Tag: Montoya

KPAX002 as a treatment for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): a prospective, randomized trial

Abstract:

Mitochondrial dysfunction and a hypometabolic state are present in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). KPAX002 consists of low-dose methylphenidate hydrochloride to treat a hypometabolic state combined with key micronutrients intended to broadly support mitochondrial function.

The objective of this study was to evaluate KPAX002 as a treatment for fatigue and concentration disturbance symptoms in ME/CFS subjects. This phase 2 randomized, double-blinded, placebo-controlled trial was conducted at 4 sites in the United States. A total of 135 subjects with ME/CFS were randomly assigned to either KPAX002 (n=67) or placebo (n=68) for 12 weeks of treatment. The primary endpoint was change in the Checklist Individual Strength (CIS) total score from baseline to Week 12. Secondary measurements included visual analog scales for fatigue and concentration disturbance symptoms.

In the intent-to-treat population, the mean reduction in the CIS total score from baseline to week 12 for the KPAX002 and placebo groups was -16.9 (± 23.52) and -13.8 (± 22.15), respectively (95% confidence interval, -11.1, 4.0; P=0.359). On the visual analog scale for fatigue, the mean reduction from baseline to week 12 was -18.2 mm (± 25.05) and -11.1 mm (± 22.08) for the KPAX002 and placebo groups, respectively (95% confidence interval, -11.5, 2.3; P=0.189). The two groups demonstrating the most robust response to KPAX002 were subjects with more severe ME/CFS symptoms at baseline (P=0.086) and subjects suffering from both fatigue and pain (P=0.057). The incidence of adverse events was not statistically different between the two groups.

Treatment with KPAX002 resulted in a reduction in fatigue and concentration disturbance symptoms in multiple analyses. Two key subgroups of patients whose response approached statistical significance were identified.

Source: Jose G Montoya, Jill N Anderson, Danya L Adolphs, Lucinda Bateman, Nancy Klimas, Susan M Levine, Donn W Garvert, Jon D Kaiser. KPAX002 as a treatment for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): a prospective, randomized trial. Int J Clin Exp Med 2018;11(3):2890-2900 www.ijcem.com /ISSN:1940-5901/IJCEM0065685 (Full article)

Value of Circulating Cytokine Profiling During Submaximal Exercise Testing in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Myalgic Encephalomyelitis or Chronic Fatigue Syndrome (ME/CFS) is a heterogeneous syndrome in which patients often experience severe fatigue and malaise following exertion. Immune and cardiovascular dysfunction have been postulated to play a role in the pathophysiology. We therefore, examined whether cytokine profiling or cardiovascular testing following exercise would differentiate patients with ME/CFS.

Twenty-four ME/CFS patients were matched to 24 sedentary controls and underwent cardiovascular and circulating immune profiling. Cardiovascular analysis included echocardiography, cardiopulmonary exercise and endothelial function testing. Cytokine and growth factor profiles were analyzed using a 51-plex Luminex bead kit at baseline and 18 hours following exercise. Cardiac structure and exercise capacity were similar between groups.

Sparse partial least square discriminant analyses of cytokine profiles 18 hours post exercise offered the most reliable discrimination between ME/CFS and controls (κ = 0.62(0.34,0.84)). The most discriminatory cytokines post exercise were CD40L, platelet activator inhibitor, interleukin 1-β, interferon-α and CXCL1. In conclusion, cytokine profiling following exercise may help differentiate patients with ME/CFS from sedentary controls.

Source: Kegan J. Moneghetti, Mehdi Skhiri, Kévin Contrepois, Yukari Kobayashi, Holden Maecker, Mark Davis, Michael Snyder, Francois Haddad & Jose G. Montoya. Value of Circulating Cytokine Profiling During Submaximal Exercise Testing in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Scientific Reports volume 8, Article number: 2779 (2018). doi:10.1038/s41598-018-20941-w. Received:02 November 2017. Accepted:26 January 2018. Published online:09 February 2018. https://www.nature.com/articles/s41598-018-20941-w (Full article)

Cytokine signature associated with disease severity in chronic fatigue syndrome patients

Abstract:

Although some signs of inflammation have been reported previously in patients with myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS), the data are limited and contradictory. High-throughput methods now allow us to interrogate the human immune system for multiple markers of inflammation at a scale that was not previously possible.

To determine whether a signature of serum cytokines could be associated with ME/CFS and correlated with disease severity and fatigue duration, cytokines of 192 ME/CFS patients and 392 healthy controls were measured using a 51-multiplex array on a Luminex system. Each cytokine’s preprocessed data were regressed on ME/CFS severity plus covariates for age, sex, race, and an assay property of newly discovered importance: nonspecific binding.

