Infectious mononucleosis is a common trigger for ME/CFS in teens. But why do some teens recover while others do not?

Studies indicate that when you ask an adolescent what triggered their Chronic Fatigue Syndrome, up to three-quarters are going to say mononucleosis (or glandular fever) or some other sudden, often vicious mono-like illness. With fully fifty percent of them testing positive for mono, it’s no wonder that Epstein-Barr virus, the pathogen that almost always causes ‘classic mono’, has received more interest than any other virus in ME/CFS.

Infectious Mononucleosis IM) (aka glandular fever) has always been understood to be a serious illness that often requires lengthy recovery periods. As time has gone on, though, a dark underbelly to IM has been exposed: IM is known to cause lengthy disability in about ten percent of its victim.

This study, which was part of a larger effort (which will be covered below), tried to uncover what factors put an adolescent who came down with infectious mononucleosis at risk for Chronic Fatigue Syndrome. Its primary graces were its size (300 plus adolescents in the original sample), its team of experienced ME/CFS researchers and physicians, and its use of a Lenny Jason revised edition of the Fukuda definition to diagnose ME/CFS.

Predictors of post-infectious chronic fatigue syndrome in adolescents. Leonard A. Jasona*Ben Z. KatzbYukiko Shiraishic,Cynthia J. MearsdYoung Ima & Renee R. Taylore. Health Psychology and Behavioral Medicine: An Open Access Journal. Volume 2Issue 1, 2014

Given past associations in some studies but not others, it made sense to determine if a very stressful event during the course of IM set patients up for an ME/CFS-like illness. The Dubbo study finding that illness severity was a key factor in progression to ME/CFS prompted the use of an autonomic nervous system symptom questionnaire to determine illness severity. A perceived stress questionnaire focused more on perceived stress, a psychiatric interview determined rates of mood disorders, and a family questionnaire uncovered possible family issues.

Did family issues, stressful events during the illness, mood disorders, perceived stress, or illness severity increase the risk of coming down with ME/CFS? Let’s find out.


That 24% of the adolescents had still not fully recovered six months later confirmed how severe an impact EBV infection can have on adolescents. The fact that almost 80% of the unrecovered adolescents met the criteria for ME/CFS confirmed the major contribution Epstein-Barr virus must be making to the pool of Chronic Fatigue Syndrome patients every year.


Stress of any kind, whether ‘perceived’, in the family or from a major event, did not increase the risk of coming down with ME/CFS

The almost 90% female dominance in the patients that met the CFS criteria was remarkable. The study did not show the gender makeup of the original 300 person cohort, but it was surely more evenly split between females and males given that IM overviews do not mention gender dominance. By 12 and 24 months into the study all the ME/CFS cases were women.

A stepwise-regression analysis indicated that behaviorists will be unable to argue that socio-economic status, family stress, the presence of mood disorders, stressful life events, or even the current presence of stress tip IM patients into Chronic Fatigue Syndrome.

Instead the adolescent’s entry into ME/CFS was advanced, as predicted by the Dubbo study, simply by how severe the initial illness was as measured by the autonomic nervous symptom index and days spent in bed. Essentially, the harder someone got whacked by Epstein-Barr virus in the first place, the less likely they were to recover, and the more likely they were to come down with Chronic Fatigue Syndrome.

That, of course, suggests that the ME/CFS patients-to-be had more difficulty fighting off the virus, a finding that serendipitously a recently published study suggested is true. (A blog on that will be out shortly.)

Other studies have found different results. A Dutch study finding that family stress increased the risk of ME/CFS, however, was confounded both by an inadequate definition and by study referrals to a psychologist which predicted a higher than normal rate of behavioral issues.

This study’s sampling approach ensured that no such biases were present.


The paper did not suggest why IM illness severity was such a powerful predictor of Chronic Fatigue Syndrome, but we can speculate.


Equal numbers of males and females probably come down with infectious mononucleosis, but far more women do not recover from it

Equal numbers of males and females probably come down with infectious mononucleosis, but far more women do not recover from it

This study suggests that females have much more trouble recovering from IM than males. The very high rate of IM diagnoses during a time of major hormonal changes ( 15-17 year old age group) appears to lend credence to Broderick’s hormonal-HPA axis model. This model predicts that hormonal changes, perhaps triggered by an infectious event, are much more likely to push women, and not men, into a low cortisol and immune deficient ME/CFS-like state.

