Tag: Montoya

New Therapy For Chronic Fatigue Syndrome To Be Tested

Press Release: A preliminary study suggests there may be hope in the offing for some sufferers of chronic fatigue syndrome with a new therapy being tested by researchers at the Stanford University School of Medicine.

José Montoya, MD, associate professor of medicine (infectious diseases), and postdoctoral scholar Andreas Kogelnik, MD, PhD, have used the drug valganciclovir – an antiviral often used in treating diseases caused by human herpes viruses – to treat a small number of CFS patients.

The researchers said they treated 25 patients during the last three years, 21 of whom responded with significant improvement that was sustained even after going off the medication at the end of the treatment regimen, which usually lasts six months. The first patient has now been off the drug for almost three years and has had no relapses. A paper describing the first dozen patients Montoya and Kogelnik treated with the drug was published in the December issue of Journal of Clinical Virology.

“This study is small and preliminary, but potentially very important,” said Anthony Komaroff, MD, professor of medicine at Harvard Medical School, who was not involved in the study. “If a randomized trial confirmed the value of this therapy for patients like the ones studied here, it would be an important landmark in the treatment of this illness.”

Montoya has received a $1.3 million grant from Roche Pharmaceutical, which manufactures the drug under the brand name Valcyte, to conduct a randomized, placebo-controlled, double-blind study set to begin this quarter at Stanford. The study will assess the effectiveness of the drug in treating a subset of CFS patients.

Montoya is speaking about his efforts at the biannual meeting of the International Association for Chronic Fatigue Syndrome in Fort Lauderdale on Jan. 11 and 12.

Chronic fatigue syndrome has baffled doctors and researchers for decades, because aside from debilitating fatigue, it lacks consistent symptoms. Although many genetic, infectious, psychiatric and environmental factors have been proposed as possible causes, none has been nailed down. It was often derided as “yuppie flu,” since it seemed to occur frequently in young professionals, though the Centers for Disease Control and Prevention says it’s most common in the middle-aged. But to those suffering from it, CFS is all too real and its effects are devastating, reducing once-vigorous individuals to the ranks of the bedridden, with an all-encompassing, painful and sleep-depriving fatigue.

More than 1 million Americans suffer from the disorder, according to the CDC. The disease often begins with what appears to be routine flulike symptoms, but then fails to subside completely – resulting in chronic, waxing and waning debilitation for years.

Valganciclovir is normally used against diseases caused by viruses in the herpes family, including cytomegalovirus, Epstein-Barr virus and human herpes virus-6. These diseases usually affect patients whose immune systems are severely weakened, such as transplant and cancer patients. Montoya, who had used the drug in treating such patients for years, decided to try using it on a CFS patient who came to him in early 2004 with extremely high levels of antibodies for three of the herpes family viruses in her blood. At the time, she had been suffering from CFS for five years.

When a virus infects someone, the levels of antibodies cranked out by the immune system in response typically increase until the virus is overcome, then slowly diminish over time. But Montoya’s patient had persistently high antibodies for the three viruses. In addition, the lymph nodes in her neck were significantly enlarged, some up to eight times their normal size, suggesting her immune system was fighting some kind of infection, even though a comprehensive evaluation had failed to point to any infectious cause.

Concerned about the unusual elevations in antibody levels as well as the swelling of her lymph nodes, Montoya decided to prescribe valganciclovir. “I thought by giving an antiviral that was effective against herpes viruses for a relatively long period of time, perhaps we could impact somehow the inflammation that she had in her lymph nodes,” said Montoya.

Within four weeks, the patient’s lymph nodes began shrinking. Six weeks later she phoned Montoya from her home in South America, describing how she was now exercising, bicycling and going back to work at the company she ran before her illness. “We were really shocked by this,” recalled Montoya.

Of the two dozen patients Montoya and Kogelnik have since treated, the 20 that responded all had developed CFS after an initial flulike illness, while the non-responders had suffered no initial flu.

Some of the patients take the drug for more than six months, such as Michael Manson, whose battle with CFS has lasted more than 18 years. The former triathlete was stricken with a viral infection a year after his marriage. After trying unsuccessfully to overcome what he thought were lingering effects of the flu, he had no choice but to drastically curtail all his activities and eventually stop working.

During his longest period of extreme fatigue, 13 1/2 weeks, Manson said, “My wife literally thought I was passing away. I could hear the emotion in her voice as she tried to wake me, but I couldn’t wake up to console her. That was just maddening.”

Now in his seventh month of treatment, Manson is able to go backpacking with his children with no ill after-effects. Prior to starting the treatment, Manson’s three children, ages 9 to 14, had never seen him healthy.

Montoya and Kogelnik emphasized that even if their new clinical trial validates the use of valganciclovir in treating some CFS patients, the drug may not be effective in all cases. In fact, the trial will assess the effectiveness of the medication among a specific subset of CFS patients; namely, those who have viral-induced dysfunction of the central nervous system.