On average, TGF-β was elevated (P = 0.0052) and resistin was lower (P = 0.0052) in patients compared with controls. Seventeen cytokines had a statistically significant upward linear trend that correlated with ME/CFS severity: CCL11 (Eotaxin-1), CXCL1 (GROα), CXCL10 (IP-10), IFN-γ, IL-4, IL-5, IL-7, IL-12p70, IL-13, IL-17F, leptin, G-CSF, GM-CSF, LIF, NGF, SCF, and TGF-α. Of the 17 cytokines that correlated with severity, 13 are proinflammatory, likely contributing to many of the symptoms experienced by patients and establishing a strong immune system component of the disease. Only CXCL9 (MIG) inversely correlated with fatigue duration.

Source: Montoya JG, Holmes TH, Anderson JN, Maecker HT, Rosenberg-Hasson Y, Valencia IJ, Chu L, Younger JW, Tato CM, Davis MM. Cytokine signature associated with disease severity in chronic fatigue syndrome patients. Proc Natl Acad Sci U S A. 2017 Jul 31. pii: 201710519. doi: 10.1073/pnas.1710519114. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/28760971

Fecal metagenomic profiles in subgroups of patients with myalgic encephalomyelitis/chronic fatigue syndrome

 

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by unexplained persistent fatigue, commonly accompanied by cognitive dysfunction, sleeping disturbances, orthostatic intolerance, fever, lymphadenopathy, and irritable bowel syndrome (IBS). The extent to which the gastrointestinal microbiome and peripheral inflammation are associated with ME/CFS remains unclear. We pursued rigorous clinical characterization, fecal bacterial metagenomics, and plasma immune molecule analyses in 50 ME/CFS patients and 50 healthy controls frequency-matched for age, sex, race/ethnicity, geographic site, and season of sampling.

Results: Topological analysis revealed associations between IBS co-morbidity, body mass index, fecal bacterial composition, and bacterial metabolic pathways but not plasma immune molecules. IBS co-morbidity was the strongest driving factor in the separation of topological networks based on bacterial profiles and metabolic pathways. Predictive selection models based on bacterial profiles supported findings from topological analyses indicating that ME/CFS subgroups, defined by IBS status, could be distinguished from control subjects with high predictive accuracy. Bacterial taxa predictive of ME/CFS patients with IBS were distinct from taxa associated with ME/CFS patients without IBS.

Increased abundance of unclassified Alistipes and decreased Faecalibacterium emerged as the top biomarkers of ME/CFS with IBS; while increased unclassified Bacteroides abundance and decreased Bacteroides vulgatus were the top biomarkers of ME/CFS without IBS. Despite findings of differences in bacterial taxa and metabolic pathways defining ME/CFS subgroups, decreased metabolic pathways associated with unsaturated fatty acid biosynthesis and increased atrazine degradation pathways were independent of IBS co-morbidity. Increased vitamin B6 biosynthesis/salvage and pyrimidine ribonucleoside degradation were the top metabolic pathways in ME/CFS without IBS as well as in the total ME/CFS cohort. In ME/CFS subgroups, symptom severity measures including pain, fatigue, and reduced motivation were correlated with the abundance of distinct bacterial taxa and metabolic pathways.

Conclusions: Independent of IBS, ME/CFS is associated with dysbiosis and distinct bacterial metabolic disturbances that may influence disease severity. However, our findings indicate that dysbiotic features that are uniquely ME/CFS-associated may be masked by disturbances arising from the high prevalence of IBS co-morbidity in ME/CFS. These insights may enable more accurate diagnosis and lead to insights that inform the development of specific therapeutic strategies in ME/CFS subgroups.

 

Source: Dorottya Nagy-Szakal, Brent L. Williams, Nischay Mishra, Xiaoyu Che, Bohyun Lee, Lucinda Bateman, Nancy G. Klimas, Anthony L. Komaroff, Susan Levine, Jose G. Montoya, Daniel L. Peterson, Devi Ramanan, Komal Jain, Meredith L. Eddy, Mady Hornig and W. Ian Lipkin. Fecal metagenomic profiles in subgroups of patients with myalgic encephalomyelitis/chronic fatigue syndrome. Microbiome20175:44. DOI: 10.1186/s40168-017-0261-y https://microbiomejournal.biomedcentral.com/articles/10.1186/s40168-017-0261-y#MOESM1 (Full article)

 

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

 

Brain abnormalities found in chronic fatigue patients

An imaging study by Stanford University School of Medicine investigators has found distinct differences between the brains of patients with chronic fatigue syndrome and those of healthy people.

The findings could lead to more definitive diagnoses of the syndrome and may also point to an underlying mechanism in the disease process.

It’s not uncommon for CFS patients to face several mischaracterizations of their condition, or even suspicions of hypochondria, before receiving a diagnosis of CFS. The abnormalities identified in the study, to be published Oct. 29 in Radiology, may help to resolve those ambiguities, said lead author Michael Zeineh, MD, PhD, assistant professor of radiology.

