For more than a decade after the 1918 influenza pandemic, a mysterious Parkinson-like syndrome with sleep disturbance, hypomimia, and a high mortality rate developed in thousands of people across the globe. In 1920 the U.S. Surgeon General declared that the syndrome, popularly termed “encephalitis lethargica,” was caused by influenza. However, opinions varied, mainly as cases of encephalitis lethargica frequently differed from respiratory infections thought to represent influenza (1). More than a century later, questions remain regarding the cause, transmission, and availability of effective treatments, and lastly, will it happen again?

While still amid the COVID-19 pandemic globally, postinfectious sequelae may again be a thorny and more long-lasting issue with little current understanding or treatment to offer patients. The pandemic's terrible human impact has been most frequently measured in deaths and hospitalizations. However, consequences affect both those with and those without COVID-19, with spillover effects not only on postponed health care and prevention but socioeconomic disruption that may prompt anxiety, depression, and posttraumatic stress disorder. In studies of SARS-CoV-2 infections, up to 61% of patients have experienced symptoms that persist for months after COVID-19, occurring in hospitalized and nonhospitalized adults, adolescents, and children. However, the absence of well-defined control groups or reliance on serologic testing or self-reporting will limit improving our current understanding (2–5).

Even if only 10% of patients experience persistent symptoms after COVID-19, the number afflicted will easily be tens of millions. Described symptoms are wide-ranging from depression and anxiety to rashes, cardiac issues, and gastrointestinal distress. The Centers for Disease Control and Prevention lists 18 new or ongoing, and mostly subjective, symptoms that may arise even after asymptomatic infection (6). Many patients could be easily diagnosed with common disorders other than COVID-19, such as myalgic encephalomyelitis or chronic fatigue syndrome, fibromyalgia, irritable bowel syndrome, migraine disorder, or anxiety or depression.

How to tease out directly what is a post–COVID-19 disorder versus the indirect impact of the pandemic on human life is more than a tall order. Simple explanations are unlikely for wide-ranging disease manifestations (7). For example, the hope of precision medicine to offer a straightforward approach to acute SARS-CoV-2 infection means subtyping that may include differences in viral variants, host responses, and treatment effects. Factor then additional influences in recuperation, premorbid health, and external stressors may mean galactic complexities for enumerating post–COVID-19 phenotypes. Despite these challenges, opportunities exist to leverage the already substantial knowledge and scientific resources gained from the coronavirus to understand mechanisms that produce such problems as fatigue and pain. Perhaps there are common mechanisms, whether an aberrant response to viral infection or loss of a job?

Many postinfectious disorders have defied detailed scientific understanding or precise diagnosis, causing contention among clinicians, researchers, and patients. Some, such as the common cold due to rhinovirus infection, appear to have little effect on health. In contrast, others, such as primary Epstein–Barr virus infection and Coxiella burnetii (Q fever), precipitate a postinfectious syndrome infection in 11% to 12% of patients (8). Both infectious mononucleosis and Lyme disease may cause persistent symptoms after the resolution of acute illness in the minority. Frustration frequently arises in these often marginalized patients with symptoms that some clinicians dismiss as only nonphysiologic or related to mental health. On another angle, some alternative practitioners offer false hope with antibiotic treatments, using Lyme disease as a stand-in for chronic, medically unexplained symptoms without a basis in demonstrable infection. Moreover, desperate patients seek information through social media and take non–evidence-based treatments for chronic Lyme disease, partly due to modern mainstream medicine's lack of effective approaches (9).

As a clinician who has evaluated patients who may or may not have Lyme disease, Epstein–Barr virus, or other infections as causes for their symptoms, I see there are gaps in the field's knowledge that should inform research priorities into the aftermath of COVID-19. More important, if science does not move with dispatch in addressing post–COVID-19 care in a multidisciplinary manner, the vacuum will be quickly filled by pseudoscience and quackery. Moreover, engagement of patients and advocates early in the design of studies, clinical guidelines, and public messaging may lessen the development of a parallel universe of care through a cottage industry.

Studies that lead to clear case definitions for a post–COVID-19 diagnosis may well be split into objective pathologic findings and those with only apparent subjective symptoms. Then, understanding risk factors leading to post–COVID-19 problems will also help guide vaccine-hesitant people toward immunization or greater care to avoid contracting the infection. While diagnostic tests that solidly confirm prior SARS-CoV-2 infection are essential for those without such documentation, the diagnostic Holy Grail would be biomarkers that could implicate a postviral explanation or, better yet, a predisposition to such an outcome. Validated assays may then help inform appropriate interventions. Regardless, prospective longitudinal studies should lead to key findings, including patient cohorts with asymptomatic, mild, and severe COVID-19. Accompanying biorepositories that include viral and human samples of well-characterized cohorts will also facilitate research and aid U.S. Food and Drug Administration approval of diagnostic tests.