“This could be a solution for a subset of patients, but that subset could be quite large,” said Kristin Loomis, executive director of the HHV-6 Foundation, which has helped fund a significant portion of the preparatory work for the clinical trial. “These viruses have been suspected in CFS for decades, but researchers couldn’t prove it because they are so difficult to detect in the blood. If Montoya’s results are confirmed, he will have made a real breakthrough.”

“What is desperately needed is the completion of the randomized, double-blind, placebo-controlled clinical trial that we are about to embark on,” Montoya said.

 

Source: Stanford University Medical Center. “New Therapy For Chronic Fatigue Syndrome To Be Tested.” ScienceDaily. ScienceDaily, 9 January 2007. https://www.sciencedaily.com/releases/2007/01/070108191506.htm

 

Metagenomic Investigation of Plasma in Individuals with ME/CFS Highlights the Importance of Technical Controls to Elucidate Contamination and Batch Effects

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating disease causing indefinite fatigue. ME/CFS has long been hypothesised to have an infectious cause; however, no specific infectious agent has been identified.

We used metagenomics to analyse the RNA from plasma samples from 25 individuals with ME/CFS and compare their microbial content to technical controls as well as three control groups: individuals with alternatively diagnosed chronic Lyme syndrome (N = 13), systemic lupus erythematosus (N = 11), and healthy controls (N = 25).

We found that the majority of sequencing reads were removed during host subtraction, thus there was very low microbial RNA content in the plasma. The effects of sample batching and contamination during sample processing proved to outweigh the effects of study group on microbial RNA content, as the few differences in bacterial or viral RNA abundance we did observe between study groups were most likely caused by contamination and batch effects.

Our results highlight the importance of including negative controls in all metagenomic analyses, since there was considerable overlap between bacterial content identified in study samples and control samples. For example, Proteobacteria, Firmicutes, Actinobacteria, and Bacteriodes were found in both study samples and plasma-free negative controls. Many of the taxonomic groups we saw in our plasma-free negative control samples have previously been associated with diseases, including ME/CFS, demonstrating how incorrect conclusions may arise if controls are not used and batch effects not accounted for.

 

Source: Miller RR, Uyaguari-Diaz M, McCabe MN, Montoya V, Gardy JL, Parker S, Steiner T, Hsiao W, Nesbitt MJ, Tang P, Patrick DM; CCD Study Group. Metagenomic Investigation of Plasma in Individuals with ME/CFS Highlights the Importance of Technical Controls to Elucidate Contamination and Batch Effects. PLoS One. 2016 Nov 2;11(11):e0165691. doi: 10.1371/journal.pone.0165691. ECollection 2016. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5091812/ (Full article)

 

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)

 

Right arcuate fasciculus abnormality in chronic fatigue syndrome

Abstract:

PURPOSE: To identify whether patients with chronic fatigue syndrome (CFS) have differences in gross brain structure, microscopic structure, or brain perfusion that may explain their symptoms.

MATERIALS AND METHODS: Fifteen patients with CFS were identified by means of retrospective review with an institutional review board-approved waiver of consent and waiver of authorization. Fourteen age- and sex-matched control subjects provided informed consent in accordance with the institutional review board and HIPAA. All subjects underwent 3.0-T volumetric T1-weighted magnetic resonance (MR) imaging, with two diffusion-tensor imaging (DTI) acquisitions and arterial spin labeling (ASL). Open source software was used to segment supratentorial gray and white matter and cerebrospinal fluid to compare gray and white matter volumes and cortical thickness. DTI data were processed with automated fiber quantification, which was used to compare piecewise fractional anisotropy (FA) along 20 tracks. For the volumetric analysis, a regression was performed to account for differences in age, handedness, and total intracranial volume, and for the DTI, FA was compared piecewise along tracks by using an unpaired t test. The open source software segmentation was used to compare cerebral blood flow as measured with ASL.

RESULTS: In the CFS population, FA was increased in the right arcuate fasciculus (P = .0015), and in right-handers, FA was also increased in the right inferior longitudinal fasciculus (ILF) (P = .0008). In patients with CFS, right anterior arcuate FA increased with disease severity (r = 0.649, P = .026). Bilateral white matter volumes were reduced in CFS (mean ± standard deviation, 467 581 mm(3) ± 47 610 for patients vs 504 864 mm(3) ± 68 126 for control subjects, P = .0026), and cortical thickness increased in both right arcuate end points, the middle temporal (T = 4.25) and precentral (T = 6.47) gyri, and one right ILF end point, the occipital lobe (T = 5.36). ASL showed no significant differences.