Other studies by this group of the same cohort, however, did not find low cortisol level in the ME/CFS adolescents, nor did they find low natural killer cell functioning or increased rates of orthostatic intolerance. This suggests that, to the extent that they’re present in adolescents with ME/CFS, they may come along later in the disorder.

Immune System

There remains therefore an overwhelming body of evidence reinforcing the link to an infectious etiology in at least a subset of CFS patients, despite the fact that specific viral serology is not required for diagnosing CFS. Broderick et. al.

The Dubbo study’s finding that high cytokine levels and increased symptoms very strongly predicted the appearance of Chronic Fatigue Syndrome suggested that high cytokine levels could alter brain functioning or that EBV infections could have penetrated more deeply into the body, and this group did find cytokine changes.

“Illness-specific differences in the regulation of Th17 response may be a shared component in a significant subset of CFS cases.” Broderick et. al.

An earlier study of this group did find altered levels of cytokines that are associated with a Th17 response. The Th17 response is important in reducing extracellular pathogens (primarily bacteria and fungi) and appears to figure in autoimmune and inflammatory disorders. Because EBV may be able to alter the TH17 response, it’s possible that a more extensive EBV infection altered immune functioning in the unrecovered patients.

Autonomic Nervous System

Another earlier study finding from this group suggested a predisposition to autonomic nervous system dysfunction could explain why some people did not recover. It turned out that the IM patients destined to come down with ME/CFS had higher autonomic nervous system symptoms early in the infection than those who recovered.


High rates of autonomic nervous system symptoms found early in those who progressed to ME/CFS, suggested the ANS plays a role in who recovers from IM and who does not.

This suggested the infection either affected their ANS more or that a less stable ANS system prevented them from recovering from IM. The ANS is a major immune system regulator, and this finding brings to mind Dr. Klimas’s finding (unpublished) that the ANS dysfunction during exercise appears to trigger immune activation.

Whatever the explanation, this study suggests it’s possible that simply measuring autonomic nervous symptoms early in infectious mononucleosis could pick out adolescents that are likely to come down with ME/CFS.

It also suggests autonomic nervous system dysfunction could be the gateway to ME/CFS. It’s a pity heart rate variability (HRV) measures weren’t done. Would low heart rate variability (sympathetic nervous system dominance) early in the disease have been associated with entry into ME/CFS? Hopefully future studies will answer that question.

Stopping ME/CFS at the Source – Urgent Need For More Studies

None of the psychological or stress factors predisposed adolescents with infectious mononucleosis to come down with ME/CFS. Instead, Illness severity as well as high rates of autonomic nervous symptoms and unusual cytokine patterns possibly associated with a dysfunctional TH17 immune response appeared to be precipitating factors. The fact that two mainstays of adult ME/CFS, low cortisol and reduced natural killer cell functioning, were not found suggested adolescent ME/CFS, at least in the earlier stages, may be fundamentally different from adult ME/CFS.

This was a big, expensive study, the likes of which  don’t come around all that often in ME/CFS. The results, however, illuminated more about what we don’t know about pediatric ME/CFS than what we do. With brain imaging findings showing early changes in brain structure and connections in people progressing from acute to chronic pain, perhaps brain imaging would be more enlightening. The autonomic nervous system symptoms suggest that system should be more carefully analyzed.

declining graph

The burden over time in familiescan be very high.

As time goes on recovery rates continue to improve. By 24 months 4% of the original cohort still met the criteria for ME/CFS. The authors pointed out that that percentage, which doesn’t reflect ill adolescents who do not met the CDC criteria for CFS, is still far too high.

The authors noted the sometimes dire consequences a chronically ill adolescent can have on the family. They urge more studies to determine what happens to turn what is usually a time-limited disorder into what can be a lifetime burden and all that that implies.

“The prevention of the progression from IM to CFS not only saves the patient from the potential of lifelong disability, financial dependency, and the ensuing depression, but may save the family from life-altering care-giving and financial responsibilities; stresses of which alter the family dynamics so drastically and detrimentally that the family unit itself may not survive.”


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