Background. Infectious mononucleosis (IM) is a risk factor for chronic fatigue. Reduced activity is the most consistent factor found to be associated with poor outcome following the onset of infectious mononucleosis. However, little is known about the biological mechanisms involved in the pathogenesis of chronic fatigue following IM and no study, so far, has examined the relation between certain illness beliefs and poor outcome. This study explored immunological, endocrine, behavioural and cognitive responses to the acute illness and assessed which components of these groups of risk factors predicted a chronic course.

Method. Using a prospective cohort design, 71 primary care patients with IM were enrolled onto the study and interviewed. Their recovery was explored by postal questionnaire up to 1 year later.

Results. In the univariate analysis, increased baseline levels of immune activation were associated with fatigue at baseline and 3 months. Cortisol levels were not associated with fatigue at any point. Using multivariate models of clinical and psychosocial baseline factors, severity of symptoms and illness perceptions were found to predict fatigue 3 months later. At 6 months, fatigue was best predicted by female gender and illness perceptions, and at 12 months by female gender and a symptoms–disability factor.

Conclusions. In the multivariate analysis no factors were found to predict poor outcome at all time-points. Instead the pattern of predictors changed over time, partly but not completely consistent with our a priori predictions. Larger studies are needed to explore further the predictive nature of biopsychosocial factors in the pathogenesis of chronic fatigue related to IM. The psycho-behavioural predictors found in this study are amenable to intervention. Such interventions should be tested in randomized controlled trials.