By Laura M. Barron and Philip R. Fischer, MD, DTM&H

Ms. Barron is a student at Mayo Clinic Alix School of Medicine, Rochester, MN. Dr. Fischer is Professor of Pediatrics, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN.

Ms. Barron and Dr. Fischer report no financial relationships relevant to this field of study.

SYNOPSIS: Chronic disabling fatigue affects up to 2% of adolescents and often follows Epstein-Barr virus-related mononucleosis. No clinically significant infectious, immune, neuroendocrine, or autonomic biomarker or pathophysiologic mechanism has been identified to differentiate those with mononucleosis who go on to develop chronic fatigue from those who recover.

SOURCE: Kristiansen MS, Stabursvik J, O’Leary EC, et al. Clinical symptoms and markers of disease mechanisms in adolescent chronic fatigue following Epstein-Barr virus infection: An exploratory cross-sectional study. Brain Behav Immun 2019;80:551-563.

Up to 2% of adolescents experience pervasive, debilitating chronic fatigue. The mechanisms by which chronic fatigue develops are poorly understood. Nonetheless, acute Epstein-Barr virus (EBV) infection seems to be a common trigger of chronic fatigue. Previous studies have shown no significant difference in viral load when comparing patients with acute EBV who subsequently develop chronic fatigue and adolescents with acute EBV who return to premorbid functioning. Both the markers with and mechanisms by which chronic fatigue develops in a subset of adolescents with acute EBV are unknown.

The authors of this prospective, cross-sectional study aimed to compare the symptoms as well as the autonomic, neuroendocrine, immune, and infectious markers of disease in Norwegian adolescents 12 through 20 years of age with and without chronic fatigue six months after EBV infection. The researchers stratified 200 patients into the chronic fatigue (EBV CF+) or non-fatigue (EBV CF-) categories based on questionnaire responses. Patient samples were obtained for EBV polymerase chain reaction, catecholamine analysis, C-reactive protein assay, and immune cell phenotyping. Additionally, assessment of autonomic function incorporated the use of noninvasive, continuous cardiovascular monitoring of patients in various positional states, including supine at rest, supine with controlled breathing of 15 breaths per minute, and standing for three minutes. Patients also completed the Autonomic Symptom Profile, Hospital Anxiety and Depression Scale, and Chalder Fatigue Questionnaire. Of note, the 70 healthy controls with a similar age and sex distribution to EBV participants were evaluated just once, while patients were evaluated initially and six months later.

Patients in the EBV CF+ group reported higher scores for all clinical symptoms compared to the EBV CF- group. However, there were no significant differences in markers of infection, including viral load, between these groups. Immunologically, patients in the EBV CF+ group had slightly increased levels of C-reactive protein (CRP) and total T cell (CD3+) count when compared to the EBV CF- group. Interestingly, there was no significant elevation in CRP levels in the EBV CF+ group as compared to healthy controls. Other significant differences included an increased level of plasma norepinephrine and epinephrine in the EBV CF+ group when compared to the EBV CF- group. Overall, the two EBV groups had similar autonomic responses. However, there was slightly different heart rate variability in the EBV CF+ group, demonstrated by a decreased low frequency to high frequency ratio (LF:HF) during the supine rest condition, and a slightly decreased reduction in LF:HF during controlled breathing.

Based on these findings, researchers concluded that the increased symptom burden evident in a subset of adolescents six months post-EBV infection does not significantly correlate with a specific autonomic, neuroendocrine, immune, or infectious marker. Rather, the difference in markers between the EBV CF+ and CF- groups noted earlier were deemed to be clinically insignificant.


Fatigue is common in adolescents, with busy schedules, early school start times, and continuous access to technology presenting obstacles to both quantity and quality of sleep. However, in a subset of previously healthy adolescents, sudden-onset fatigue following infection or injury may become incapacitating, with devastating consequences, including recurrent school absences, social isolation, and frequent medical care visits. Kristiansen and colleagues found no biomarker indicating a risk of subsequent post-mononucleosis chronic fatigue, and their extensive evaluation did not identify any clear pathophysiologic mechanism by which chronic fatigue develops.

Clinically, in chronically tired teenagers, the possibility of an underlying pathophysiologic disorder should be considered, with a differential diagnosis including such conditions as iron deficiency, hypothyroidism, and depression. When accompanied by symptoms such as loss of consciousness, lightheadedness, nausea, headache, gastrointestinal problems, and cognitive changes, fatigue may be a presenting sign of a specific syndrome of orthostatic intolerance. Orthostatic intolerance is defined as difficulty maintaining an upright posture due to symptoms that subside when supine, and includes a broad category of orthostatic disorders.1

Interestingly, many adolescents with orthostatic intolerance report experiencing a viral illness prior to the onset of symptoms. Thus, the question remains why some adolescents are capable of returning to baseline functioning following a viral illness, while others continue to experience significant long-term sequelae.