While a basic understanding of postinfectious fatigue may inform novel approaches to treatment, effective interventions are needed now. Clinical trial design should repurpose existing drugs or other interventions through studies that examine both medium- and long-term outcomes. Incorporating a placebo control is highly desirable because interventional studies of patients with long-term symptoms after Lyme disease have found up to a 36% response rate in placebo groups (10).

Novelty tends to spur new resources and investigators in infectious diseases. The National Institutes of Health has committed more than $1 billion to post–COVID-19 research, and the World Health Organization is coordinating global efforts. All are more than welcome infusions that will hopefully invigorate the study of postinfectious syndromes. Undoubtedly, the challenges to understand and treat postinfectious complications of SARS-CoV-2 will be daunting, but never have such resources been allocated. Understanding the basis of postinfectious sequelae will garner greater legitimacy and spur the prospect of successful treatments. The race is on, and it should not only focus on quality science and clinical trials but address head-on human behavior and anticipate controversy. Operation Warp Speed is by all accounts a success in developing effective vaccines for COVID-19. A similar program is long overdue to help those with postinfectious complications. Let not post–COVID-19 sequelae become our encephalitis lethargica of this century.

References

• 1. Dourmashkin RR . What caused the 1918-30 epidemic of encephalitis lethargica. J R Soc Med. 1997;90:515-20. [PMID: 9370993] CrossrefMedlineGoogle Scholar
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• 8. Hickie I ,  Davenport T ,  Wakefield D , et al; Dubbo Infection Outcomes Study Group. Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study. BMJ. 2006;333:575. [PMID: 16950834] CrossrefMedlineGoogle Scholar
• 9. Feder HM Jr, Johnson BJ, O’Connell S, et al; Ad Hoc International Lyme Disease Group. A critical appraisal of “chronic Lyme disease.”. N Engl J Med. 2007;357:1422-30. [PMID: 17914043] CrossrefMedlineGoogle Scholar
• 10. Klempner MS ,  Baker PJ ,  Shapiro ED , et al. Treatment trials for post-Lyme disease symptoms revisited. Am J Med. 2013;126:665-9. [PMID: 23764268] doi:10.1016/j.amjmed.2013.02.014 CrossrefMedlineGoogle Scholar

中文翻译：

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了解 COVID-19 后情况的竞赛

在 1918 年流感大流行之后的十多年里，一种神秘的帕金森样综合征伴随着睡眠障碍、睡眠不足和高死亡率在全球数千人中发展起来。1920 年，美国卫生署署长宣布该综合征（俗称“昏睡脑炎”）是由流感引起的。然而，意见不一，主要是因为昏睡脑炎病例经常不同于被认为代表流感的呼吸道感染 (1)。一个多世纪后，关于有效治疗的原因、传播和可用性的问题仍然存在，最后，它会再次发生吗？

虽然仍处于全球 COVID-19 大流行之中，但感染后后遗症可能再次成为一个棘手且更持久的问题，目前对患者的了解或治疗很少。大流行对人类的可怕影响最常通过死亡和住院来衡量。然而，后果会影响那些患有和没有 COVID-19 的人，不仅对推迟的医疗保健和预防产生溢出效应，而且可能引发焦虑、抑郁和创伤后应激障碍的社会经济破坏。在对 SARS-CoV-2 感染的研究中，高达 61% 的患者在 COVID-19 后出现持续数月的症状，发生在住院和非住院成人、青少年和儿童中。然而，

即使只有 10% 的患者在 COVID-19 后出现持续症状，但患病人数很容易达到数千万。所描述的症状范围广泛，从抑郁和焦虑到皮疹、心脏问题和胃肠道不适。疾病控制和预防中心列出了 18 种新的或持续的、主要是主观的症状，即使在无症状感染后也可能出现 (6)。许多患者很容易被诊断出患有 COVID-19 以外的常见疾病，例如肌痛性脑脊髓炎或慢性疲劳综合征、纤维肌痛、肠易激综合征、偏头痛或焦虑或抑郁。

如何直接梳理出什么是 COVID-19 后疾病与大流行对人类生活的间接影响，不仅仅是一项艰巨的任务。对广泛的疾病表现不可能有简单的解释 (7)。例如，精准医学希望为急性 SARS-CoV-2 感染提供一种直接的方法，这意味着亚型可能包括病毒变异、宿主反应和治疗效果的差异。将恢复、病前健康和外部压力因素的其他影响因素考虑在内可能意味着银河系的复杂性，以枚举 COVID-19 后的表型。尽管存在这些挑战，但仍有机会利用从冠状病毒中获得的大量知识和科学资源来了解产生疲劳和疼痛等问题的机制。也许有共同的机制，

