BACKGROUND Public trust in the human papilloma virus (HPV) vaccination programme has been challenged by reports of potential severe adverse effects. The reported adverse symptoms were heterogeneous and overlapping with those characterised as chronic fatigue syndrome (CFS) and have been described as CFS-like symptoms. Evidence suggests that CFS is often precipitated by an infection. The aim of the study was to examine if an infection in temporal proximity to HPV vaccination is a risk factor for suspected adverse effects following HPV vaccination. METHODS AND FINDINGS The study was a nationwide register-based cohort study and case-crossover analysis. The study population consisted of all HPV vaccinated females living in Denmark, born between 1974 and 2006, and vaccinated between January 1, 2006 and December 31, 2017. The exposure was any infection in the period ± 1 month around time of first HPV vaccination and was defined as (1) hospital-treated infection; (2) redemption of anti-infective medication; or (3) having a rapid streptococcal test done at the general practitioner. The outcome was referral to a specialised hospital setting (5 national HPV centres opened June 1, 2015) due to suspected adverse effects following HPV vaccination. Multivariable logistic regression was used to estimate the association between infection and later HPV centre referral. The participants were 600,400 HPV-vaccinated females aged 11 to 44 years. Of these, 48,361 (9.7%) females had a hospital-treated infection, redeemed anti-infective medication, or had a rapid streptococcal test ± 1 month around time of first HPV vaccination. A total of 1,755 (0.3%) females were referred to an HPV centre. Having a hospital-treated infection in temporal proximity to vaccination was associated with significantly elevated risk of later referral to an HPV centre (odds ratio (OR) 2.75, 95% confidence interval (CI) 1.72 to 4.40; P < 0.001). Increased risk was also observed among females who redeemed anti-infective medication (OR 1.56, 95% CI 1.33 to 1.83; P < 0.001) or had a rapid streptococcal test (OR 1.45, 95% CI 1.10 to 1.93; P = 0.010). Results from a case-crossover analysis, which was performed to adjust for potential unmeasured confounding, supported the findings. A key limitation of the study is that the HPV centres did not open until June 1, 2015, which may have led to an underestimation of the risk of suspected adverse effects, but stratified analyses by year of vaccination yielded similar results. CONCLUSIONS Treated infection in temporal proximity to HPV vaccination is associated with increased risk for later referral with suspected adverse vaccine effects. Thus, the infection could potentially be a trigger of the CFS-like symptoms in a subset of the referred females. To our knowledge, the study is the first to investigate the role of infection in the development of suspected adverse effects after HPV vaccination and replication of these findings are needed in other studies.

中文翻译：

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在丹麦，与 HPV 疫苗接种时间接近的感染和疫苗接种后的不良反应：一项基于全国登记的队列研究和病例交叉分析。

背景 公众对人乳头瘤病毒 (HPV) 疫苗接种计划的信任受到潜在严重不良反应报告的挑战。报告的不良症状是异质性的，与慢性疲劳综合征 (CFS) 的特征重叠，并被描述为 CFS 样症状。有证据表明 CFS 通常由感染引起。该研究的目的是检查在时间上接近 HPV 疫苗接种的感染是否是 HPV 疫苗接种后疑似不良反应的危险因素。方法和结果 该研究是一项全国性的基于登记册的队列研究和病例交叉分析。研究人群包括居住在丹麦、出生于 1974 年至 2006 年、并于 2006 年 1 月 1 日至 2017 年 12 月 31 日期间接种过 HPV 疫苗的所有女性。暴露是指第一次接种 HPV 疫苗前后 ± 1 个月内的任何感染，定义为 (1) 医院治疗感染；(2)抗感染药物的兑换；(3) 在全科医生处进行快速链球菌测试。由于怀疑接种 HPV 疫苗后的不良反应，结果被转诊至专科医院（2015 年 6 月 1 日开设了 5 个国家 HPV 中心）。多变量逻辑回归用于估计感染与后来的 HPV 中心转诊之间的关联。参与者是 600,400 名年龄在 11 至 44 岁之间的 HPV 疫苗接种女性。其中，48,361 (9.7%) 名女性在第一次接种 HPV 疫苗前后 ± 1 个月内发生了住院感染、服用抗感染药物或进行了快速链球菌检测。总共 1,755 (0. 3%) 女性被转介到 HPV 中心。在时间上接近疫苗接种时发生医院治疗感染与以后转诊到 HPV 中心的风险显着升高相关（比值比 (OR) 2.75，95% 置信区间 (CI) 1.72 至 4.40；P < 0.001）。在使用抗感染药物（OR 1.56，95% CI 1.33 至 1.83；P < 0.001）或进行快速链球菌检测（OR 1.45，95% CI 1.10 至 1.93；P = 0.010）的女性中，也观察到风险增加。为调整潜在的未测量混杂因素而进行的病例交叉分析的结果支持了这些发现。该研究的一个关键限制是 HPV 中心直到 2015 年 6 月 1 日才开放，这可能导致低估了疑似不良反应的风险，但按疫苗接种年份进行的分层分析得出了类似的结果。结论 在时间上接近 HPV 疫苗接种时治疗的感染与以后转诊的风险增加有关，并且怀疑有疫苗不良反应。因此，感染可能会触发一部分被推荐的女性出现 CFS 样症状。据我们所知，该研究是第一个调查感染在 HPV 疫苗接种后疑似不良反应发展中的作用的研究，并且在其他研究中需要复制这些发现。