In Kristiansen’s study, the increased symptom burden reported by adolescents in the post-EBV chronic fatigue group was not significantly reflected in specific autonomic, neuroendocrine, immune, or infectious markers. Rather, these markers were quite similar overall between the post-EBV chronic fatigue and non-fatigued groups. This discrepancy between patient reported symptoms and objective laboratory and clinical data can present a significant challenge to the diagnosis and management of these patients, leading to frustration for patients and clinicians alike.

Structural disorders are those in which there is a detectable abnormality leading to physical symptoms. For example, a broken bone can be identified by radiography, and a blood test reveals hepatitis. As shown in this study, post-viral chronic fatigue does not fall under the category of structural disorders, because there is no clear marker distinguishing patients who did not return to baseline post-EBV functioning from those who did. In some cases, when no known structural disorder can be found after rigorous medical workup, physicians may seek a psychiatric cause for disease. However, many patients who do not qualify for a psychiatric diagnosis still experience debilitating symptoms while having completely normal test results. These patients can be described best as having a functional disorder, defined as a collection of bothersome physical symptoms that compromise routine activities but for which there is no identifiable organic or psychiatric pathology.2 Although the underlying pathophysiologic mechanism of many functional disorders, including chronic fatigue, is not completely understood, these patients still have defined conditions that are capable of improving with treatment.2

Autonomic dysfunction can be seen commonly in conjunction with chronic fatigue. Postural orthostatic tachycardia syndrome (POTS) is a form of autonomic dysfunction characterized by chronic symptoms of orthostatic intolerance and excessive postural tachycardia in the absence of orthostatic hypotension. At least half of patients with this debilitating functional disorder have noted that it was preceded by some type of febrile illness, such as EBV.3 In this study, the autonomic responses to orthostatic maneuvers in the chronically fatigued post-EBV patients did not differ significantly from the non-fatigued group. It is also possible that, despite a lack of differences between the overall groups, there were some individuals with excessive postural tachycardia. However, as postulated by the study team, the lack of postural tachycardia in many subjects may be due to the absence of significant deconditioning in the chronic fatigue group (whereas many patients with chronic fatigue are deconditioned), as evidenced by the similar activity level between the two groups. With many POTS patients spending a significant portion of the day in bed due to fatigue, the subsequent deconditioning is thought to play a role in the development of orthostatic symptoms.4 Thus, a key component of functional recovery in patients with POTS is daily cardiovascular exercise with the goal of reversing this deconditioning.3

Although the exact mechanism by which POTS and other forms of chronic fatigue develop is unknown, a multidisciplinary approach to treatment, including exercise, cognitive-behavioral therapy, increased salt and fluid intake, and beta-blockers, can lead to functional recovery in the majority of these patients.3,5,6

Of course, research into the mechanisms of chronic fatigue development continues. The Epstein-Barr virus protein deoxyuridine triphosphate nucleotidohydrolase (dUTPase) acts on nerve cell processes related to fatigue, and levels of antibodies against EBV dUTPase have been inversely correlated with post-infection fatigue.7 Further studies will be needed to determine if this protein and/or antibodies to it are clinically relevant to the development of chronic fatigue following viral infections.


  1. Stewart JM, Boris JR, Chelimsky G, et al. Pediatric disorders of orthostatic intolerance. Pediatrics 2018;141:e20171673.
  2. Sunde KE, Hilliker DR, Fischer PR. Understanding and managing adolescents with conversion and functional disorders. Pediatr Rev [in press].
  3. Kizilbash SJ, Ahrens SP, Bruce BK, et al. Adolescent fatigue, POTS, and recovery: A guide for clinicians. Curr Probl Pediatr Adolesc Health Care 2014;44:108-133.
  4. Benarroch EE. Postural tachycardia syndrome: A heterogeneous and multifactorial disorder. Mayo Clinic Proc 2012;87:1214-1225.
  5. Lai CC, Fischer PR, Brands CK, et al. Outcomes in adolescents with postural orthostatic tachycardia syndrome treated with midodrine and beta-blockers. Pacing Clin Electrophysiol 2009;32:234-238.
  6. Bhatia R, Kizilbash SJ, Ahrens SP, et al. Outcomes of adolescent-onset postural orthostatic tachycardia syndrome. J Pediatr 2016;173:149-153.
  7. Williams MV, Cox B, Lafuse WP, Ariza ME. Epstein-Barr virus dUTPase induces neuroinflammatory mediators: Implications for myalgic encephalomyelitis/chronic fatigue syndrome. Clin Ther 2019;42:848-863.