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From the Tahoe Outbreak to COVID-19 Dr. Peterson and Simmaron Take on the Coronavirus – and ME/CFS

“Testing is so important to everyone in our community, especially front-line workers and people who are at higher risk of severe disease. Simmaron is excited to serve our neighbors and lead the way to broader testing, so we help keep Nevada safe and learn more about this outbreak.” Courtney Miller, President of Simmaron’s Board.

Peterson COVID-19

COVID-19 brought Dr. Peterson’s mind back to the first infectious disease outbreak he’d encountered – the 1984 Incline outbreak – which helped introduce ME/CFS to the U.S.

As Dr. Daniel Peterson watched an infectious disease outbreak bear down on his community like a freight train, his mind flashed back to a time, almost over 35 years ago, when a mysterious infectious event had sent scores of sick people to his office.

The pathogen in what became the infamous 1984 Incline Village outbreak, which helped to put chronic fatigue syndrome (ME/CFS) on the map, has never been definitively identified. The inability to identify it has had significant ramifications: the patients weren’t believed and the paltry CDC investigation chalked their symptoms up to hysteria.

Being able to identify the original pathogen could have changed much for those involved and for how the disease was portrayed. Decades later, some of those afflicted still remain ill with chronic fatigue syndrome (ME/CFS). Theirs and Dr. Peterson’s lives took a course change that no one could have anticipated.

Since then Dr. Peterson focused specifically on the post-infectious cohort of ME/CFS patients. He was one of the few doctors to use Ampligen – an immune modulator – and introduced the use of the powerful antiviral Vistide to the field. He brought decades of experience dealing with post-infectious illnesses to the formation of the Simmaron Research Foundation ten years ago.

Report From Paris: Peterson Reports Antiviral (Vistide) Effective in Treating Herpesvirus Infected Chronic Fatigue Syndrome (ME/CFS) Patients

In the decade since, at the core of Dr. Peterson and Simmaron’s research has been a unique collaboration with Columbia University’s Center for Infection and Immunity (CII), led by Dr. Ian Lipkin. CII’s Dr. Mady Hornig is also a member of Simmaron’s Scientific Advisory Board.

Together, they have published 8 peer-reviewed manuscripts assessing the immune response across blood, spinal fluid and microbiota, identifying multiple subsets of ME/CFS and characterizing post-infectious immune patterns. The NIH’s current intramural study of ME/CFS focused on post-infectious patients is an overdue but pivotal, and it turns out timely, acknowledgment of the role of infection in triggering this chronic disease.

Dr Nath Talks on the ME/CFS NIH Intramural Study

Thirty-five years after Tahoe’s CFS outbreak much has changed. We have technologies that can identify a pathogen almost in the blink of an eye. The identity of the SARS-CoV-2 virus hasn’t been in doubt since early January.

Some issues remain however. The low coronavirus testing capability in the North Tahoe region meant that even today many, probably most people infected with the virus, were not going to get tested – leaving them in anxious limbo, tying Dr. Peterson’s hands to some extent, and leaving a key question unanswered.

Catching it in the Act

This time the coronavirus offered the opportunity to catch ME/CFS in the act.

This time the coronavirus offered the opportunity to catch ME/CFS in the act.

That question involved ME/CFS. Peterson knew that COVID-19 – the illness associated with the SARS-CoV-2 virus – was likely to birth an immense ME/CFS cohort. This time the outbreak presented a unique opportunity to catch the process of coming down with ME/CFS in the act. It also presented an opportunity to educate a whole generation of doctors about post-infectious illnesses and ME/CFS.

That could only really happen, though, if Dr. Peterson and other doctors and researchers knew their patients had been infected with the coronavirus. COVID-19, after all, will be taken seriously. The common cold will not. It was critical, therefore, to get people tested.

Just as inadequate testing tied Peterson’s hands almost 40 years ago, shortages in vital test kit components were tying his hands today.