CONCLUSION: Bilateral white matter atrophy is present in CFS. No differences in perfusion were noted. Right hemispheric increased FA may reflect degeneration of crossing fibers or strengthening of short-range fibers. Right anterior arcuate FA may serve as a biomarker for CFS.

(©) RSNA, 2014.

 

Source: Zeineh MM, Kang J, Atlas SW, Raman MM, Reiss AL, Norris JL, Valencia I, Montoya JG. Right arcuate fasciculus abnormality in chronic fatigue syndrome. Radiology. 2015 Feb;274(2):517-26. doi: 10.1148/radiol.14141079. Epub 2014 Oct 29. https://www.ncbi.nlm.nih.gov/pubmed/25353054

 

Randomized clinical trial to evaluate the efficacy and safety of valganciclovir in a subset of patients with chronic fatigue syndrome

Abstract:

There is no known treatment for chronic fatigue syndrome (CFS). Little is known about its pathogenesis. Human herpesvirus 6 (HHV-6) and Epstein-Barr virus (EBV) have been proposed as infectious triggers.

Thirty CFS patients with elevated IgG antibody titers against HHV-6 and EBV were randomized 2:1 to receive valganciclovir (VGCV) or placebo for 6 months in a double-blind, placebo-controlled trial. Clinical endpoints aimed at measuring physical and mental fatigue included the Multidimensional Fatigue Inventory (MFI-20) and Fatigue Severity Scale (FSS) scores, self-reported cognitive function, and physician-determined responder status. Biological endpoints included monocyte and neutrophil counts and cytokine levels.

VGCV patients experienced a greater improvement by MFI-20 at 9 months from baseline compared to placebo patients but this difference was not statistically significant. However, statistically significant differences in trajectories between groups were observed in MFI-20 mental fatigue subscore (P = 0.039), FSS score (P = 0.006), and cognitive function (P = 0.025). VGCV patients experienced these improvements within the first 3 months and maintained that benefit over the remaining 9 months. Patients in the VGCV arm were 7.4 times more likely to be classified as responders (P = 0.029). In the VGCV arm, monocyte counts decreased (P < 0.001), neutrophil counts increased (P = 0.037) and cytokines were more likely to evolve towards a Th1-profile (P < 0.001). Viral IgG antibody titers did not differ between arms.

VGCV may have clinical benefit in a subset of CFS patients independent of placebo effect, possibly mediated by immunomodulation and/or antiviral effect. Further investigation with longer treatment duration and a larger sample size is warranted.

TRIAL REGISTRATION: ClinicalTrials.gov NCT00478465.

© 2013 Wiley Periodicals, Inc.

 

Source: Montoya JG, Kogelnik AM, Bhangoo M, Lunn MR, Flamand L, Merrihew LE, Watt T, Kubo JT, Paik J, Desai M. Randomized clinical trial to evaluate the efficacy and safety of valganciclovir in a subset of patients with chronic fatigue syndrome. J Med Virol. 2013 Dec;85(12):2101-9. doi: 10.1002/jmv.23713. Epub 2013 Aug 19. https://www.ncbi.nlm.nih.gov/pubmed/23959519

 

Daily cytokine fluctuations, driven by leptin, are associated with fatigue severity in chronic fatigue syndrome: evidence of inflammatory pathology

Abstract:

BACKGROUND: Chronic fatigue syndrome (CFS) is a debilitating disorder characterized by persistent fatigue that is not alleviated by rest. The lack of a clearly identified underlying mechanism has hindered the development of effective treatments. Studies have demonstrated elevated levels of inflammatory factors in patients with CFS, but findings are contradictory across studies and no biomarkers have been consistently supported. Single time-point approaches potentially overlook important features of CFS, such as fluctuations in fatigue severity. We have observed that individuals with CFS demonstrate significant day-to-day variability in their fatigue severity.

METHODS: Therefore, to complement previous studies, we implemented a novel longitudinal study design to investigate the role of cytokines in CFS pathophysiology. Ten women meeting the Fukuda diagnostic criteria for CFS and ten healthy age- and body mass index (BMI)-matched women underwent 25 consecutive days of blood draws and self-reporting of symptom severity. A 51-plex cytokine panel via Luminex was performed for each of the 500 serum samples collected. Our primary hypothesis was that daily fatigue severity would be significantly correlated with the inflammatory adipokine leptin, in the women with CFS and not in the healthy control women. As a post-hoc analysis, a machine learning algorithm using all 51 cytokines was implemented to determine whether immune factors could distinguish high from low fatigue days.

RESULTS: Self-reported fatigue severity was significantly correlated with leptin levels in six of the participants with CFS and one healthy control, supporting our primary hypothesis. The machine learning algorithm distinguished high from low fatigue days in the CFS group with 78.3% accuracy.

CONCLUSIONS: Our results support the role of cytokines in the pathophysiology of CFS.

