To gain a more detailed understanding of the link between Epstein Barr Virus (EBV) — which causes glandular fever, also known as Infectious Mononucleosis or ‘mono’ — and ME/CFS, Professor Leonard Jason and colleagues have published a study that follows a group of college students — a population in which EBV infection is common — over a 7-year period.
The research team concluded that their findings indicate that ME/CFS following an EBV infection tends to persist over the long term, particularly for those in whom the disease was more severe at the start.
Often, studies looking at the link between ME/CFS and EBV are retrospective, this means that they recruit participants when they already have ME/CFS, and look back in time at factors that may be linked with the disease onset. While this methodology can provide useful insights into potential disease mechanisms, retrospective study designs are limited in several ways, including:
- Potential issues with accuracy as the data used in retrospective studies was collected for purposes other than the current research; this can lead to issues with missing data, errors, and incomplete records, with no way for the researchers to check or rectify the issues.
- Retrospective studies are susceptible to different types of bias including selection bias (when certain groups of individuals are more likely to be included in the study than others leading to skewed results) and recall bias (where participants may not accurately remember past exposures of events; this is particularly problematic in studies relying on self-reported data).
- As retrospective studies look back in time, there are challenges establishing whether relationships are causal (an association in which a change in one variable directly results in a change of another).
Unlike retrospective study designs, the type of study used by Jason and colleagues, known as a longitudinal study which follows participants up over time, is particularly valuable as it allow researchers to observe changes, track trends, identify risk factors, and – especially where participants are recruited before the exposure of interest occurs – allow researchers to more accurately look at causal relationships.
In Jason’s study, an initial sample of 4,501 students were recruited before they had either an EBV infection or ME/CFS. Of these, 5.3% (238 students) went on to develop an EBV infection.
Of the 238 students who had an EBV infection, 132 were assessed at a 6-month follow-up. Findings indicated that 49 students met ME/CFS criteria (the Fukuda criteria for CFS, or either the Canadian Consensus Criteria or the Institute of Medicine criteria for ME/CFS), 23 students had ‘persisting symptoms’ but did not meet diagnostic criteria, and 60 students were ‘symptom-free’ and classed by the research team as controls.
Notably, participants with ME/CFS were grouped based on the number of criteria they met:
- 31 students meeting only one (according to the researchers this was usually only the Fukuda criteria) were classed as “moderate”,
- 18 students meeting more than one of the criteria were classed as “severe”.
Participants who took part in the 6 month follow up were subsequently invited to a 7 year follow up. Here, 14 people with severe ME/CFS, 23 in the moderate group, 16 with persisting symptoms, and 51 controls agreed to take part.
Of these:
- 79% (11/14) of those in the ‘severe’ group still met ME/CFS criteria 7 years after EBV infection.
- 30% (7/23) of those in the ‘moderate’ group still met ME/CFS criteria 7 years after EBV infection.
- 25% (4/16) of those with persisting symptoms that did not meet ME/CFS criteria at 6 months met ME/CFS criteria 7 years after EBV infection.
- 6% (3/51) of the control group met ME/CFS criteria 7 years after EBV infection.
It is important to recognise that in this study, the definitions for moderate and severe ME/CFS do not match those which are more widely adopted, such as those described in the in the 2021 NICE guidelines for the disease. Additionally, the Fukuda criteria used in this study diagnoses “CFS” rather than “ME/CFS”, and does not require post exertional malaise (PEM) – said to be the ‘cardinal symptom of ME/CFS – for a diagnosis of the disease to be made. As the majority of those in the “moderate” were said to only meet the Fukuda criteria, they appear not to meet more stringent ME/CFS diagnostic criteria. This limits the conclusions that can be made based on the results, and decreases the relevance of the findings in clinical practice.
While the study does highlight the association between EBV infection and ME/CFS, both at a 6-month follow-up, and at 7 years post infection, more research is needed in larger groups of participants to establish whether the same pattern can be observed for recognised ME/CFS severity categories when ME/CFS criteria which require PEM for a diagnosis of the disease to be made are utilised.