Solving the Testing Snafu

What to do? Dr. Peterson and the Simmaron Research Foundation had formed a strong connection with Coppe Labs – an FDA CLIA certified pathogen testing lab with high-complexity clinical testing status.  The founder of the lab, Dr. Konstance Knox, actually sits on the Simmaron Research Foundation’s Scientific Advisory Board. Dr. Knox has been testing ME/CFS patients for viral infection, reactivation and antibodies for decades.

Coppe labs

Dr. Peterson, the Simmaron Research Foundation and Coppe labs collaborated to bring a new coronavirus test to the North Tahoe region.

Peterson, Simmaron staff, and Knox brainstormed. The nasopharyngeal swabs currently being used to identify the virus were available but the viral media they needed to be placed in was not.  But what about the urogenital swabs being used for some rapid polymerase chain reaction test (PCR) testing? They could be shipped frozen in saline to labs for testing.

An application for an Emergency Use Authorization (EUA) from the Food and Drug Administration to collect and test samples using that technique was granted. So was an application to provide an IgG antibody test.

Gunnar Gottschalk, PhD, Simmaron’s Clinical Research Director and emerging scientist trained by Dr. Peterson, Simmaron and Rush University, led the effort.

“The supply chain crisis has severely hindered the nation’s COVID-19 testing capability. We repurposed materials and sought a creative solution which helped our collaborative team achieve FDA authorization rather quickly for both the PCR and the IgG antibody test. This ingenuity, along with the hard work of our research staff, places us in a position to be the leader for COVID-19 testing in Northern Nevada.”

Over the past several weeks, over 500 people have been tested in the Tahoe area for the virus. Since getting approval, the Simmaron Research Foundation has been seeking local funding to allow it to test economically disadvantaged residents.

This Time It’s Different

This time it’s different.  Many of those sickened by the virus will not have to live in limbo. Doctors will be able to follow COVID-19 treatment guidelines knowing that their patients actually have COVID-19. Doctors will be able to treat patients and track their stages of recovery without being ostracized or looked down up. Simmaron can help elucidate the long term impacts of this virus and use that to inform our understanding of chronic ME/CFS.

This time, if pandemic patients develop ME/CFS, doctors will know they did so not because of an unidentified, usually benign cold virus but because of COVID-19 – a fearsome pathogen we know can wreak havoc on many systems of the body. They won’t be able to sweep ME/CFS under the rug with claims of hysteria, depression or somatization like they did 35 years ago.

Knowing COVID-19 is involved is a potential game changer not just for the patients who have trouble recovering, and the doctors treating them, but for the field of ME/CFS itself. The opportunity exists for this disease to finally be taken seriously.

Finally, it shouldn’t pass notice that simply by taking center stage in the Northern Tahoe COVID-19 testing effort, the Simmaron Research Foundation – which is devoted to understanding and treating ME/CFS – is spreading the word on ME/CFS and publicly rooting it in the science of post-viral disease – something the world is likely soon to become all too familiar with.

To learn more about Simmaron Research’s COVID-19 testing effort:

Email: covid19@simmaron.com
Visit: simmaronresearch.com

To donate to Simmaron Research, visit: https://donatenow.networkforgood.org/SimmaronResearch

A Never-Ending Immune Battle in ME/CFS? The Regulatory T-cell / Herpesvirus Hypothesis

The failed Rituximab trial might seem like the death knell for autoimmunity in chronic fatigue syndrome (ME/CFS) but it’s not – not by a long shot. While the B-cells that Rituximab targeted are at the heart of much autoimmunity, T-cells can also cause autoimmune diseases. They also play a very important role in stopping infections.

Nuno Sepulveda

Once Sepúlveda, a theoretical immunologist, learned about ME/CFS he knew he had to be involved.

This interesting paper, conceived and led by a Portuguese researcher named Nuno Sepúlveda, PhD suggests that both options are on the table in ME/CFS. He proposes that a battle between a subset of T-cells called regulatory T cells (Tregs) and herpesviruses may be causing ME/CFS.

Nuno Sepúlveda’s PhD is in theoretical immunology, and he’s on the faculty of the London School of Hygiene and Tropical Medical.

The study, the third Sepúlveda has co-authored on ME/CFS, is the tale of both a new hypothesis and a new researcher entering the field.