“Using a trio of sophisticated imaging methodologies, we found that CFS patients’ brains diverge from those of healthy subjects in at least three distinct ways,” Zeineh said.

CFS affects between 1 million and 4 million individuals in the United States and millions more worldwide. Coming up with a more precise number of cases is tough because it’s difficult to actually diagnose the disease. While all CFS patients share a common symptom — crushing, unremitting fatigue that persists for six months or longer — the additional symptoms can vary from one patient to the next, and they often overlap with those of other conditions.

Scientific Challenge

“CFS is one of the greatest scientific and medical challenges of our time,” said the study’s senior author, Jose Montoya, MD, professor of infectious diseases and geographic medicine. “Its symptoms often include not only overwhelming fatigue but also joint and muscle pain, incapacitating headaches, food intolerance, sore throat, enlargement of the lymph nodes, gastrointestinal problems, abnormal blood-pressure and heart-rate events, and hypersensitivity to light, noise or other sensations.”

The combination of symptoms can devastate a patient’s life for 10, 20 or even 30 years, said Montoya, who has been following 200 CFS patients for several years in an effort to identify the syndrome’s underlying mechanisms. He hopes to accelerate the development of more-effective treatments than now exist. (A new Stanford Medicine magazine story describes the study in more detail.)

“In addition to potentially providing the CFS-specific diagnostic biomarker we’ve been desperately seeking for decades, these findings hold the promise of identifying the area or areas of the brain where the disease has hijacked the central nervous system,” Montoya said.

“If you don’t understand the disease, you’re throwing darts blindfolded,” said Zeineh. “We asked ourselves whether brain imaging could turn up something concrete that differs between CFS patients’ and healthy people’s brains. And, interestingly, it did.”

The Stanford investigators compared brain images of 15 CFS patients chosen from the group Montoya has been following to those of 14 age- and sex-matched healthy volunteers with no history of fatigue or other conditions causing symptoms similar to those of CFS.

Three Key Findings

The analysis yielded three noteworthy results, the researchers said. First, an MRI showed that overall white-matter content of CFS patients’ brains, compared with that of healthy subjects’ brains, was reduced. The term “white matter” largely denotes the long, cablelike nerve tracts carrying signals among broadly dispersed concentrations of “gray matter.” The latter areas specialize in processing information, and the former in conveying the information from one part of the brain to another.

That finding wasn’t entirely unexpected, Zeineh said. CFS is thought to involve chronic inflammation, quite possibly as a protracted immunological response to an as-yet unspecified viral infection. Inflammation, meanwhile, is known to take a particular toll on white matter.

But a second finding was entirely unexpected. Using an advanced imaging technique — diffusion-tensor imaging, which is especially suited to assessing the integrity of white matter — Zeineh and his colleagues identified a consistent abnormality in a particular part of a nerve tract in the right hemisphere of CFS patients’ brains. This tract, which connects two parts of the brain called the frontal lobe and temporal lobe, is called the right arcuate fasciculus, and in CFS patients it assumed an abnormal appearance.

Furthermore, there was a fairly strong correlation between the degree of abnormality in a CFS patient’s right arcuate fasciculus and the severity of the patient’s condition, as assessed by performance on a standard psychometric test used to evaluate fatigue.

Right vs. Left

Although the right arcuate fasciculus’s function is still somewhat mysterious, its counterpart in the brain’s left hemisphere has been extensively explored. The left arcuate fasciculus connects two critical language areas of the left side of the brain termed Wernicke’s and Broca’s areas, which are gray-matter structures several centimeters apart. These two structures are important to understanding and generating speech, respectively. Right-handed people almost always have language organized in this fashion exclusively in the left side of the brain, but the precise side (left or right) and location of speech production and comprehension are not so clear-cut in left-handed people. (It’s sometimes said that every left-hander’s brain is a natural experiment.) So, pooling left- and right-handed people’s brain images can be misleading. And, sure enough, the finding of an abnormality in the right arcuate fasciculus, pronounced among right-handers, was murky until the two left-handed patients and four left-handed control subjects’ images were exempted from the analysis.

Bolstering these observations was the third finding: a thickening of the gray matter at the two areas of the brain connected by the right arcuate fasciculus in CFS patients, compared with controls. Its correspondence with the observed abnormality in the white matter joining them makes it unlikely that the two were chance findings, Zeineh said.

Although these results were quite robust, he said, they will need to be confirmed. “This study was a start,” he said. “It shows us where to look.” The Stanford scientists are in the planning stages of a substantially larger study.

 

Source: Stanford University Medical Center. “Brain abnormalities found in chronic fatigue patients.” ScienceDaily. ScienceDaily, 29 October 2014.  https://www.sciencedaily.com/releases/2014/10/141029084118.htm

 

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