NIH-funded study examines mono, chronic fatigue syndrome in college students

Press Release: Eurekalert, Jan 22, 2021: Many college students fully recover from infectious mononucleosis (which is almost always caused by Epstein-Barr virus) within 1-6 weeks, but some go on to develop chronic fatigue syndrome, also called myalgic encephalomyelitis (ME/CFS). A longitudinal study from DePaul University and Northwestern University followed 4,501 college students to examine risk factors that may trigger longer illness. The research appears in the journal Clinical Infectious Diseases and was funded by the National Institute of Allergy and Infectious Diseases.

Previous retrospective studies found that risk factors for developing ME/CFS after catching mono included preexisting physical symptoms and the number of days spent in bed, according to co-principal investigators Leonard A. Jason, professor of psychology at DePaul University; and Dr. Ben Z. Katz, a professor of pediatrics at Northwestern University Feinberg School of Medicine and a pediatric infectious disease specialist at Ann & Robert H. Lurie Children’s Hospital of Chicago.

“We are the only study to collect comprehensive biological and behavioral data prior to illness onset, which for the first time allowed us to identify some of the predisposing circumstances or conditions that make certain individuals more likely to get ill due to mono and stay ill,” says Jason, director of the Center for Community Research at DePaul.

Of the 4,501 college students in the study, 238 or 5.3% developed mononucleosis; and 55 of those (23%) met criteria for ME/CFS six months later, 20 of whom (8%) met criteria for severe ME/CFS. Researchers found that those who developed ME/CFS had more physical symptoms and immune irregularities at baseline, but they did not start out with statistically significantly more psychological symptoms such as stress, depression, anxiety or abnormal coping.

“Some people who are attacked by a virus stay sick. What we’ve found is that their emotional functioning and psychological states are not statistically different from those who get attacked by the same virus and recover. This becomes important validating information for those people who have this illness,” says Jason.

Participants in the study each completed seven different surveys to assess potential symptoms of ME/CFS. They also received a comprehensive psychiatric exam, and provided samples of serum, plasma and white blood cells. In future publications, researchers aim to analyze cytokine networks in participants’ blood and other risk factors. Deficiencies in certain cytokines “might suggest predisposing irregularities in immune response,” write the researchers. Vicky Whittemore, the Program Director at the National Institute of Neurological Disorders and Stroke (NINDS), stated that NINDS is supporting follow-up research to continue to study this cohort, and to examine possible predictors of COVID-19 as well.

“Since we have baseline data on nearly all of the 4500 students, we can use our same database to tease out risk factors for COVID infection as well as prolonged recovery from that illness,” says Katz.

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Other co-authors on the study are Joseph Colter, Mohammed F. Islam and Madison Sunnquist of DePaul’s Center for Community Research.

The study, “Risks for Developing ME/CFS in College Students Following Infectious Mononucleosis: A Prospective Cohort Study” was supported by the National Institute of Allergy and Infectious Diseases, grant number AI 105781.

Research at Ann & Robert H. Lurie Children’s Hospital of Chicago is conducted through the Stanley Manne Children’s Research Institute. The Manne Research Institute is focused on improving child health, transforming pediatric medicine and ensuring healthier futures through the relentless pursuit of knowledge. Lurie Children’s is ranked as one of the nation’s top children’s hospitals by U.S. News & World Report. It is the pediatric training ground for Northwestern University Feinberg School of Medicine. Last year, the hospital served more than 220,000 children from 48 states and 49 countries.

Risks for Developing ME/CFS in College Students Following Infectious Mononucleosis: A Prospective Cohort Study

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) involves severe fatigue, unrefreshing sleep, and cognitive impairment, leading to functional difficulties; prior studies have not evaluated risk factors with behavioral and immune data collected prior to developing ME/CFS.. Up to 5% of university students develop infectious mononucleosis (IM) annually, and 9-12% meet criteria for ME/CFS six months later. We sought to determine predictors of ME/CFS.

