Department of Epidemiology Research, Statens Serum Institut, Artillerivej 5, 2300 Copenhagen S, Denmark
Department of Drug Design and Pharmacology, University of Copenhagen, Denmark.
BMJ. 2020 Sep 2;370:m2930. doi: 10.1136/bmj.m2930.
To evaluate the association between quadrivalent human papillomavirus vaccination and syndromes with autonomic dysfunction, such as chronic fatigue syndrome, complex regional pain syndrome, and postural orthostatic tachycardia syndrome.
Population-based self-controlled case series.
Information on human papillomavirus vaccinations and selected syndromes with autonomic dysfunction (chronic fatigue syndrome, complex regional pain syndrome, and postural orthostatic tachycardia syndrome) identified using ICD-10 (international classification of diseases, revision 10) diagnostic codes from Danish nationwide registers.
869 patients with autonomic dysfunction syndromes from a cohort of 1 375 737 Danish born female participants aged 10 to 44 years during 2007-16.
Self-controlled case series rate ratios (95% confidence intervals) of the composite outcome of chronic fatigue syndrome, complex regional pain syndrome, and postural orthostatic tachycardia syndrome, adjusted for age and season, comparing female participants vaccinated and unvaccinated with the quadrivalent human papillomavirus vaccine. Chronic fatigue syndrome, complex regional pain syndrome, and postural orthostatic tachycardia syndrome were also considered separately in secondary analyses.
During 10 581 902 person years of follow-up, 869 female participants with syndromes of autonomic dysfunction (136 with chronic fatigue syndrome, 535 with complex regional pain syndrome, and 198 with postural orthostatic tachycardia syndrome) were identified. Quadrivalent human papillomavirus vaccination did not statistically significantly increase the rate of a composite outcome of all syndromes with autonomic dysfunction in a 365 day risk period following vaccination (rate ratio 0.99, 95% confidence interval 0.74 to 1.32) or the rate of any individual syndrome in the risk period (chronic fatigue syndrome (0.38, 0.13 to 1.09), complex regional pain syndrome (1.31, 0.91 to 1.90), or postural orthostatic tachycardia syndrome (0.86, 0.48 to 1.54)).
When vaccination is introduced, adverse events could occur in close temporal relation to the vaccine purely by chance. These results do not support a causal association between quadrivalent human papillomavirus vaccination and chronic fatigue syndrome, complex regional pain syndrome, or postural orthostatic tachycardia syndrome, either individually or as a composite outcome. An increased risk of up to 32% cannot be formally excluded, but the statistical power of the study suggests that a larger increase in the rate of any syndrome associated with vaccination is unlikely.
评估四价人乳头瘤病毒疫苗接种与自主神经功能障碍相关综合征（如慢性疲劳综合征、复杂性区域疼痛综合征和体位性心动过速综合征）之间的关联。
基于人群的自身对照病例系列研究。
利用丹麦全国登记处的国际疾病分类第 10 次修订版（ICD-10）诊断代码，从丹麦的一项包括 1375737 名 10-44 岁女性参与者的队列中，确定人乳头瘤病毒疫苗接种和自主神经功能障碍相关综合征（慢性疲劳综合征、复杂性区域疼痛综合征和体位性心动过速综合征）的信息。
869 名自主神经功能障碍综合征患者，来自于上述队列中的 869 名女性参与者，年龄为 10-44 岁。
比较女性参与者接种和未接种四价人乳头瘤病毒疫苗后的慢性疲劳综合征、复杂性区域疼痛综合征和体位性心动过速综合征复合结局的自身对照病例系列发生率比（95%置信区间），并根据年龄和季节进行调整。在次要分析中还分别考虑了慢性疲劳综合征、复杂性区域疼痛综合征和体位性心动过速综合征。
在 10581902 人年的随访期间，确定了 869 名患有自主神经功能障碍综合征的女性参与者（136 名患有慢性疲劳综合征，535 名患有复杂性区域疼痛综合征，198 名患有体位性心动过速综合征）。在接种后的 365 天风险期内，四价人乳头瘤病毒疫苗接种并没有显著增加所有自主神经功能障碍相关综合征的复合结局发生率（发生率比为 0.99，95%置信区间为 0.74 至 1.32）或风险期内任何单个综合征的发生率（慢性疲劳综合征为 0.38，0.13 至 1.09；复杂性区域疼痛综合征为 1.31，0.91 至 1.90；体位性心动过速综合征为 0.86，0.48 至 1.54）。
当引入疫苗接种时，不良事件可能仅仅由于偶然原因而在疫苗接种的密切时间关系中发生。这些结果不支持四价人乳头瘤病毒疫苗接种与慢性疲劳综合征、复杂性区域疼痛综合征或体位性心动过速综合征之间存在因果关系，无论是单独还是作为复合结局。不能正式排除高达 32%的风险增加，但研究的统计效力表明，与疫苗接种相关的任何综合征发生率的较大增加不太可能。
