Tag: Peterson

Multi-Site Clinical Assessment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (MCAM): Design and Implementation of a Prospective/Retrospective Rolling Cohort Study

Abstract:

In the Multi-Site Clinical Assessment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (MCAM), we relied on expert clinician diagnoses to enroll patients from 7 specialty clinics in the United States in order to perform a systematic collection of data on measures of myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS). Healthy persons and those with other illnesses that share some features with ME/CFS were enrolled in comparison groups. The major objectives were to:

1) use standardized questionnaires to measure illness domains of ME/CFS and to evaluate patient heterogeneity overall and between clinics;

2) describe the course of illness, identify the measures that best correlate with meaningful clinical differences, and assess the performances of questionnaires as patient/person-reported outcome measures;

3) describe prescribed medications, orders for laboratory and other tests, and management tools used by expert clinicians to care for persons with ME/CFS;

4) collect biospecimens for future hypothesis testing and for evaluation of morning cortisol profiles; and

5) identify measures that best distinguish persons with ME/CFS from those in the comparison groups and detect subgroups of persons with ME/CFS who may have different underlying causes.

Enrollment began in 2012 and is planned to continue in multiple stages through 2017. We present the MCAM methods in detail, along with an initial description of the 471 patients with ME/CFS who were enrolled in stage 1.

Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health 2017. This work is written by (a) US Government employee(s) and is in the public domain in the US

 

Source: Unger ER, Lin JS, Tian H, Natelson BH, Lange G, Vu D, Blate M, Klimas NG, Balbin EG, Bateman L, Allen A, Lapp CW, Springs W, Kogelnik AM, Phan CC, Danver J, Podell RN, Fitzpatrick T, Peterson DL, Gottschalk CG, Rajeevan MS; MCAM Study Group. Multi-Site Clinical Assessment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (MCAM): Design and Implementation of a Prospective/Retrospective Rolling Cohort Study. Am J Epidemiol. 2017 Mar 17:1-10. doi: 10.1093/aje/kwx029. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/28338983

 

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

 

Distinct plasma immune signatures in ME/CFS are present early in the course of illness

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is an unexplained incapacitating illness that may affect up to 4 million people in the United States alone. There are no validated laboratory tests for diagnosis or management despite global efforts to find biomarkers of disease. We considered the possibility that inability to identify such biomarkers reflected variations in diagnostic criteria and laboratory methods as well as the timing of sample collection during the course of the illness.

Accordingly, we leveraged two large, multicenter cohort studies of ME/CFS to assess the relationship of immune signatures with diagnosis, illness duration, and other clinical variables. Controls were frequency-matched on key variables known to affect immune status, including season of sampling and geographic site, in addition to age and sex. We report here distinct alterations in plasma immune signatures early in the course of ME/CFS (n = 52) relative to healthy controls (n = 348) that are not present in subjects with longer duration of illness (n = 246).

Analyses based on disease duration revealed that early ME/CFS cases had a prominent activation of both pro- and anti-inflammatory cytokines as well as dissociation of intercytokine regulatory networks. We found a stronger correlation of cytokine alterations with illness duration than with measures of illness severity, suggesting that the immunopathology of ME/CFS is not static. These findings have critical implications for discovery of interventional strategies and early diagnosis of ME/CFS.

 

Source: Hornig M, Montoya JG, Klimas NG, Levine S, Felsenstein D, Bateman L, Peterson DL, Gottschalk CG, Schultz AF, Che X, Eddy ML, Komaroff AL, Lipkin WI. Distinct plasma immune signatures in ME/CFS are present early in the course of illness. Sci Adv. 2015 Feb;1(1). pii: e1400121. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4465185/ (Full article)

 

Cytokines in the cerebrospinal fluids of patients with chronic fatigue syndrome/myalgic encephalomyelitis

Abstract:

OBJECTIVES: Previous research has provided evidence for dysregulation in peripheral cytokines in patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME). To date only one study has examined cytokines in cerebrospinal fluid (CSF) samples of CFS/ME patients. The purpose of this pilot study was to examine the role of cytokines in CSF of CFS/ME patients.

METHODS: CSF was collected from 18 CFS/ME patients and 5 healthy controls. The CSF samples were examined for the expression of 27 cytokines (interleukin- (IL-) 1β, IL-1ra, IL-2, IL-4, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12p70, IL-13, IL-15, IL-17, basic FGF, eotaxin, G-CSF, GM-CSF, IFN-γ, IP-10, MCP-1 (MCAF), MIP-1α, MIP-1β, PDGF-BB, RANTES, TNF-α, and VEGF) using the Bio-Plex Human Cytokine 27-plex Assay.

