Tag: Epstein-Barr

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)

Epstein-Barr Virus Induced Gene-2 Upregulation Identifies a Particular Subtype of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis

Abstract:

Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) is a chronic multisystem disease characterized by a variety of symptoms, and exhibits various features of an autoimmune-like disease. Subtypes are well recognized but to date are difficult to identify objectively. The disease may be triggered by infection with a variety of micro-organisms, including Epstein-Barr virus (EBV).

A subset of CFS/ME patients exhibit up regulation of EBV virus induced gene 2 (EBI2) mRNA in peripheral blood mononuclear cells (PBMC), and these patients appear to have a more severe disease phenotype and lower levels of EBNA1 IgG. EBI2 is induced by EBV infection and has been found to be upregulated in a variety of autoimmune diseases. EBI2 is a critical gene in immunity and central nervous system function; it is a negative regulator of the innate immune response in monocytes. Its heterogeneous expression in CFS/ME could explain the variable occurrence of a variety of immune and neurological abnormalities which are encountered in patients with CFS/ME.

The EBI2 subtype occurred in 38-55% CFS/ME patients in our studies. Further work is required to confirm the role of EBV and of EBI2 and its oxysterol ligands in CFS/ME, and to identify the most practical means to identify patients of the EBI subtype. There are two EBI2 antagonists currently in development, and these may hold promise in the treatment of CFS/ME patients of the EBI subtype.

Source: Kerr JR. Epstein-Barr Virus Induced Gene-2 Upregulation Identifies a Particular Subtype of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis. Front Pediatr. 2019 Mar 13;7:59. doi: 10.3389/fped.2019.00059. eCollection 2019. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6424879/ (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

No evidence found for an increased risk of long-term fatigue following human papillomavirus vaccination of adolescent girls

Abstract:

INTRODUCTION: In 2013, the Netherlands Pharmacovigilance Center Lareb published an overview of reports of long-lasting fatigue following bivalent HPV-vaccination (2vHPV). After an update of this overview in 2015, concerns regarding the safety of 2vHPV was picked up by the media, which led to further reports of long-lasting fatigue. Therefore, the Dutch National Institute for Public Health and the Environment (RIVM) investigated a possible association between HPV-vaccination and long-term fatigue.

METHODS: In this retrospective cohort study conducted in the Integrated Primary Care Information database, we investigated the occurrence of chronic fatigue syndrome (CFS), fatigue ≥6 months and 3-6 months in all girls born in 1991-2000 during the follow-up period January 1st 2007-December 31st 2014 (2007-2008 pre-vaccination and 2009-2014 post-vaccination). Patients with certain fatigue ≥6 m were asked for consent to link their primary care information with vaccination data. Incidence rates per 10,000 person years (PY) for 12-16-year-old girls were compared between pre- and post-HPV-vaccine era. A self-controlled case series (SCCS) analysis was performed using consenting vaccinated cases. A primary high-risk period of 12 months after each dose was defined.

RESULTS: The cohort consisted of 69,429 12-16-year-old girls accounting for 2758 PY pre-vaccination and 57,214 PY post-vaccination. Differences between pre- and post-vaccination incidences (CFS: 3.6 (95% CI 0.5-25.7)/10,000 PY and 0.9 (0.4-2.1); certain fatigue ≥6 m: 7.3 (1.8-29.0) and 19.4 (16.1-23.4); certain fatigue 3-6 m: 0.0 and 16.6 (13.6-20.3), respectively) were not statistically significant. SCCS analyses in 16 consenting vaccinated cases resulted in an age-adjusted RR of 0.62 (95%CI 0.07-5.49).

CONCLUSIONS: Fatigue ≥6 m and 3-6 m was frequently found among adolescent girls, but CFS was rarely diagnosed. No statistically significant increased incidence rates were found post-vaccination compared to similar age groups of girls pre-vaccination. The SCCS analysis included a low number of cases but revealed no elevated risk of certain fatigue ≥6 m in the high-risk period.