Methods: We enrolled college students at the start of the school year (Time 1), identified those who developed IM (Time 2) and followed them for 6 months (Time 3), identifying three groups: those who developed ME/CFS, those who developed severe ME/CFS (meeting >1 set of criteria) and those who were asymptomatic. We conducted 8 behavioral and psychological surveys and analyzed cytokines at three time points.

Results: 238 of the 4501 students (5.3%) developed IM; 6 months later, 55 of the 238 (23%) met criteria for ME/CFS and 157 (66%) were asymptomatic. 67 of the 157 asymptomatic students served as controls. Students with severe-ME/CFS were compared to students who were asymptomatic at three time points. The former group was not different from the latter group at Time 1 (prior to developing IM) in stress, coping, anxiety or depression, but were different in several behavioral measures and had significantly lower levels of IL-6 and IL-13. At Time 2 (when they developed IM), the two ME/CFS groups tended to have more autonomic complaints and behavioral symptoms while the severe- ME/CFS group had higher levels of IL-12 and lower levels of IL-13 than the recovered group.

Conclusion: At baseline, those who developed ME/CFS had more physical symptoms and immune irregularities, but not more psychological symptoms, than those who recovered.

Source: Leonard A Jason, PhD, Joseph Cotler, PhD, Mohammed F Islam, PhD, Madison Sunnquist, PhD, Ben Z Katz, MD, Risks for Developing ME/CFS in College Students Following Infectious Mononucleosis: A Prospective Cohort Study, Clinical Infectious Diseases, , ciaa1886, https://doi.org/10.1093/cid/ciaa1886

Clinical symptoms and markers of disease mechanisms in adolescent chronic fatigue following Epstein-Barr virus infection: An exploratory cross-sectional study

Abstract:

INTRODUCTION: Acute Epstein-Barr virus (EBV) infection is a trigger of chronic fatigue (CF) and Chronic Fatigue Syndrome (CFS). The aim of this cross-sectional study was to explore clinical symptoms as well as markers of disease mechanisms in fatigued and non-fatigued adolescents 6 months after EBV-infection, and in healthy controls.

MATERIALS AND METHODS: A total of 200 adolescents (12-20 years old) with acute EBV infection were assessed 6 months after the initial infectious event and divided into fatigued (EBV CF+) and non-fatigued (EBV CF-) cases based on questionnaire score. The EBV CF+ cases were further sub-divided according to case definitions of CFS. In addition, a group of 70 healthy controls with similar distribution of sex and age was included. Symptoms were mapped with a questionnaire. Laboratory assays included EBV PCR and serology; detailed blood leukocyte phenotyping and serum high-sensitive C-reactive protein; and plasma and urine cortisol and catecholamines. Assessment of autonomic activity was performed with continuous, non-invasive monitoring of cardiovascular variables during supine rest, controlled breathing and upright standing. Differences between EBV CF+ and EBV CF- were assessed by simple and multiple linear regression adjusting for sex as well as symptoms of depression and anxiety. A p-value ≤ 0.05 was considered statistically significant. This study is part of the CEBA-project (Chronic fatigue following acute Epstein-Barr virus infection in adolescents).

RESULTS: The EBV CF+ group had significantly higher scores for all clinical symptoms. All markers of infection and most immune, neuroendocrine and autonomic markers were similar across the EBV CF+ and EBV CF- group. However, the EBV CF+ group had slightly higher serum C-reactive protein (0.48 vs 0.43 mg/L, p=0.031, high-sensitive assay), total T cell (CD3+) count (median 1573 vs 1481 x 106 cells/L, p=0.012), plasma norepinephrine (1420 vs 1113 pmol/L, p=0.01) and plasma epinephrine (363 vs 237 nmol/L, p=0.032); lower low-frequency:high frequency (LF/HF) ratio of heart rate variability at supine rest (0.63 vs 0.76, p=0.008); and an attenuated decline in LF/HF ratio during controlled breathing (-0.11 vs -0.25, p=0.002). Subgrouping according to different CFS diagnostic criteria did not significantly alter the results. Within the EBV CF+ group, there were no strong correlations between clinical symptoms and markers of disease mechanisms. In a multiple regression analysis, serum CRP levels were independently associated with serum cortisol (B= 4.5 x 10-4, p<0.001), urine norepinephrine (B=9.6 x 10-2, p=0.044) and high-frequency power of heart rate variability (B= -3.7 x 10-2, p=0.024).

