Category: Viruses

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

Does the microbiome and virome contribute to myalgic encephalomyelitis/chronic fatigue syndrome?

Abstract:

Myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) (ME/CFS) is a disabling and debilitating disease of unknown aetiology. It is a heterogeneous disease characterized by various inflammatory, immune, viral, neurological and endocrine symptoms. Several microbiome studies have described alterations in the bacterial component of the microbiome (dysbiosis) consistent with a possible role in disease development. However, in focusing on the bacterial components of the microbiome, these studies have neglected the viral constituent known as the virome.

Viruses, particularly those infecting bacteria (bacteriophages), have the potential to alter the function and structure of the microbiome via gene transfer and host lysis. Viral-induced microbiome changes can directly and indirectly influence host health and disease. The contribution of viruses towards disease pathogenesis is therefore an important area for research in ME/CFS.

Recent advancements in sequencing technology and bioinformatics now allow more comprehensive and inclusive investigations of human microbiomes. However, as the number of microbiome studies increases, the need for greater consistency in study design and analysis also increases. Comparisons between different ME/CFS microbiome studies are difficult because of differences in patient selection and diagnosis criteria, sample processing, genome sequencing and downstream bioinformatics analysis. It is therefore important that microbiome studies adopt robust, reproducible and consistent study design to enable more reliable and valid comparisons and conclusions to be made between studies. This article provides a comprehensive review of the current evidence supporting microbiome alterations in ME/CFS patients. Additionally, the pitfalls and challenges associated with microbiome studies are discussed.

Source: Newberry F, Hsieh SY, Wileman T, Carding SR. Does the microbiome and virome contribute to myalgic encephalomyelitis/chronic fatigue syndrome? Clin Sci (Lond). 2018 Mar 9;132(5):523-542. doi: 10.1042/CS20171330. Print 2018 Mar 15. https://www.ncbi.nlm.nih.gov/pubmed/29523751

Phylogenetic analysis of short enteroviral sequences from patients with chronic fatigue syndrome

Abstract:

This study used phylogenetic analysis based on a region of the 5′ non-translated region (5’NTR) of a variety of enteroviral sequences to compare sequences associated with chronic fatigue syndrome (CFS) and those from enteroviruses causing acute infections. Direct sequencing of PCR products was used to obtain the nucleic acid sequences from CFS patients. The inferred phylogenetic tree identified three groupings, one correlating with the diagnosis of CFS.

The analysis identified a close relationship between the chronic fatigue enteroviral sequences, and showed that 19/20 were distinct from previously described enteroviruses. These results suggest there is persistence of enterovirus infection in some CFS patients and indicate the presence of distinct novel enterovirus sequences.

 

Source: Galbraith DN, Nairn C, Clements GB. Phylogenetic analysis of short enteroviral sequences from patients with chronic fatigue syndrome. J Gen Virol. 1995 Jul;76 ( Pt 7):1701-7. http://www.ncbi.nlm.nih.gov/pubmed/9049375

 

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)

Serological profiling of the EBV immune response in Chronic Fatigue Syndrome using a peptide microarray

Abstract:

BACKGROUND: Epstein-Barr-Virus (EBV) plays an important role as trigger or cofactor for various autoimmune diseases. In a subset of patients with Chronic Fatigue Syndrome (CFS) disease starts with infectious mononucleosis as late primary EBV-infection, whereby altered levels of EBV-specific antibodies can be observed in another subset of patients.

METHODS: We performed a comprehensive mapping of the IgG response against EBV comparing 50 healthy controls with 92 CFS patients using a microarray platform. Patients with multiple sclerosis (MS), systemic lupus erythematosus (SLE) and cancer-related fatigue served as controls. 3054 overlapping peptides were synthesised as 15-mers from 14 different EBV proteins. Array data was validated by ELISA for selected peptides. Prevalence of EBV serotypes was determined by qPCR from throat washing samples.

RESULTS: EBV type 1 infections were found in patients and controls. EBV seroarray profiles between healthy controls and CFS were less divergent than that observed for MS or SLE. We found significantly enhanced IgG responses to several EBNA-6 peptides containing a repeat sequence in CFS patients compared to controls. EBNA-6 peptide IgG responses correlated well with EBNA-6 protein responses. The EBNA-6 repeat region showed sequence homologies to various human proteins.

CONCLUSION: Patients with CFS had a quite similar EBV IgG antibody response pattern as healthy controls. Enhanced IgG reactivity against an EBNA-6 repeat sequence and against EBNA-6 protein is found in CFS patients. Homologous sequences of various human proteins with this EBNA-6 repeat sequence might be potential targets for antigenic mimicry.

