The world has been kept in suspense since early 2020 by coronavirus disease 2019 (COVID-19), a multi-organ disease caused by the highly contagious severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). Cephalalgia, the most frequent early symptom of COVID-19, not only is painful but is a disabling condition that causes substantial personal suffering, impaired quality of life, and economic burden [1]. Headache in acute viral illness is seen as a consequence of the immune response, whereas the mechanism of action leading to its persistence thereafter is not well understood.

In this issue, Fernandes-de-las-Penas et al. [2] confirm that headache is not only frequent in the acute phase of SARS-CoV-2 infection but is a notable COVID-19 sequela in a subgroup of patients. Their findings are based on a meta-analysis of various scientific databases up to May 2021, which involved 28,438 COVID-19 survivors from 35 studies (longitudinal design in 40%). The cohort's mean age was 46.6 years, 57% were male, and the methodological quality was high in 45% of the studies. The overall rate of headache as an onset symptom or on hospital admission was 47.1%. The rate of headache did not differ between hospitalized and non-hospitalized patients, indicating that the immune response per se but not disease severity may be of relevance. The prevalence of post-COVID-19 headache declined during the disease course but remained at a frequency of 8.4% after 6 months.

Using the numbers provided by the meta-analysis, approximately 99 million people have developed headache during acute COVID-19 so far, and almost 16 million survivors were still experiencing headache half a year later (as of 20 March 2021). This staggering number shows the need to build awareness in the medical community and prevent disparities in healthcare [3]. In this regard, headache in acute COVID-19 is more intense in women and is characterized by bilateral headache predominantly affecting the forehead, with pressing quality and severe intensity, and is frequently accompanied by typical migraine symptoms [1]. Individuals with headache during acute COVID-19 are generally younger and have a higher frequency of fever.

Investigations to understand the pathogenesis of headache in acute viral illness and as a persistent symptom are still only beginning. Interestingly, the anti-inflammatory cytokine interleukin-10 is higher in individuals with acute COVID-19 headache, which could reflect a homeostatic response to counteract an intense pro-inflammatory immune response [4]. Concerning post-viral headache, central sensitization, a process in central pain pathways associated with synaptic plasticity and increased neuronal responsiveness induced by neuroinflammatory stimuli, may play a decisive role. There is currently minimal understanding of the clinical spectrum and predisposing factors for post-COVID-19 cephalalgia. There is also a need to determine the relevance of somatic and psychiatric comorbidities and the significance of persistent headache in the long COVID-19 symptom complex. A wide range of symptoms are discussed as part of long COVID-19 and include fatigue, headache, shortness of breath, lack or distorted smell function, muscle weakness, low fever, and cognitive dysfunction. Notably, some individuals with post-COVID-19 headache had a pre-existing primary headache syndrome, and SARS-CoV-2 infection might have triggered exacerbation or chronification. There is also speculation that a subgroup of individuals with post-COVID-19 headache may be experiencing new daily persistent headache (NDPH), one of the most treatment-refractory primary headache disorders [5]. NDPH is characterized as a "headache that is daily from the onset, and very soon unremitting, typically occurring in individuals without prior headache history". NDPH may have features suggestive of migraine or tension-type headache. A unifying pathway leading to post-COVID-19 headache is therefore unlikely. There is much to be done before eagerly awaited therapeutic options and preventive strategies can be developed.

自 2020 年初以来，2019 年冠状病毒病 (COVID-19) 一直悬而未决，这是一种由高度传染性的严重急性呼吸系统综合症冠状病毒 2 (SARS-CoV-2) 引起的多器官疾病。头痛是 COVID-19 最常见的早期症状，不仅是痛苦的，而且是一种致残疾病，会导致严重的个人痛苦、生活质量下降和经济负担 [ 1 ]。急性病毒性疾病的头痛被视为免疫反应的结果，而导致其持续存在的作用机制尚不清楚。

在这个问题上，Fernandes-de-las-Penas 等人。[ 2] 证实头痛不仅在 SARS-CoV-2 感染的急性期频繁发生，而且在一个亚组患者中是显着的 COVID-19 后遗症。他们的发现基于对截至 2021 年 5 月的各种科学数据库的荟萃分析，其中涉及来自 35 项研究的 28,438 名 COVID-19 幸存者（纵向设计占 40%）。该队列的平均年龄为 46.6 岁，57% 为男性，45% 的研究方法学质量较高。作为发病症状或入院时头痛的总体发生率为 47.1%。住院和非住院患者的头痛发生率没有差异，这表明免疫反应本身而非疾病严重程度可能具有相关性。COVID-19 后头痛的患病率在病程期间下降，但在 6 个月后仍保持在 8.4% 的频率。

根据荟萃分析提供的数字，到目前为止，约有 9900 万人在急性 COVID-19 期间出现头痛，半年后（截至 2021 年 3 月 20 日）仍有近 1600 万幸存者出现头痛。这个惊人的数字表明需要在医学界建立意识并防止医疗保健方面的差异 [ 3 ]。在这方面，急性 COVID-19 的头痛在女性中更为剧烈，其特点是双侧头痛，主要累及前额，具有压迫性和剧烈强度，并且经常伴有典型的偏头痛症状 [ 1 ]。急性 COVID-19 期间头痛的个体通常更年轻，发烧频率更高。

了解急性病毒性疾病中头痛的发病机制以及作为持续症状的调查仍才刚刚开始。有趣的是，患有急性 COVID-19 头痛的个体的抗炎细胞因子白细胞介素 10 较高，这可能反映了体内平衡反应以抵消强烈的促炎免疫反应 [ 4]]。关于病毒后头痛，中枢敏化是一种与突触可塑性相关的中枢疼痛通路过程，以及由神经炎症刺激引起的神经元反应性增加，可能起着决定性的作用。目前对 COVID-19 后头痛的临床谱和诱发因素知之甚少。还需要确定躯体和精神合并症的相关性以及持续性头痛在长期 COVID-19 症状复合体中的重要性。作为长期 COVID-19 的一部分，讨论了广泛的症状，包括疲劳、头痛、呼吸急促、嗅觉功能缺乏或扭曲、肌肉无力、低烧和认知功能障碍。值得注意的是，一些患有 COVID-19 后头痛的人之前就存在原发性头痛综合征，SARS-CoV-2 感染可能引发了恶化或慢性化。也有人猜测，一部分 COVID-19 后头痛患者可能正在经历新的每日持续性头痛 (NDPH)，这是最难治的原发性头痛疾病之一。5 ]。NDPH 的特征是“从发病开始每天都会出现头痛，并且很快就会持续，通常发生在没有头痛史的个体中”。NDPH 可能具有提示偏头痛或紧张型头痛的特征。因此，不太可能出现导致 COVID-19 后头痛的统一途径。在制定期待已久的治疗方案和预防策略之前，还有很多工作要做。