 

Source: Stringer EA, Baker KS, Carroll IR, Montoya JG, Chu L, Maecker HT, Younger JW. Daily cytokine fluctuations, driven by leptin, are associated with fatigue severity in chronic fatigue syndrome: evidence of inflammatory pathology. J Transl Med. 2013 Apr 9;11:93. doi: 10.1186/1479-5876-11-93. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3637529/ (Full article)

 

Response to valganciclovir in chronic fatigue syndrome patients with human herpesvirus 6 and Epstein-Barr virus IgG antibody titers

Abstract:

Valganciclovir has been reported to improve physical and cognitive symptoms in patients with chronic fatigue syndrome (CFS) with elevated human herpesvirus 6 (HHV-6) and Epstein-Barr virus (EBV) IgG antibody titers. This study investigated whether antibody titers against HHV-6 and EBV were associated with clinical response to valganciclovir in a subset of CFS patients.

An uncontrolled, unblinded retrospective chart review was performed on 61 CFS patients treated with 900 mg valganciclovir daily (55 of whom took an induction dose of 1,800 mg daily for the first 3 weeks). Antibody titers were considered high if HHV-6 IgG ≥ 1:320, EBV viral capsid antigen (VCA) IgG ≥ 1:640, and EBV early antigen (EA) IgG ≥ 1:160. Patients self-rated physical and cognitive functioning as a percentage of their functioning prior to illness. Patients were categorized as responders if they experienced at least 30% improvement in physical and/or cognitive functioning. Thirty-two patients (52%) were categorized as responders. Among these, 19 patients (59%) responded physically and 26 patients (81%) responded cognitively. Baseline antibody titers showed no significant association with response.

After treatment, the average change in physical and cognitive functioning levels for all patients was +19% and +23%, respectively (P < 0.0001). Longer treatment was associated with improved response (P = 0.0002). No significant difference was found between responders and non-responders among other variables analyzed. Valganciclovir treatment, independent of the baseline antibody titers, was associated with self-rated improvement in physical and cognitive functioning for CFS patients who had positive HHV-6 and/or EBV serologies. Longer valganciclovir treatment correlated with an improved response.

Copyright © 2012 Wiley Periodicals, Inc.

 

Source: Watt T, Oberfoell S, Balise R, Lunn MR, Kar AK, Merrihew L, Bhangoo MS, Montoya JG. Response to valganciclovir in chronic fatigue syndrome patients with human herpesvirus 6 and Epstein-Barr virus IgG antibody titers. J Med Virol. 2012 Dec;84(12):1967-74. doi: 10.1002/jmv.23411. https://www.ncbi.nlm.nih.gov/pubmed/23080504

 

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)

 

Use of valganciclovir in patients with elevated antibody titers against Human Herpesvirus-6 (HHV-6) and Epstein-Barr Virus (EBV) who were experiencing central nervous system dysfunction including long-standing fatigue

Abstract:

BACKGROUND:Twelve patients with long-standing symptoms of central nervous system (CNS) dysfunction were found to have elevated antibody titres to human herpesvirus-6 (HHV-6) and Epstein-Barr virus (EBV). All patients had four or more of the following neurocognitive symptoms: impaired cognitive functioning, slowed processing speed, sleep disturbance, short-term memory deficit, fatigue and symptoms consistent with depression.

OBJECTIVES: We sought to determine whether elevated antibodies to EBV and HHV-6 indicated chronic viral activation in patients with CNS dysfunction and if their symptoms could be improved by suppressing viral activity with oral valganciclovir.

STUDY DESIGN: Patients with high IgG antibody titers against HHV-6 and EBV who were suffering from central nervous system dysfunction and debilitating fatigue for more than one year (median 3 years, range 1-8 years) were treated with 6 months of valganciclovir in an open label study.

RESULTS: Nine out of 12 (75%) patients experienced near resolution of their symptoms, allowing them all to return to the workforce or full time activites. In the nine patients with a symptomatic response to treatment, EBV VCA IgG titers dropped from 1:2560 to 1:640 (p = 0.008) and HHV-6 IgG titers dropped from a median value of 1:1280 to 1:320 (p = 0.271). Clinically significant hematological toxicity or serious adverse events were not observed among the 12 patients.

CONCLUSION: These preliminary clinical and laboratory observations merit additional studies to establish whether this clinical response is mediated by an antiviral effect of the drug, indirectly via immunomodulation or by placebo effect.

 

Source: Kogelnik AM, Loomis K, Hoegh-Petersen M, Rosso F, Hischier C, Montoya JG. Use of valganciclovir in patients with elevated antibody titers against Human Herpesvirus-6 (HHV-6) and Epstein-Barr Virus (EBV) who were experiencing central nervous system dysfunction including long-standing fatigue. J Clin Virol. 2006 Dec;37 Suppl 1:S33-8. https://www.ncbi.nlm.nih.gov/pubmed/17276366