许多感染后疾病没有得到详细的科学理解或精确的诊断，引起临床医生、研究人员和患者之间的争论。有些，例如鼻病毒感染引起的普通感冒，似乎对健康影响不大。相比之下，其他的，如原发性 Epstein-Barr 病毒感染和Coxiella burnetii（Q 热），在 11% 至 12% 的患者中导致感染后综合征感染 (8)。传染性单核细胞增多症和莱姆病都可能在少数人的急性疾病消退后引起持续症状。这些经常被边缘化的患者经常感到沮丧，他们的症状被一些临床医生认为只是非生理性的或与心理健康有关的症状。从另一个角度来看，一些替代从业者通过抗生素治疗提供了虚假的希望，使用莱姆病作为慢性、医学上无法解释的症状的替代品，而没有明显感染的基础。此外，绝望的患者通过社交媒体寻求信息并对慢性莱姆病采取非循证治疗，部分原因是现代主流医学缺乏有效的方法 (9)。

作为评估可能患有或不患有莱姆病、爱泼斯坦-巴尔病毒或其他感染作为其症状原因的患者的临床医生，我看到该领域的知识存在差距，应将研究重点告知 COVID- 19. 更重要的是，如果科学不以多学科的方式解决 COVID-19 后护理问题，那么真空将很快被伪科学和骗术填补。此外，患者和倡导者在研究设计、临床指南和公共信息的早期参与可能会减少通过家庭手工业发展平行世界的护理。

导致 COVID-19 后诊断明确病例定义的研究很可能分为客观病理发现和仅具有明显主观症状的那些。然后，了解导致 COVID-19 后问题的风险因素也将有助于指导对疫苗犹豫不决的人进行免疫接种或加强护理以避免感染。虽然明确证实先前 SARS-CoV-2 感染的诊断测试对于那些没有此类文件的人来说是必不可少的，但诊断性的圣杯将是可能暗示病毒后解释，或者更好的是，对这种结果的倾向的生物标志物。然后，经过验证的检测可能有助于为适当的干预措施提供信息。无论如何，前瞻性纵向研究应得出关键发现，包括无症状、轻度和重度 COVID-19 的患者队列。

虽然对感染后疲劳的基本了解可能会为新的治疗方法提供信息，但现在需要有效的干预措施。临床试验设计应通过检查中期和长期结果的研究来重新利用现有药物或其他干预措施。加入安慰剂对照是非常可取的，因为对莱姆病后出现长期症状患者的干预研究发现安慰剂组的反应率高达 36% (10)。

新颖性往往会激发新的资源和传染病研究人员。美国国立卫生研究院已承诺为 COVID-19 后研究投入超过 10 亿美元，世界卫生组织正在协调全球努力。所有这些都非常受欢迎，有望激发对感染后综合征的研究。毫无疑问，理解和治疗 SARS-CoV-2 感染后并发症的挑战将是艰巨的，但从来没有分配过这样的资源。了解感染后后遗症的基础将获得更大的合法性并激发成功治疗的前景。比赛正在进行，它不仅应该关注质量科学和临床试验，还应该解决正面的人类行为并预测争议。众所周知，Operation Warp Speed 在为 COVID-19 开发有效疫苗方面取得了成功。一个类似的计划早就应该帮助那些感染后并发症的人。不要让 COVID-19 后的后遗症成为我们本世纪的昏睡脑炎。

参考

• 1. 杜尔马什金 RR . 是什么导致了 1918-30 年嗜睡脑炎的流行。 JR 社会医学。 1997 年；90：515-20。[PMID：9370993] CrossrefMedlineGoogle Scholar
• 2. 莫林 ,  萨瓦莱 ,  范太 , 等; COMEBAC 研究组写作委员会. COVID-19 住院后一组患者的四个月临床状态。 杂志。 2021 年；325：1525-1534。[PMID：33729425] 做：10.1001/jama.2021.3331 CrossrefMedlineGoogle Scholar
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• 8. 希基我 ,  达文波特 ,  韦克菲尔德 , 等; Dubbo感染结果研究组. 病毒和非病毒病原体引起的感染后和慢性疲劳综合征：前瞻性队列研究。 英国医学杂志。 2006 年；333：575。[PMID：16950834] CrossrefMedlineGoogle Scholar
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