RESULTS: Of the 27 cytokines examined, only IL-10 was significantly reduced in the CFS/ME patients in comparison to the controls.

CONCLUSIONS: This preliminary investigation suggests that perturbations in inflammatory cytokines in the CSF of CFS/ME patients may contribute to the neurological discrepancies observed in CFS/ME.

 

Source: Peterson D, Brenu EW, Gottschalk G, Ramos S, Nguyen T, Staines D, Marshall-Gradisnik S. Cytokines in the cerebrospinal fluids of patients with chronic fatigue syndrome/myalgic encephalomyelitis. Mediators Inflamm. 2015;2015:929720. doi: 10.1155/2015/929720. Epub 2015 Mar 5. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4365360/ (Full article)

 

Cytokine network analysis of cerebrospinal fluid in myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome is an unexplained debilitating disorder that is frequently associated with cognitive and motor dysfunction. We analyzed cerebrospinal fluid from 32 cases, 40 subjects with multiple sclerosis and 19 normal subjects frequency-matched for age and sex using a 51-plex cytokine assay.

Group-specific differences were found for the majority of analytes with an increase in cases of CCL11 (eotaxin), a chemokine involved in eosinophil recruitment. Network analysis revealed an inverse relationship between interleukin 1 receptor antagonist and colony-stimulating factor 1, colony-stimulating factor 2 and interleukin 17F, without effects on interleukin 1α or interleukin 1β, suggesting a disturbance in interleukin 1 signaling.

Our results indicate a markedly disturbed immune signature in the cerebrospinal fluid of cases that is consistent with immune activation in the central nervous system, and a shift toward an allergic or T helper type-2 pattern associated with autoimmunity.

 

Source: Hornig M, Gottschalk G, Peterson DL, Knox KK, Schultz AF, Eddy ML, Che X, Lipkin WI. Cytokine network analysis of cerebrospinal fluid in myalgic encephalomyelitis/chronic fatigue syndrome. Mol Psychiatry. 2016 Feb;21(2):261-9. doi: 10.1038/mp.2015.29. Epub 2015 Mar 31. https://www.ncbi.nlm.nih.gov/pubmed/25824300

 

A multicenter blinded analysis indicates no association between chronic fatigue syndrome/myalgic encephalomyelitis and either xenotropic murine leukemia virus-related virus or polytropic murine leukemia virus

Abstract:

The disabling disorder known as chronic fatigue syndrome or myalgic encephalomyelitis (CFS/ME) has been linked in two independent studies to infection with xenotropic murine leukemia virus-related virus (XMRV) and polytropic murine leukemia virus (pMLV). Although the associations were not confirmed in subsequent studies by other investigators, patients continue to question the consensus of the scientific community in rejecting the validity of the association. Here we report blinded analysis of peripheral blood from a rigorously characterized, geographically diverse population of 147 patients with CFS/ME and 146 healthy subjects by the investigators describing the original association. This analysis reveals no evidence of either XMRV or pMLV infection. I

MPORTANCE Chronic fatigue syndrome/myalgic encephalomyelitis has an estimated prevalence of 42/10,000 in the United States, with annual direct medical costs of $7 billion. Here, the original investigators who found XMRV and pMLV (polytropic murine leukemia virus) in blood of subjects with this disorder report that this association is not confirmed in a blinded analysis of samples from rigorously characterized subjects. The increasing frequency with which molecular methods are used for pathogen discovery poses new challenges to public health and support of science. It is imperative that strategies be developed to rapidly and coherently address discoveries so that they can be carried forward for translation to clinical medicine or abandoned to focus resource investment more productively. Our study provides a paradigm for pathogen discovery that may be helpful to others working in this field.

