Predictors for Developing Severe Myalgic Encephalomyelitis/Chronic Fatigue Syndrome following Infectious Mononucleosis

Abstract

Background: About 10% of individuals who contract infectious mononucleosis (IM) have symptoms 6 months later that meet criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Our study for the first time examined whether it is possible to predict who will develop ME/CFS following IM. Methods: We have reported on a prospectively recruited cohort of 4,501 college students, of which 238 (5.3%) developed IM. Those who developed IM were followed-up at six months to determine whether they recovered or met criteria for ME/CFS. The present study focuses on 48 students who after six months had a diagnosis of ME/CFS, and a matched control group of 58 students who had no further symptoms after their IM. All of these 106 students had data at baseline (at least 6 weeks prior to the development of IM), when experiencing IM, and 6 months following IM. Of those who did not recover from IM, there were two groups: 30 were classified as ME/CFS and 18 were classified as severe ME/CFS. We measured the results of 7 questionnaires, physical examination findings, the severity of mononucleosis and cytokine analyses at baseline (pre-illness) and at the time of IM. We examined predictors (e.g., pre-illness variables as well as variables at onset of IM) of those who developed ME/CFS and severe ME/CFS following IM. Results: From analyses using receiver operating characteristic statistics, the students who had had severe gastrointestinal symptoms of stomach pain, bloating, and an irritable bowel at baseline and who also had abnormally low levels of the immune markers IL-13 and/or IL-5 at baseline, as well as severe gastrointestinal symptoms when then contracted IM, were found to have a nearly 80% chance of having severe ME/CFS persisting six months following IM. Conclusions: Our findings are consistent with emerging literature that gastrointestinal distress and autonomic symptoms, along with several immune markers, may be implicated in the development of severe ME/CFS. Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating illness affecting over a million people in the US1. Six months after having had Infectious Mononucleosis (IM), about 9-12% of individuals are diagnosed with this syndrome. For example, Hickie et al.2 showed an 11% rate of ME/CFS six months following acute infection with Epstein-Barr virus as well as following two other similar systemic infections. Katz et al.3 found similar outcomes following IM in youth. In a recent prospective, longitudinal study, university students were assessed prior to IM, at the time of IM, and at a six-month follow-up. Those who developed severe ME/CFS had differences in several pre-illness domains compared to those who recovered from IM without further symptoms4. In addition, Katz et al.5 found that the severity of IM was predictive of severe ME/CFS 6 months following IM. We have used these baseline pre-illness behavioral and immune data along with severity of IM data to predict who will develop severe ME/CFS six months following IM.

Pre-illness data reveals differences in multiple metabolites and metabolic pathways in those who do and do not recover from infectious mononucleosis

“…These metabolites are thus candidate biomarkers for predicting the development of severe ME/CFS 6 months following IM in college students and suggest changes in metabolic pathways that may plausibly contribute to the pathophysiology of ME/CFS in general. These findings and others 10,25–27 reinforce biological differences between those who fully recover following IM and those who go on to develop severe ME/CFS 6 months later.…”

Pathogenic mechanisms of post-acute sequelae of SARS-CoV-2 infection (PASC)

“…The trigger for COVID-19 is the SARS-CoV-2 infection. ME/CFS is a complex disease frequently triggered by an infection with EBV (the virus that causes mononucleosis) or parvovirus B19 even though various other viral and nonviral triggers have also been reported ( Chu et al, 2019 ; Fluge et al, 2021 ; Jason et al, 2022 ; Sotzny et al, 2018 ). The evidence is clear that in COVID-19 and potentially in PASC patients, the initial SARS-CoV-2 infection resurrects latent viruses such as EBV ( Fluge et al, 2021 ), which could trigger ME/CFS.…”

Predictors of Postviral Symptoms Following Epstein-Barr Virus-Associated Infectious Mononucleosis in Young People – Data from the IMMUC Study

“…In addition, chronic fatigue was predicted by (very) early exanthema and facial edema, possibly indicative of IM-associated vascular inflammation [23-25], and was associated with early musculoskeletal symptoms and (very) early moderate to severe GI symptoms. Interestingly, GI symptoms prior to IM have been associated with the development of ME/CFS [15]. Taken together, these findings suggest that preexisting or early autonomic symptoms in the context of IM might predict post-viral disease.…”