CONCLUSIONS: In adolescents, CF and CFS 6 months after acute EBV infection are associated with high symptom burden, but no signs of increased viral load and only subtle alterations of immune, autonomic, and neuroendocrine markers of which no one is strongly correlated with symptom scores. A slight sympathetic over parasympathetic predominance is evident in CF and might explain slightly increased CRP levels.

Copyright © 2019. Published by Elsevier Inc.

Source: Kristiansen MS, Stabursvik J, O’Leary EC, Pedersen M, Asprusten TT, Leegaard T, Osnes LT, Tjade T, Skovlund E, Godang K, Wyller VBB. 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 Apr 27. pii: S0889-1591(19)30133-3. doi: 10.1016/j.bbi.2019.04.040. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/31039432

Fatigue in Epstein-Barr virus infected adolescents and healthy controls: A prospective multifactorial association study

Abstract:

OBJECTIVE: Acute Epstein-Barr virus (EBV) infection is a known trigger of both acute and chronic fatigue. The aim of this study was to investigate associations to fatigue in adolescents with EBV infection during the initial stage and six months after, as well as in healthy controls.

METHODS: 200 adolescents (12-20 years old) with EBV infection were assessed as soon as possible after the onset of symptoms (EBVbaseline) and six months later (EBVsix months, 5 drop-outs). Also, 70 healthy controls (HC) were included. Associations between current fatigue and 148 different variables (including symptoms, functional abilities and biomarkers) were investigated separately for EBVbaseline, EBVsix months and HC using linear regression modelling.

RESULTS: Fatigue was associated with symptoms of sleeping difficulties, negative emotions, and quality of life under all circumstances. Fatigue was independently associated with markers of immune response at EBVsix months and in HC, not at EBVbaseline. An association between fatigue and markers of autonomic cardiovascular control was only present at EBVsix months. Cognitive functioning shifted from a positive association to fatigue at EBVbaseline to a negative trend at EBVsix months. Markers of infection were not associated with fatigue at EBVbaseline, EBVsix months nor in HC.

CONCLUSION: Irrespective of the cause, fatigue is important for quality of life and is highly associated with negative emotions. Markers of infection and immune response had respectively none and barely any association to fatigue. Autonomic alterations and cognitive dysfunction were exclusively associated with fatigue long after infection, corroborating findings from studies of the Chronic Fatigue Syndrome.

Copyright © 2019. Published by Elsevier Inc.

Source: Pedersen M, Asprusten TT, Godang K, Leegaard TM, Osnes LT, Skovlund E, Tjade T, Øie MG, Wyller VBB. Fatigue in Epstein-Barr virus infected adolescents and healthy controls: A prospective multifactorial association study. J Psychosom Res. 2019 Apr 10. pii: S0022-3999(18)30946-2. doi: 10.1016/j.jpsychores.2019.04.008. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/31003854

EBV-requisitioning physicians’ guess on fatigue state 6 months after acute EBV infection

Abstract:

We assessed referring medical practitioner’s ability to predict chronic fatigue development in adolescents presenting with acute infectious mononucleosis. Compared with ‘not fatigued’ being predicted as ‘unsurely fatigued’ and ‘likely fatigued’ were both strongly associated with developing fatigue 6 months later (OR 2.5, 95% CI 1.16% to 5.47% and 3.2, 95% CI 1.19% to 8.61%, respectively, P=0.012). The positive and negative predictive values were 66% and 62%, respectively. Disentangling the physician’s intuition may be of interest in further investigations of risk factors and prophylactic factors for fatigue development.