 

Source: Alter HJ, Mikovits JA, Switzer WM, Ruscetti FW, Lo SC, Klimas N, Komaroff AL, Montoya JG, Bateman L, Levine S, Peterson D, Levin B, Hanson MR, Genfi A, Bhat M, Zheng H, Wang R, Li B, Hung GC, Lee LL, Sameroff S, Heneine W, Coffin J, Hornig M, Lipkin WI. A multicenter blinded analysis indicates no association between chronic fatigue syndrome/myalgic encephalomyelitis and either xenotropic murine leukemia virus-related virus or polytropic murine leukemia virus. MBio. 2012 Sep 18;3(5). pii: e00266-12. doi: 10.1128/mBio.00266-12. Print 2012. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3448165/ (Full article)

 

Cytotoxic lymphocyte microRNAs as prospective biomarkers for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis

Abstract:

BACKGROUND: Immune dysfunction associated with a disease often has a molecular basis. A novel group of molecules known as microRNAs (miRNAs) have been associated with suppression of translational processes involved in cellular development and proliferation, protein secretion, apoptosis, immune function and inflammatory processes. MicroRNAs may be implicated in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME), where immune function is impaired. The objective of this study was to determine the association between miRNAs in cytotoxic cells and CFS/ME.

METHODS: Natural Killer (NK) and CD8(+)T cells were preferentially isolated from peripheral blood mononuclear cells from all participants (CFS/ME, n=28; mean age=41.8±9.6 years and controls, n=28; mean age=45.3±11.7 years), via negative cell enrichment. Following total RNA extraction and subsequent synthesis of cDNA, reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) was used to determine the expression levels of nineteen miRNAs.

RESULTS: There was a significant reduction in the expression levels of miR-21, in both the NK and CD8(+)T cells in the CFS/ME sufferers. Additionally, the expression of miR-17-5p, miR-10a, miR-103, miR-152, miR-146a, miR-106, miR-223 and miR-191 was significantly decreased in NK cells of CFS/ME patients in comparison to the non-fatigued controls.

LIMITATIONS: The results from these investigations are not yet transferable into the clinical setting, further validatory studies are now required.

CONCLUSIONS: Collectively these miRNAs have been associated with apoptosis, cell cycle, development and immune function. Changes in miRNAs in cytotoxic cells may reduce the functional capacity of these cells and disrupt effective cytotoxic activity along with other immune functions in CFS/ME patients.

Copyright © 2012 Elsevier B.V. All rights reserved.

 

Source: Brenu EW, Ashton KJ, van Driel M, Staines DR, Peterson D, Atkinson GM, Marshall-Gradisnik SM. Cytotoxic lymphocyte microRNAs as prospective biomarkers for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis. J Affect Disord. 2012 Dec 10;141(2-3):261-9. doi: 10.1016/j.jad.2012.03.037. Epub 2012 May 8. https://www.ncbi.nlm.nih.gov/pubmed/22572093

 

A double-blind, placebo-controlled, randomized, clinical trial of the TLR-3 agonist rintatolimod in severe cases of chronic fatigue syndrome

Abstract:

BACKGROUND: Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a severely debilitating disease of unknown pathogenesis consisting of a variety of symptoms including severe fatigue. The objective of the study was to examine the efficacy and safety of a TLR-3 agonist, rintatolimod (Poly I: C(12)U), in patients with debilitating CFS/ME.

METHODS AND FINDINGS: A Phase III prospective, double-blind, randomized, placebo-controlled trial comparing twice weekly IV rintatolimod versus placebo was conducted in 234 subjects with long-standing, debilitating CFS/ME at 12 sites. The primary endpoint was the intra-patient change from baseline at Week 40 in exercise tolerance (ET). Secondary endpoints included concomitant drug usage, the Karnofsky Performance Score (KPS), Activities of Daily Living (ADL), and Vitality Score (SF 36). Subjects receiving rintatolimod for 40 weeks improved intra-patient placebo-adjusted ET 21.3% (p = 0.047) from baseline in an intention-to-treat analysis. Correction for subjects with reduced dosing compliance increased placebo-adjusted ET improvement to 28% (p = 0.022). The improvement observed represents approximately twice the minimum considered medically significant by regulatory agencies. The rintatolimod cohort vs. placebo also reduced dependence on drugs commonly used by patients in an attempt to alleviate the symptoms of CFS/ME (p = 0.048). Placebo subjects crossed-over to receive rintatolimod demonstrated an intra-patient improvement in ET performance at 24 weeks of 39% (p = 0.04). Rintatolimod at 400 mg twice weekly was generally well-tolerated.

CONCLUSIONS/SIGNIFICANCE: Rintatolimod produced objective improvement in ET and a reduction in CFS/ME related concomitant medication usage as well as other secondary outcomes.

TRIAL REGISTRATION: ClinicalTrials.gov NCT00215800.

