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

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.

We propose to model chronic fatigue syndrome (CFS) by studying patients taking interferon-alpha (IFN-alpha) for chronic viral hepatitis C (HCV) infection. IFN-alpha treatment leads to acute fatigue in the majority of patients. Most importantly, a proportion of patients continue to experience persistent fatigue, together with other CFS-like-symptoms, for many months after the cessation of treatment, that is, in the absence of the pro-inflammatory stimulus. This phenomenon strikingly resembles CFS, which also persists after the viral/immune trigger has been eliminated.

In order to develop this as a model of CFS, in our three-year project we want to:
1) assess a cohort (n=100) of patients throughout the IFN-alpha treatment and at 6 months after cessation of treatment, and identify the group who develop the persistent post-treatment fatigue (expected n=50);
2) validate this model, by comparing the clinical and biomarkers profiles in patients who experience persistent post-treatment fatigue, patients with CFS (n=50), and healthy controls (n=50);
3) identify the risk factors and the biomarkers trajectories (before and during IFN-alpha treatment) that identify those patients who will later experience persistent post-treatment fatigue.

We will measure: fatigue, mood, and other CFS-like symptoms; medical and psychiatric history; childhood and recent stressors; social support; illness and treatment perceptions; physical fitness; quality of life; and occupational function. Moreover, we will measure blood biomarkers: serum cytokines; cortisol at awakening and during the day; and leukocytes gene expression.

The project will build onto an existing pilot study in HCV patients, an established collaboration with Liver Units across London, and the research-led clinical service for CFS patients at King's College Hospital. Thus, the project has great chances of success.

Our research on chronic fatigue syndrome (CFS) will benefit health and biological scientists; policy makers; stakeholders in health care; the interested lay public (especially those with a personal investment in understanding CFS), and, finally, patients with CFS.

Social and health scientists will benefit from our data: we will explain the mechanisms underlying the development of chronic fatigue, offer novel aetiological hypotheses to be confirmed in CFS patients, identify a group who are particularly indicated to test novel therapeutic interventions, and suggest new potential biological targets for the pharmacological treatment of CFS.

Policy makers will benefit from the evidence offered by our study: it will guide them in prioritising resources, in the difficult times ahead, by identifying important stages in the development of chronic fatigues and hence where and when to deliver screening and intervention programmes.

Stakeholders will benefit from understanding what happens to people while they are developing chronic fatigue: charities, non-governmental organisations, and regulatory bodies, all aimed at improving the clinical and social outcomes of CFS patients, will want to know how health, well-being, quality of life and occupational functioning is impacted by changes in biology and behaviour, and how these people can thus be helped.

Finally, the lay public, and especially patients and carers who have been personally touched by CFS, will benefit from all of our work: a non-stigmatising approach based on a sound biological basis, and an explanatory model that is not deterministic and that emphasises not only risk factors but also the protective factors that could be sought out.