Source: Asprusten TT, Pedersen M, Skovlund E, Wyller VB. EBV-requisitioning physicians’ guess on fatigue state 6 months after acute EBV infection. BMJ Paediatr Open. 2019 Mar 1;3(1):e000390. doi: 10.1136/bmjpo-2018-000390. eCollection 2019. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6422241/ (Full article)

A Validated Scale for Assessing the Severity of Acute Infectious Mononucleosis

Abstract:

OBJECTIVES: To develop a scale for the severity of mononucleosis.

STUDY DESIGN: One to 5 percent of college students develop infectious mononucleosis annually, and about 10% meet criteria for chronic fatigue syndrome (CFS) 6 months following infectious mononucleosis. We developed a severity of mononucleosis scale based on a review of the literature. College students were enrolled, generally when they were healthy. When the students developed infectious mononucleosis, an assessment was made as to the severity of their infectious mononucleosis independently by 2 physicians using the severity of mononucleosis scale. This scale was correlated with corticosteroid use and hospitalization. Six months following infectious mononucleosis, an assessment is made for recovery from infectious mononucleosis or meeting 1 or more case definitions of CFS.

RESULTS: In total, 126 severity of mononucleosis scales were analyzed. The concordance between the 2 physician reviewers was 95%. All 3 hospitalized subjects had severity of mononucleosis scores ≥2. Subjects with severity of mononucleosis scores of ≥1 were 1.83 times as likely to be given corticosteroids. Students with severity of mononucleosis scores of 0 or 1 were less likely to meet more than 1 case definition of CFS 6 months following infectious mononucleosis.

CONCLUSIONS: The severity of mononucleosis scale has interobserver, concurrent and predictive validity for hospitalization, corticosteroid use, and meeting criteria for CFS 6 months following infectious mononucleosis.

Copyright © 2019 Elsevier Inc. All rights reserved.

Source: Katz BZ, Reuter C, Lupovitch Y, Gleason K, McClellan D, Cotler J, Jason LA. A Validated Scale for Assessing the Severity of Acute Infectious Mononucleosis. J Pediatr. 2019 Mar 7. pii: S0022-3476(19)30123-4. doi: 10.1016/j.jpeds.2019.01.035. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/30853204

Predictors of chronic fatigue in adolescents six months after acute Epstein-Barr virus infection: a prospective cohort study

Abstract:

INTRODUCTION: Acute Epstein-Barr virus (EBV) infection is a trigger of chronic fatigue and Chronic Fatigue Syndrome (CFS). This study investigated baseline predictors of chronic fatigue six months after an acute EBV infection.

MATERIALS AND METHODS: A total of 200 adolescents (12-20 years old) with acute EBV infection were assessed for 149 possible baseline predictors and followed prospectively. We performed linear regression to assess possible associations between baseline predictors and fatigue (Chalder Fatigue Questionnaire total score) six months after the acute EBV infection. A total of 70 healthy controls were included for cross-sectional reference. This study is part of the CEBA-project (Chronic fatigue following acute Epstein-Barr virus infection in adolescents).

RESULTS: In the final multiple linear regression model, fatigue six months after acute EBV infection was significantly and independently predicted by the following baseline variables (regression coefficient B[95% CI]): Sensory sensitivity (0.8[0.09 to 1.6]), pain severity (0.2[0.02 to 0.3]), functional impairment (1000 steps/day) (-0.3[-0.5 to -0.08]), negative emotions (anxiety) (0.4[0.2 to 0.6]), verbal memory (correct word recognition) (1.7[0.1 to 3.3]), plasma C-reactive protein (2.8[1.1 to 4.4] for CRP values >0.86) and plasma Vitamin B12 (-0.005[-0.01 to -0.001]).

CONCLUSIONS: Development of fatigue after acute EBV infection is to a larger extent predicted by baseline variables related to symptoms and functions than to baseline variables reflecting infectious and immune processes.

TRIAL REGISTRATION: ClinicalTrials, ID: NCT02335437, ttps://clinicaltrials.gov/ct2/show/NCT02335437.