 

Source: Strayer DR, Carter WA, Stouch BC, Stevens SR, Bateman L, Cimoch PJ, Lapp CW, Peterson DL; Chronic Fatigue Syndrome AMP-516 Study Group, Mitchell WM.Collaborators (12). A double-blind, placebo-controlled, randomized, clinical trial of the TLR-3 agonist rintatolimod in severe cases of chronic fatigue syndrome. PLoS One. 2012;7(3):e31334. doi: 10.1371/journal.pone.0031334. Epub 2012 Mar 14.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3303772/ (Full article)

 

Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome

Abstract:

Chronic fatigue syndrome (CFS) is a debilitating disease of unknown etiology that is estimated to affect 17 million people worldwide. Studying peripheral blood mononuclear cells (PBMCs) from CFS patients, we identified DNA from a human gammaretrovirus, xenotropic murine leukemia virus-related virus (XMRV), in 68 of 101 patients (67%) as compared to 8 of 218 (3.7%) healthy controls. Cell culture experiments revealed that patient-derived XMRV is infectious and that both cell-associated and cell-free transmission of the virus are possible. Secondary viral infections were established in uninfected primary lymphocytes and indicator cell lines after their exposure to activated PBMCs, B cells, T cells, or plasma derived from CFS patients. These findings raise the possibility that XMRV may be a contributing factor in the pathogenesis of CFS.

Comment in:

Erratum in: Partial retraction. Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome. [Science. 2011]

Retraction in: Retraction. [Science. 2011]

 

Source: Lombardi VC, Ruscetti FW, Das Gupta J, Pfost MA, Hagen KS, Peterson DL, Ruscetti SK, Bagni RK, Petrow-Sadowski C, Gold B, Dean M, Silverman RH, Mikovits JA. Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome. Science. 2009 Oct 23;326(5952):585-9. doi: 10.1126/science.1179052. Epub 2009 Oct 8. http://science.sciencemag.org/content/326/5952/585.long (Full article)

 

Frequent HHV-6 reactivation in multiple sclerosis (MS) and chronic fatigue syndrome (CFS) patients

Abstract:

BACKGROUND: HHV-6 is a ubiquitous virus and its infection usually occurs in childhood and then becomes a latent infection. HHV-6 reactivation has been shown to play a role in the pathogenesis of AIDS and several other diseases.

OBJECTIVES: To determine what role HHV-6 infection or reactivation plays in the pathogenesis of multiple sclerosis (MS) and chronic fatigue syndrome (CFS).

RESULTS: Twenty-one MS and 35 CFS patients were studied and followed clinically. In these patients, we measured HHV-6 IgG and IgM antibody levels and also analyzed their peripheral blood mononuclear cells (PBMCs) for the presence of HHV-6, using a short term culture assay. In both MS and CFS patients, we found higher levels of HHV-6 IgM antibody and elevated levels of IgG antibody when compared to healthy controls. Seventy percent of the MS patients studied contained IgM antibodies for HHV-6 late antigens (capsid), while only 15% of the healthy donors (HD) and 20% of the patients with other neurological disorders (OND) had HHV-6 IgM antibodies. Higher frequency of IgM antibody was also detected in CFS patients (57.1%) compared to HD (16%). Moreover, 54% of CFS patients exhibited antibody to HHV-6 early protein (p41/38) compared to only 8.0% of the HD. Elevated IgG antibody titers were detected in both the MS and the CFS patients. PBMCs from MS, CFS and HD were analyzed in a short term culture assay in order to detect HHV-6 antigen expressing cells and to characterize the viral isolates obtained as either Variant A or B. Fifty-four percent of MS patients contained HHV-6 early and late antigen producing cells and 87% of HHV-6 isolates were Variant B. Isolates from CFS, patients were predominately Variant A (70%) and isolates from HD were predominately Variant B (67%). Moreover, one isolate from OND was also Variant B. Persistent HHV-6 infection was found in two CFS patients over a period of 2.5 years and HHV-6 specific cellular immune responses were detected in PBMCs from ten CFS patients.

CONCLUSION: In both MS and CFS patients, we found increased levels of HHV-6 antibody and HHV-6 DNA. A decrease in cellular immune responses was also detected in CFS patients. These data suggest that HHV-6 reactivation plays a role in the pathogenesis of these disorders.

 

Source: Ablashi DV, Eastman HB, Owen CB, Roman MM, Friedman J, Zabriskie JB, Peterson DL, Pearson GR, Whitman JE. Frequent HHV-6 reactivation in multiple sclerosis (MS) and chronic fatigue syndrome (CFS) patients. J Clin Virol. 2000 May;16(3):179-91. http://www.ncbi.nlm.nih.gov/pubmed/10738137