Copyright © 2018 The Authors. Published by Elsevier Ltd. All rights reserved.

Source: Schurink-Van’t Klooster TM, Kemmeren JM, van der Maas NAT, van de Putte EM, Ter Wolbeek M, Nijhof SL, Vanrolleghem A5, van Vliet JA, Sturkenboom M, de Melker HE. No evidence found for an increased risk of long-term fatigue following human papillomavirus vaccination of adolescent girls. Vaccine. 2018 Sep 19. pii: S0264-410X(18)31268-4. doi: 10.1016/j.vaccine.2018.09.019. [Epub ahead of print]  https://www.sciencedirect.com/science/article/pii/S0264410X18312684?via%3Dihub (Full article)

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

Valacyclovir treatment in Epstein-Barr virus subset chronic fatigue syndrome: thirty-six months follow-up

Abstract:

BACKGROUND: We hypothesized that subset classification of Epstein-Barr virus (EBV) in chronic fatigue syndrome (CFS) is required. At first, a blinded-random placebo-controlled trial of valacyclovir in EBV CFS subset was performed (Group 1), and this EBV subset was followed for thirty-six months (Group 2). Patients were given valacyclovir at 14.3 mg/kg every 6 hours. The validated Energy Index (EI) point score assessing physical functional capacity, Holter monitor, multigated (radionuclide) MUGA rest/stress ventriculographic examination, EBV serum IgM viral capsid antibodies (VCA), and EBV early antigen diffuse (EA) were followed.

After six-months, Group 1 CFS patients receiving valacyclovir experienced an increased mean least square EI point score +1.12 units (122 kcal/day), while the placebo cohort increased +0.42 EI units (65 kcal/day). EI point scores at Group 2 increased progressively. Sinus tachycardias decreased and abnormal cardiac wall motion improved. Serum antibody titers to EBV VCA IgM decreased. Patients resumed normal activities.

 

Source: Lerner AM, Beqaj SH, Deeter RG, Fitzgerald JT. Valacyclovir treatment in Epstein-Barr virus subset chronic fatigue syndrome: thirty-six months follow-up. In Vivo. 2007 Sep-Oct;21(5):707-13. http://iv.iiarjournals.org/content/21/5/707.long (Full article)

 

Diagnostic evaluation of 2′, 5′-oligoadenylate synthetase activities and antibodies against Epstein-Barr virus and Coxiella burnetii in patients with chronic fatigue syndrome in Japan

Abstract:

To investigate the association of viral infections with chronic fatigue syndrome (CFS), we assayed 2′, 5′-oligoadenylate synthetase (2-5AS) activities in peripheral blood mononuclear cells from CFS patients in Japan. These patients were diagnosed in two hospitals, H1 and H2, located in different areas of the country.

The activities were detected in 19 (86%) and 7 (32%) of each of the 22 patients in H1 and H2, respectively, while they were detected in only four (11%) out of the 38 healthy controls. IFN-alpha was similarly detected in a few CFS patients and healthy controls.

We also assayed the antibody titers against Epstein-Barr virus (EBV) and Coxiella burnetii in these patients. The EBV anti-EA-IgG antibodies were detected in two (9%) and seven (32%) of each of the 22 patients in H1 and H2, respectively. Anti-C. burnetii IgG antibodies were detected in six (27%) out of 22 patients in H1 but not in 22 patients in H2, while they were detected in one (11%) of the nine healthy controls.

Some CFS patients may be associated with EBV or C. burnetii infection. There were some statistical correlations between the 2-5AS activities and antibody titers of EA-IgG (P < 0.05, Student’s t-test) but not to the antibody titers of C. burnetii. The up-regulation of 2-5AS activities suggests immunological dysfunctions with some virus infections in the CFS patients. Our results indicate that 2-5AS activities are useful for a diagnostic marker of CFS and for exploring the complicated pathogenesis of CFS.