I asked Sepúlveda how he got involved.

My interest in ME/CFS and the conception of this research came a bit by chance as most things in life. I am a statistician by training but I did a PhD project on theoretical immunology in Gulbenkian Institute for Science in the outskirts of Lisbon. In my PhD theory (supervised by Dr Jorge Carneiro, second author of the paper), I developed mathematical theories on how regulatory T cells regulate autoimmunity throughout life; these cells are thought to be master regulators of the adaptive immune system.

In my post-doctoral research, I was a statistical geneticist and a biostatistician doing research in genetics, immunology and epidemiology of tropical and infectious diseases.

Along the way I met Luis Nacul and Eliana Lacerda (we are all from the same faculty/institution) who asked me to help them with the statistical analysis of UK biobank data.

One day I came across a review paper about autoimmunity and ME/CFS, and I got amazed that no one had done a comprehensive assessment of the role of regulatory T cells on ME/CFS.  So I thought to resuscitate my old work on regulatory T cells and give it a go. Then I got hooked up in the field.

We can see how this field widens. Luis Nacul PhD, the senior author of the study, has spent much of his career deeply embedded in ME/CFS. The former leader of the CureME team at the London School of Hygiene and Tropical Medicine, as well as the UK ME/CFS biobank, Nacul is now the Medical and Research Director of the Complex Chronic Diseases Program at BC Women’s Hospital in Vancouver, Canada. He enrolled Sepulveda in taking on ME/CFS.

The Model

“Given this observation, one can hypothesize that these (ME/CFS) patients might be healthy individuals who, by chance, were infected with a microorganism with a strong molecular mimicry to a human protein.” Sepúlveda et. al.

Nuno Sepúlveda 1 2Jorge Carneiro 3Eliana Lacerda 4Luis Nacul 4 Myalgic Encephalomyelitis/Chronic Fatigue Syndrome as a Hyper-Regulated Immune System Driven by an Interplay Between Regulatory T Cells and Chronic Human Herpesvirus Infections. Frontiers in Immunology.   eCollection 

The story begins with the infectious onset that many people with ME/CFS experience. The ferocious immune response that pathogens evoke puts a strain on the immune system’s regulatory processes. The “policeman” of the immune system  – the regulatory T or Treg cells – are tasked with ensuring that the immune system in its frenzy doesn’t run amok and start attacking the human body.
Regulatory T-cell (Treg) (red) cosying up to an antigen (blue)

Regulatory T-cell (Treg) (red) cosying up to an antigen (blue)

It’s an inexact science. As with any complex system, the immune system walks a fine line between too much and too little regulation. Too much suppression by the Tregs will impair the immune system’s ability to fight off invaders, while too little suppression could result in autoimmunity. Each of us is genetically predisposed one way or the other.

People genetically predisposed to more Treg activity would be better at suppressing autoimmunity, but they might also be more prone to letting infections flourish when their Treg cells mistake the pathogenic antigens as self –  and call off the immune response.

Other individuals predisposed to less Treg activity might be more effective at wiping our pathogens, but more prone to developing autoimmunity. (Since infections, evolutionarily speaking, are more destructive, the authors believe this subset might be more prevalent.)

The big question is where do people with ME/CFS fit in?  On the one hand, many of their symptoms mimic those found in autoimmune diseases – suggesting they may be immunologically predisposed to have an overly strong immune response to pathogens but are poor regulators of that response.

On the other, many people come down with ME/CFS in response to an infection – which suggests they weren’t all that good at fighting off pathogens.

The Third Way – the ME/CFS Way?

There is a third way, though – a kind of a worst of both worlds way –  and that’s what this group’s mathematical modeling, the first of its kind done in ME/CFS, uncovered. If the authors are right it could explain why people with ME/CFS are in such a fix.

The Herpesviruses

The authors demonstrated how such a situation could happen by modeling the effect of herpesviruses on the T regulatory cells in ME/CFS in different immunological contexts.