Copyright © 2018. Published by Elsevier Inc.

Source: Pedersen M, Asprusten TT, Godang K, Leegaard TM, Osnes LT, Skovlund E, Tjade T, Øie MG, Wyller VBB. Predictors of chronic fatigue in adolescents six months after acute Epstein-Barr virus infection: a prospective cohort study. Brain Behav Immun. 2018 Sep 24. pii: S0889-1591(18)30625-1. doi: 10.1016/j.bbi.2018.09.023. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/30261303

A Prospective Study of Infectious Mononucleosis in College Students

Abstract:

BACKGROUND: The present study aims to prospectively investigate possible biological and psychological factors present in college students who will go on to develop chronic fatigue syndrome (CFS) following Infectious Mononucleosis (IM). Identification of risk factors predisposing patients towards developing CFS may help to understand the underlying mechanisms and ultimately prevent its occurrence. Our study is enrolling healthy college students over the age of 18. Enrollment began in March of 2013 and is ongoing.

METHODS: Biological and psychological data are collected when students are well (Stage 1), when they develop IM (Stage 2), and approximately 6 months after IM diagnosis (Stage 3).

RESULTS: Two case studies demonstrate the progression of student symptomology across all three stages.

CONCLUSION: The Case Studies presented illustrate the usefulness of a prospective research design that tracks healthy students, following their trajectory of IM illness to either a) full recovery or b) diagnosis with CFS.

Source: Jason LA, Katz B, Gleason K, McManimen S, Sunnquist M, Thorpe T. A Prospective Study of Infectious Mononucleosis in College Students. Int J Psychiatry (Overl Park). 2017;1(2). pii: http://www.opastonline.com/wp-content/uploads/2017/01/a-prospective-study-of-infectious-mononucleosis-in-college-students-IJP-17-016.pdf. Epub 2017 Jan 20. (Full article)

Hit-and-run Injury To The Brain: New Evidence On Chronic Fatigue Causation

Press Release: A seven-year tracking study has prompted scientists to suggest that chronic fatigue syndrome could be the result of brain injuries inflicted during the early stages of glandular fever.

Australian researchers have put the suggestion in this week’s Journal of Infectious Diseases, which reveals new findings from the ‘Dubbo Infection Outcomes Study’. Since 1999, a team led by UNSW Professor Andrew Lloyd have been tracking the long-term health of individuals infected with Epstein-Barr virus (EBV), Ross River virus (RRV) or Q fever infection. Their goal is to discover whether the post-infection fatigue syndrome that may affect up to 100,000 Australians is caused by the persistence of EBV, a weakened immune system, psychological vulnerability, or some combination of these.

Glandular fever — sometimes called ‘the kissing disease’ — is caused by Epstein-Barr virus (EBV). Transmitted via saliva, its acute symptoms include fever, sore throat, tiredness, and swollen lymph glands. Most patients recover within several weeks but one in ten young people will suffer prolonged symptoms, marked by fatigue. When these symptoms persist in disabling degree for six months or more, the illness may be diagnosed as chronic fatigue syndrome (CFS).

The researchers followed the course of illness among 39 people diagnosed with acute glandular fever. Eight patients developed a ‘post-infective fatigue syndrome’ lasting six months or longer, while the remaining 31 recovered uneventfully. Detailed studies of the activity of the Epstein-Barr virus in the blood and the immune response against the virus were conducted on blood samples collected from each individual over 12 months.

Commenting on the findings, Professor Lloyd says: “Our findings reveal that neither the virus nor an abnormal immune response explain the post-infective fatigue syndrome. We now suspect it’s more like a hit and run injury to the brain.

“We believe that the parts of the brain that control perception of fatigue and pain get damaged during the acute infection phase of glandular fever. If you’re still sick several weeks after infection, it seems that the symptoms aren’t being driven by the activity of the virus in body, it’s happening in the brain.”

The research team comprising scientists from the University of New South Wales, the University of Sydney and the Queensland Institute of Medical Research plan to test their ‘brain injury’ hypothesis by doing neurological tests on the study participants.