Source: Loebel M, Eckey M, Sotzny F, Hahn E, Bauer S, Grabowski P, Zerweck J, Holenya P, Hanitsch LG, Wittke K, Borchmann P, Rüffer JU, Hiepe F, Ruprecht K, Behrends U, Meindl C, Volk HD, Reimer U, Scheibenbogen C. Serological profiling of the EBV immune response in Chronic Fatigue Syndrome using a peptide microarray. PLoS One. 2017 Jun 12;12(6):e0179124. doi: 10.1371/journal.pone.0179124. eCollection 2017. http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0179124 (Full article)

XMRV and Public Health: The Retroviral Genome Is Not a Suitable Template for Diagnostic PCR, and Its Association with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Appears Unreliable

Abstract:

A few years ago, a highly significant association between the xenotropic murine leukemia virus-related virus (XMRV) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a complex debilitating disease of poorly understood etiology and no definite treatment, was reported in Science, raising concern for public welfare. Successively, the failure to reproduce these findings, and the suspect that the diagnostic PCR was vitiated by laboratory contaminations, led to the retraction of the paper.

Notwithstanding, XMRV continued to be the subject of researches and public debates. Occasional positivity in humans was also detected recently, even if the data always appeared elusive and non-reproducible. In this study, we discuss the current status of this controversial association and propose that a major role in the unreliability of the results was played by the XMRV genomic composition in itself. In this regard, we present bioinformatic analyses that show: (i) aspecific, spurious annealings of the available primers in multiple homologous sites of the human genome; (ii) strict homologies between whole XMRV genome and interspersed repetitive elements widespread in mammalian genomes. 'To further detail this scenario, we screen several human and mammalian samples by using both published and newly designed primers.

The experimental data confirm that available primers are far from being selective and specific. In conclusion, the occurrence of highly conserved, repeated DNA sequences in the XMRV genome deeply undermines the reliability of diagnostic PCRs by leading to artifactual and spurious amplifications. Together with all the other evidences, this makes the association between the XMRV retrovirus and CFS totally unreliable.

Source: Panelli S, Lorusso L, Balestrieri A, Lupo G, Capelli E. XMRV and Public Health: The Retroviral Genome Is Not a Suitable Template for Diagnostic PCR, and Its Association with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Appears Unreliable. Front Public Health. 2017 May 22;5:108. doi: 10.3389/fpubh.2017.00108. ECollection 2017. http://journal.frontiersin.org/article/10.3389/fpubh.2017.00108/full (Full article)

The spread of EBV to ectopic lymphoid aggregates may be the final common pathway in the pathogenesis of ME/CFS

Abstract:

According to the hypothesis presented here, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) develops over 3 steps:

Step 1 is characterized by the aggregation of lymphoid cells in dorsal root ganglia or other nervous structures. The cause of this formation of ectopic lymphoid aggregates may be an acute infection, asymptomatic reactivations of a common neurotropic virus, exposure to a neurotoxin, or physical injury to peripheral nerves.

In step 2, Epstein-Barr virus (EBV)-infected lymphocytes or monocytes bring EBV from the circulation to one or several of these lymphoid aggregates, whereupon cell-to-cell transmission of EBV and proliferation of latently EBV-infected lymphocytes lead to the presence of many EBV-infected cells in the lymphoid aggregates. The EBV-infected cells in the aggregates ignite an inflammation in the surrounding nervous tissue. This local inflammation elicits, in turn, a wave of glial cell activation that spreads from the EBV-infected area to parts of the nervous system that are not EBV-infected, disturbing the neuron-glial interaction in both the peripheral – and central nervous system.

In step 3, immune cell exhaustion contributes to a consolidation of the pathological processes. There might be a cure: Infusions of autologous EBV-specific T-lymphocytes can perhaps remove the EBV-infected cells from the nervous system.

Copyright © 2017 Elsevier Ltd. All rights reserved.

Source: Eriksen W. The spread of EBV to ectopic lymphoid aggregates may be the final common pathway in the pathogenesis of ME/CFS. Med Hypotheses. 2017 May;102:8-15. doi: 10.1016/j.mehy.2017.02.011. Epub 2017 Feb 28. https://www.ncbi.nlm.nih.gov/pubmed/28478837

Chronic fatigue syndrome: Inherited virus can cause cognitive dysfunction and fatigue

Many experts believe that chronic fatigue syndrome (CFS) has several root causes including some viruses. Now, lead scientists Shara Pantry, Maria Medveczky and Peter Medveczky of the University of South Florida’s Morsani College of Medicine, along with the help of several collaborating scientists and clinicians, have published an article in the Journal of Medical Virology suggesting that a common virus, Human Herpesvirus 6 (HHV-6), is the possible cause of some CFS cases.

Over 95 percent of the population is infected with HHV-6 by age 3, but in those with normal immune systems the virus remains inactive. HHV-6 causes fever and rash (or roseola) in infants during early childhood, and is spread by saliva. In immunocompromised patients, it can reactivate to cause neurological dysfunction, encephalitis, pneumonia and organ failure.