HHV-6

Using HHV-6, the authors proposed that an ME/CFS state could occur when a smoldering infection is responded to by a T-cell clone with a high potential for producing an autoimmune state.

T-cell clones are populations of T-cells which contain both T regulatory cells and T effector (helper) cells.  Because their composition reflects the immune milieu around them, a T-cell clone with a high autoimmune potential reflects a T-cell clone existing in an environment loaded with self-antigens; i.e. antigens from a pathogen which look like they come from humans. In this example, an HHV-6 infection producing many self-like antigens is present.

Because the infection is smoldering and the viral load is low, though, the full T-helper immune response which would serve to stop the infection is not initiated.  Nor do the T regulatory cells fully step in to ward off an autoimmune response.

Instead, the virus, replicating slowly, triggers both responses. As the Treg cells tamp down the chronic immune response, they also shut down the the cytotoxic NK cells. With the immune system not geared up in either direction, the smoldering infection continues in perpetuity causing high energy costs as well as inflammation and fatigue, and there you have it – a metabolically exhausting state of inflammation and fatigue; i.e. ME/CFS.

Epstein-Barr Virus

A similar situation may occur with EBV when a Treg clone with a high autoimmune potential co-occurs with a low T-cell killing rate.  Instead of a blatant autoimmune response that racks the body, or an effective response to the pathogen, you get partial amounts of both: you get both a sucky immune response to a pathogen AND an autoreactive reaction.  If the authors are right it’s no wonder ME/CFS is such a puzzle and so difficult to treat.

How do the authors believe this shows up biologically? In a high density of and increased percentage of Treg cells in ME/CFS patients compared to healthy controls and people with autoimmune diseases. That’s actually what they see in their ME/CFS patients in their lab.

Different Roads Taken

Interestingly, the authors believe both autoimmune diseases and ME/CFS start off the same path – both are triggered by the cumulative effects of an autoreactive response to a common viral infection – but then both flit off on different paths.

Treg cells immune response

The ways Treg cells tamp down the immune response

Herpesviruses may be setting off autoimmune reactions in both autoimmune diseases and ME/CFS, but in ME/CFS the Treg cells kick in to dampen down the autoimmune response.

Unfortunately, as they’re doing that they’re also bollixing up the immune response to the pathogen – leaving ME/CFS patients in the strange state of both defending against a pathogen and trying to dampen down an autoimmune response at the same time – a metabolically exhausting situation.

The authors believe that a genetic predisposition affecting T-cells would probably be present in ME/CFS, and pointed to genetic polymorphisms that have been found.  Defective T-cell responses to Epstein-Barr Virus have also been found in ME/CFS. Further study of the T-cell repertoires in ME/CFS are needed, though, as well as studies to validate whether Treg density and percentages are increased in ME/CFS.

T-cells – perhaps the single most impactful immune cell in the body – have become the focus of interest of a number of other ME/CFS researchers including Derya Unutmaz at the Jackson Labs, and Mark Davis at Stanford.

Smoldering viral infections have also become a hot topic in ME/CFS. Bob Naviaux and Bhupesh Prusty propose a smoldering HHV-6 infection, and Marshall Williams proposes a smoldering Epstein-Barr infection may be present in ME/CFS, as well.

A Further Widening Field

The “widening” of the ME/CFS field is continuing with Sepúlveda. When I asked him what he’s working on next he reported he was bringing new researchers (and new funders) into the field as well. His research into this possible aspect of ME/CFS is continuing full-bore.

Currently I have a PhD student working full time on a project extending some ideas about the role of regulatory T cells on ME/CFS. This project is funded by the Portuguese Foundation for Science and Technology and my student is doing his research in the Molecular Medicine Institute in Lisbon. I am also trying to find/identify candidate molecular mimicries between viruses and human proteins that could explain ME/CFS.

Will COVID-19 Leave An Explosion of ME/CFS Cases in its Wake?

SARS CoV

The first SARS (SARS CoV) virus was more lethal but killed less people.

