢性疼痛患者常常伴发焦虑、抑郁与失眠,且疼痛与焦虑、抑郁、失眠之间关系密切,不同人群失眠的发生率也不同,对易于出现失眠的人群,需特别加以关注和心理疏导,对出现失眠症状的慢性疼痛患者,应该同时进行抗失眠治疗,适当提供抗抑郁、抗焦虑治疗,以提高慢性疼痛治疗疗效。
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表 1 纳入文献的基本特征(n)
Table 1. Basic characteristics of the included studies (n)
第一作者 年份 国家 COVID-19
患者特点年龄(岁)
(TCZ/SOC)总例数 托珠
单抗组对照组 剂量 继发感染 随访
时间(/d)托珠
单抗组对照
组Broman[5] 2022 芬兰 全身炎症住院患者 58/59 86 57 29 8 mg/kg 1 1 28 Campochiaro[6] 2020 意大利 重症患者 65/60 65 32 33 400 mg/d 4 4 28 Canziani[7] 2020 意大利 重症患者 63/64 128 64 64 8 mg/kg 20 25 30 Eimer[8] 2020 瑞典 重症患者 56/56 87 29 58 8 mg/kg 9 20 30 Galván-Román[9] 2021 西班牙 重症患者 61/64 146 58 88 8 mg/kg 3 7 12 Gordon[10] 2021 多中心 危重患者 62/61 755 353 402 8 mg/kg 1 0 69 Guaraldi[11] 2020 意大利 重症患者 67/69 544 179 365 8 mg/kg 24 14 / Hermine[12] 2022 法国 中重、危重度患者 43/57 97 51 46 8 mg/kg 27 13 95 Hill[13] 2020 美国 重症患者 / 88 43 45 400 mg/d 4 2 28 Kimmig[14] 2020 美国 危重患者 / 111 54 57 400 mg/d 29 16 / Pettit [15] 2020 美国 / 66/65 148 74 74 400 mg/d 17 6 58 Rodríguez-Baño[16] 2021 西班牙 高炎症状态患者 66/69 427 88 339 400~800 mg/d 11 36 21 Rojas-Marte[17] 2020 美国 重症患者 58.8/62 193 96 97 / 16 26 / Ruiz-Antorán[18] 2021 西班牙 重症患者 65/71.3 506 268 238 400~800 mg/d 124 72 28 Salvarani[19] 2021 意大利 重症患者 61.5/60 126 60 66 8 mg/kg 1 4 30 Sandhu[20] 2022 / 重症患者 68.2/63.9 115 66 49 8 mg/kg 30 12 / Soin[21] 2021 印度 中、重度患者 55/53 179 91 88 6 mg/kg 6 5 30 Tsai[22] 2020 美国 重症患者 62/61 132 66 66 400 mg/d 4 4 / 注: TCZ:托珠单抗; SOC:标准治疗。 -
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