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About the Dubbo Infection Outcomes Study: this is a major prospective cohort study following individuals from the time of onset of documented infection with Epstein-Barr virus (the cause of glandular fever), Ross River virus (the mosquito-borne infection which causes rash and joint pain) and Q fever (an infection common in meatworkers and those exposed to livestock).

Research Paper:
‘Prolonged illness after infectious mononucleosis is associated with altered immunity but not with increased viral load’, The Journal of Infectious Diseases, vol. 193 (2006), pp 664-671. Authors: Barbara Cameron, Mandvi Bharadwaj, Jacqueline Burrows, Chrysa Fazou, Denis Wakefield, Ian Hickie, Rosemary French, Rajiv Khanna, Andrew Lloyd.

Funding: The Dubbo Infection Outcomes Study is 82 per cent funded by the US Centers for Disease Control. It also receives funding from the National Health and Medical Research Council of Australia.

 

Source: University of New South Wales. “Hit-and-run Injury To The Brain: New Evidence On Chronic Fatigue Causation.” ScienceDaily. ScienceDaily, 1 March 2006. https://www.sciencedaily.com/releases/2006/03/060301092926.htm

 

Comorbidities treated in primary care in children with chronic fatigue syndrome / myalgic encephalomyelitis: A nationwide registry linkage study from Norway

Abstract:

BACKGROUND: Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a complex condition. Causal factors are not established, although underlying psychological or immunological susceptibility has been proposed. We studied primary care diagnoses for children with CFS/ME, with children with another hospital diagnosis (type 1 diabetes mellitus [T1DM]) and the general child population as comparison groups.

METHODS: All Norwegian children born 1992-2012 constituted the study sample. Children with CFS/ME (n = 1670) or T1DM (n = 4937) were identified in the Norwegian Patient Register (NPR) (2008-2014). Children without either diagnosis constituted the general child population comparison group (n = 1337508). We obtained information on primary care diagnoses from the Norwegian Directorate of Health. For each primary care diagnosis, the proportion and 99 % confidence interval (CI) within the three groups was calculated, adjusted for sex and age by direct standardization.

RESULTS: Children with CFS/ME were more often registered with a primary care diagnosis of weakness/general tiredness (89.9 % [99 % CI 88.0 to 91.8 %]) than children in either comparison group (T1DM: 14.5 % [99 % CI: 13.1 to 16.0 %], general child population: 11.1 % [99 % CI: 11.0 to 11.2 %]). Also, depressive disorder and anxiety disorder were more common in the CFS/ME group, as were migraine, muscle pain, and infections. In the 2 year period prior to the diagnoses, infectious mononucleosis was registered for 11.1 % (99 % CI 9.1 to 13.1 %) of children with CFS/ME and for 0.5 % (99 % CI (0.2 to 0.8 %) of children with T1DM. Of children with CFS/ME, 74.6 % (1292/1670) were registered with a prior primary care diagnosis of weakness / general tiredness. The time span from the first primary care diagnosis of weakness / general tiredness to the specialist health care diagnosis of CFS/ME was 1 year or longer for 47.8 %.

CONCLUSIONS: This large nationwide registry linkage study confirms that the clinical picture in CFS/ME is complex. Children with CFS/ME were frequently diagnosed with infections, supporting the hypothesis that infections may be involved in the causal pathway. The long time span often observed from the first diagnosis of weakness / general tiredness to the diagnosis of CFS/ME might indicate that the treatment of these patients is sometimes not optimal.

 

Source: Bakken IJ, Tveito K, Aaberg KM, Ghaderi S, Gunnes N, Trogstad L, Magnus P, Stoltenberg C, Håberg SE. Comorbidities treated in primary care in children with chronic fatigue syndrome / myalgic encephalomyelitis: A nationwide registry linkage study from Norway. BMC Fam Pract. 2016 Sep 2;17(1):128. doi: 10.1186/s12875-016-0527-7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5010760/ (Full article)