“The good news reported in our study is that antiviral drugs improve the severe neurological symptoms, including chronic pain and long-term fatigue, suffered by a certain group of patients with CFS,” said Medveczky, who is a professor of molecular medicine at USF Health and the study’s principal investigator. “An estimated 15,000 to 20,000 patients with this CFS-like disease in the United States alone may ultimately benefit from the application of this research including antiviral drug therapy.”

The link between HHV-6 infection and CFS is quite complex. After the first encounter, or “primary infection,” all nine known human herpesviruses become silent, or “latent,” but may reactivate and cause diseases upon immunosuppression or during aging. A previous study from the Medveczky laboratory showed that HHV-6 is unique among human herpesviruses; during latency, its DNA integrates into the structures at the end of chromosomes known as telomeres.

Furthermore, this integrated HHV-6 genome can be inherited from parent to child, a condition commonly referred to as “chromosomally integrated HHV-6,” or CIHHV-6. By contrast, the “latent” genome of all other human herpesviruses converts to a circular form in the nucleus of the cell, not integrated into the chromosomes, and not inheritable by future generations.

Most studies suggest that around 0.8 percent of the U.S. and U.K. population is CIHHV6 positive, thus carrying a copy of HHV-6 in each cell. While most CIHHV-6 individuals appear healthy, they may be less able to defend themselves against other strains of HHV-6 that they might encounter. Medveczky reports that some of these individuals suffer from a CFS-like illness. In a cohort of CFS patients with serious neurological symptoms, the researchers found that the prevalence of CIHHV-6 was over 2 percent, or more than twice the level found in the general public. In light of this finding, the authors of the study suggest naming this sub-category of CFS “Inherited Human Herpesvirus 6 Syndrome,” or IHS.

Medveczky’s team discovered that untreated CIHHV-6 patients with CFS showed signs that the HHV-6 virus was actively replicating: determined by the presence of HHV-6 messenger RNA (mRNA), a substance produced only when the virus is active. The team followed these patients during treatment, and discovered that the HHV-6 mRNA disappeared by the sixth week of antiviral therapy with valganciclovir, a drug used to treat closely related cytomegalovirus (HHV-5). Of note, the group also found that short-term treatment regimens, even up to three weeks, had little or no impact on the HHV-6 mRNA level.

The investigators assumed that the integrated virus had become reactivated in these patients; however, to their surprise, they found that these IHS patients were infected by a second unrelated strain of HHV-6.

The USF-led study was supported by the HHV-6 Foundation and the National Institutes of Health.

Further studies are needed to confirm that immune dysregulation, along with subsequent chronic persistence of the HHV-6 virus, is the root cause of the IHS patients’ clinical symptoms, the researchers report.

Journal Reference: Shara N. Pantry, Maria M. Medveczky, Jesse H. Arbuckle, Janos Luka, Jose G. Montoya, Jianhong Hu, Rolf Renne, Daniel Peterson, Joshua C. Pritchett, Dharam V. Ablashi, Peter G. Medveczky. Persistent human herpesvirus-6 infection in patients with an inherited form of the virus. Journal of Medical Virology, 2013; DOI:10.1002/jmv.23685

 

Source: University of South Florida (USF Health). “Chronic fatigue syndrome: Inherited virus can cause cognitive dysfunction and fatigue.” ScienceDaily. ScienceDaily, 26 July 2013. https://www.sciencedaily.com/releases/2013/07/130726092427.htm

 

Chronic Fatigue Syndrome Linked To Stomach Virus

Chronic fatigue syndrome, also known as ME (myalgic encephalitis), is linked to a stomach virus, suggests research published ahead of print in Journal of Clinical Pathology.

The researchers base their findings on 165 patients with ME, all of whom were subjected to endoscopy because of longstanding gut complaints.

Endoscopy involves the threading of a long tube with a camera on the tip through the gullet into the stomach.

Specimens of stomach tissue were also taken to search for viral proteins and compared with specimens taken from healthy people and patients with other gut diseases none of whom had been diagnosed with ME.

Patients with ME often have intermittent or persistent gut problems, including indigestion and irritable bowel syndrome.

And viral infections, such as Epstein Barr virus (glandular fever), cytomegalovirus, and parvovirus, among others, produce many of the symptoms associated with chronic fatigue syndrome.

Enteroviruses, which infect the bowel, cause severe but short lasting respiratory and gut infections.

There are more than 70 different types, and they head for the central nervous system, heart and muscles.

Most of the biopsy specimens from patients with gut problems showed evidence of mild long term inflammation, although few were infected with Helicobacter pylori, a common bacterial infection associated with inflammation.

But more than 80% of the specimens from the ME patients tested positive for enteroviral particles compared with only seven of the 34 specimens from healthy people.

In a significant proportion of patients, the initial infection had occurred many years earlier.

 

Source: BMJ Specialty Journals. (2007, September 17). Chronic Fatigue Syndrome Linked To Stomach Virus. ScienceDaily. Retrieved March 4, 2017 from  https://www.sciencedaily.com/releases/2007/09/070913132933.htm