 

Source: Ikuta K, Yamada T, Shimomura T, Kuratsune H, Kawahara R, Ikawa S, Ohnishi E, Sokawa Y, Fukushi H, Hirai K, Watanabe Y, Kurata T, Kitani T, Sairenji T. Diagnostic evaluation of 2′, 5′-oligoadenylate synthetase activities and antibodies against Epstein-Barr virus and Coxiella burnetii in patients with chronic fatigue syndrome in Japan. Microbes Infect. 2003 Oct;5(12):1096-102. http://www.ncbi.nlm.nih.gov/pubmed/14554250

 

A six-month trial of valacyclovir in the Epstein-Barr virus subset of chronic fatigue syndrome: improvement in left ventricular function

Abstract:

This study was designed to determine safety and efficacy of a 6-month trial of valacyclovir in single-virus Epstein-Barr virus (EBV) persistent infection. Phase I of this study used four specific criteria to define a subset of patients with chronic fatigue syndrome (CFS). In the second phase, myocardial dynamics were measured by MUGA rest/stress radionuclide ventriculographic (RVG) examinations pre- and posttreatment with valacyclovir.

In phase I, a trial was performed in 19 consecutive CFS patients with the following diagnostic conditions: patients met criteria for diagnosis of CFS; they had had CFS for less than 1 year. They demonstrated repetitively abnormal oscillating T waves (ischemic or flat) at 24-h Holter monitoring; and they had elevated serum IgM antibody titers to EBV viral capsid antigen and/or total diffuse early antigen as measured by the enzyme-linked immunosorbent assay method.

The treatment group comprised 10 CFS patients with no serum antibodies to human cytomegalovirus, but the control group (nine CFS patients) had, additionally, high titers of serum antibodies (IgG) to conformational structural antigens of human cytomegalovirus. Both the parallel treatment and control CFS groups received valacyclovir 1.0-1.5 gm q.6.h. for 6 months.

This valacyclovir dose achieved serum acyclovir C(max) of > 7 microm and high antiviral activity versus EBV (IC(50) of 4.4-13.3 m). In phase II, six additional CFS patients met the same four criteria as the 19 CFS patients in phase I. They had, however, been ill for a mean of 55.8 months. Thus, 25 CFS patients comprise this study.

The studies were carried out at a single outpatient practice in Birmingham, MI, U.S.A. Before initiating valacyclovir, and after 6 months of treatment, clinical and laboratory observations were made. The CFS Energy Index point score (Table I) was used to record each CFS patient’s functional capacity at baseline and after 1, 3 and 6 months of valacyclovir. Energy Index point scores, as well as EBV and human cytomegalovirus serum antibody titers were assessed.

In the second phase, left ventricular dynamics were repeated after 6 months of treatment with valacyclovir. We concluded that the 16 CFS patients (included in both phases of this study) with EBV-persistent infection (EBV single-virus subset) are improved after 6 months of continuous pharmacokinetic dosing with valacyclovir. Nine CFS patients with EBV/human cytomegalovirus co-infection did not benefit from 6 months of similar treatment. Valacyclovir is not an effective anti-human cytomegalovirus antiviral drug. Unimproved CFS patients with co-infections EBV and human cytomegalovirus may require combined treatment with valacyclovir and another drug more active against human cytomegalovirus.

This preliminary trial, with a small number of patients, may be critical to an appropriately designed larger, double-blind, placebo-controlled trial.

Copyright 2002 Prous Science

 

Source: Lerner AM, Beqaj SH, Deeter RG, Dworkin HJ, Zervos M, Chang CH, Fitzgerald JT, Goldstein J, O’Neill W. A six-month trial of valacyclovir in the Epstein-Barr virus subset of chronic fatigue syndrome: improvement in left ventricular function. Drugs Today (Barc). 2002 Aug;38(8):549-61. http://www.ncbi.nlm.nih.gov/pubmed/12582420