Persistent Fatigue Induced by Interferon-alpha: A New Immunological Model for Chronic Fatigue Syndrome

慢性疲劳综合症（CFS）是一种医学病症，患者在身体和精神上都感到持续和压倒性的疲劳和疲惫。此外，他们难以集中注意力，出现类似流感的症状，还会出现疼痛。这种情况会干扰日常生活活动，对一些患者来说，会严重致残。虽然对慢性疲劳综合症进行了多年的研究，但我们仍然不知道是什么引起的。与慢性疲劳综合症有关的一个生物系统是“免疫系统”，即致力于对抗体内感染的系统。事实上，在许多情况下，慢性疲劳综合症是由感染引发的，但即使在感染被消除后，症状仍会继续。具体来说，感染总是伴随着急性疲劳和流感样症状，这是感染驱动的免疫激活的结果；然而，在CFS患者中，免疫激活和相关的疲劳和流感样症状持续数月或数年。此外，有证据表明，CFS患者的免疫系统处于一种“过度活跃”的状态，就好像他们在与感染因子作斗争一样，即使他们没有持续感染。该项目旨在准确理解这一过程：感染和急性免疫激活如何演变为慢性疲劳综合症，以及哪些风险因素使这一过程发生在某些个体而不是其他人身上。显然，由于这些事件的不可预测性，试图在经历自然获得性感染的受试者中研究这一过程是非常困难的。相比之下，我们希望通过研究一组已有感染（慢性病毒性丙型肝炎，HCV）并接受免疫激活剂干扰素- α (ifn - α)治疗一个疗程（持续数月）的患者来模拟CFS的发展。干扰素- α是丙型肝炎病毒感染的首选治疗方法。因为它能激活免疫系统，所以ifn - α也会在所有患者中引起疲劳和流感样症状。此外，与本研究特别相关的是，相当大比例的患者在停止ifn - α治疗6个月甚至1年后仍会出现衰弱的持续性疲劳和其他类似于CFS的症状。这种现象与上文提到的慢性疲劳综合症非常相似，后者在感染/免疫触发因素消除后也会持续存在。因此，我们建议使用IFN-alpha作为模型来理解即使初始免疫触发因素不再存在，免疫触发因素如何诱导持续疲劳。为此，我们将对这些患者进行为期数月的ifn - α治疗和停止治疗后6个月的评估，以确定那些持续出现“ifn - α治疗后”疲劳的患者，并了解导致这种结果的生物学和临床变化。此外，我们将这些患者与一组CFS患者和一组健康个体进行比较，进行相同的生物学和临床评估。我们将测量与免疫功能相关的血液激素的变化，如“细胞因子”和“皮质醇”。此外，我们将评估健康指标的变化，包括身体健康、注意力、睡眠和情绪。我们相信，创建和验证这种CFS模型将产生一系列旨在改善CFS患者健康的未来研究。例如，我们将能够建立一个血液检查清单，可以预测谁会，谁不会，患上慢性疲劳综合症；我们将测试治疗“ifn - α治疗后”疲劳的新疗法，因为这些患者的临床背景是相同的，然后将这些治疗扩展到CFS患者；最后，我们将真正了解在CFS发展过程中身体发生了什么，从而确定新的治疗方法来中断这一发展。

Chronic fatigue syndrome (CFS) is a medical condition in which patients feel persistently and overwhelmingly tired and run down, both physically and mentally. In addition, they have difficulty with concentration, flu-like symptoms and aches and pains. This condition interferes with daily life activity, and, in some patients, is profoundly disabling. Although many years of research have been conduced on CFS, we still do not know what is causing it. One biological system that is involved in CFS is the "immune system", that is, the system dedicated to fight infections in our body. Indeed, in many cases CFS is triggered by an infection, but then the symptoms continue even after the infection has been eliminated. Specifically, infections are always accompanied by acute fatigue and flu-like symptoms, as a consequence of the infection-driven immune activation; however, in patients with CFS the immune activation and the associated fatigue and flu-like symptoms persist for months or years. Moreover, there is evidence that the immune system is in a state of "hyper-activity" in patients with CFS, as if they were fighting an infective agent, even though they do not have an ongoing infection. This project aims to understand exactly this process: how the infection and the acute immune activation evolve into CFS, and what are the risk factors that make this process occur in some individuals but not others. Clearly, trying to study this process in subjects experiencing naturally-acquired infections is very difficult, for the unpredictability of these events. In contrast, we want to model the development of CFS by studying a group of patients that have a pre-existing infection (chronic viral hepatitis C, HCV) and that receive a course of treatment (lasting months) with the immune activator, interferon-alpha (IFN-alpha). IFN-alpha is the treatment of choice for HCV infection. Because it activates the immune system, IFN-alpha also induces fatigue and flu-like symptoms in all patients. Moreover, and of particular relevance for this study, a considerable proportion of patients continue to experience debilitating persistent fatigue, and other symptoms that are similar to CFS, for 6 months or even one year after the cessation of IFN-alpha. This phenomenon strikingly resembles CFS, which, as mentioned above, also persists after the infective/immune trigger has been eliminated. Therefore, we are proposing to use IFN-alpha as a model to understand how an immune trigger induces persistent fatigue even when the initial immune trigger is no longer present. To do this, we will assess these patients throughout the many months of IFN-alpha treatment and at 6 months after cessation of treatment, in order to identify those with persistent "post-IFN-alpha-treatment" fatigue, and understand what biological and clinical changes lead to this outcome. Moreover, we will compare these patients with a group of patients with CFS and with a group of healthy individuals, conducting the same biological and clinical assessment. We will measure changes occurring in blood hormones that are relevant to the immune function, such as "cytokines" and "cortisol". In addition, we will asses changes in measures of well-being, including physical fitness, concentration, sleep and mood. We are confident that creating and validating this model of CFS will generate a host of future studies aimed at improving the health of people with CFS. For example, we will be able to build a check-list of blood measures that could predict who will, and who will not, develop CFS; we will test novel treatments for "post-IFN-alpha-treatment" fatigue, facilitated by the fact that these patients are homogeneous in their clinical background, and then extend these treatments to patients with CFS; and, finally, we will truly understand what happens in the body during the development of CFS, and thus identify novel therapeutic approaches to interrupt this development.