The first SARS epidemic in 2003 featuring SARS-CoV now seems like a poor dress rehearsal for today’s SARS CoV-2 outbreak. With just 8,000 cases in total and 774 deaths, (compared to almost 1,000,000 cases and 4,000 plus deaths and rising rapidly) it seems hardly worth including in the same sentence.

Yet it was a “pandemic” (infecting people in 29 countries) that landed many in the hospital and it had a chillingly high death rate – almost ten percent. The first SARS virus was far more lethal than the second one we’re dealing with now.

A few studies that tracked the survivors suggested that 2003, like 2020 surely will be, was probably a banner year for new cases of chronic fatigue syndrome (ME/CFS) and/or fibromyalgia. That’s no surprise. We’ve known since the 2006 Dubbo study that a severe infection will leave a percentage of those infected with an ME/CFS-like condition.

The Toronto Outbreak

Like the present SARS-CoV-2 epidemic in the U.S. and other countries, the first SARS virus began its spread into Canada long before the authorities realized it was there or moved to stop it.

One woman returning from Hong Kong, who came down with a fever two days later sparked the pandemic in Toronto. She was dead in two weeks. Only after her son died a week later and several other family members became ill was a link made to a new infection spreading in Hong Kong.

A couple of weeks later, Toronto health authorities instituted emergency measures allowing them to track and detain anyone possibly infected. By the time the outbreak was over 345 people had been confirmed infected and 44  had died.

The Survivors

Several studies tracked the survivors. The first one – a year after the pandemic had passed – assessed lung functioning, provided a chest x-ray, had them do a 6-minute walk test, and assessed their quality of life. Most of the participants were health care workers.

All but two had been admitted to a hospital, 16% had ended up in intensive care and 9% had been put on a respirator.

While the lung functioning and chest x-rays were normal, fatigue (60%), difficulty sleeping (44%), and shortness of breath (45%) were common 12 months later. Only 13% said they’d fully recovered.  Eighteen percent demonstrated a reduced walking distance during the 6-minute walk test.

Thirty-seven percent reported significant reductions in their physical health, and 33% reported a significant reduction in their mental health.

After one year, 17% of patients had still not returned to work, and 9% more had not returned to their pre-SARS work levels.

The conclusion of the study was confounding, dismissing the physical deficits and focusing on mental health. After noting the high degree of fatigue, the problems with sleep, the reduced walking distance, the difficulty returning to work in a significant subset in the results, the authors concluded:

“Most SARS survivors had good physical recovery from their illness, but some patients and their caregivers reported a significant reduction in mental health 1 year later.”

A 110-person 2005 UK study, on the other hand, found significantly reduced exercise capacity and health status six months after the infection. Still another post-SARS study seemed strangely eager to put a gloss on the aftermath of the epidemic as well.

Despite reporting in the results that people aged over 40 experienced significantly reduced “health-related quality of life” over “multiple domains”, and that reduced lung functioning was associated with reduced SF-36 (functional scores) and a lower score on the walk test, the authors concluded that:

“Patients had good recovery of pulmonary function and HRQoL.”

Eight Years Later – Moldofsky’s Fibromyalgia Post-SARS Study

University of Toronto professor Harvey Moldofsky was under no such illusions. A kind of an unsung hero in the ME/CFS and FM world, Moldofsky has been exploring the sleep, pain and fatigue connection in FM, in particular, over the past 30 plus years.

In 2011 – 8 years after the SARS outbreak in Toronto – Moldofsky published a study “Chronic Widespread Musculoskeletal Pain, Fatigue, Depression and Disordered Sleep in Chronic post-SARS Syndrome; A Case-Controlled Study” comparing 22  post-SARS patients with fibromyalgia patients and healthy controls.

The Forgotten

The SARS threat long over, the medical world had moved on to focus whatever the next emergency was – cancer, heart disease, diabetes, Alzheimer’s, etc. leaving behind the SARS survivors to manage as best they could.

SARS patients unable to work

Eight years after the outbreak in Toronto a group of 50 former healthcare workers remained unable to work

Eight years later, noting that a group of 50 health care workers were still unable to work and were experiencing “musculoskeletal pain, profound weakness, easy fatigability, (and) shortness of breath that accompanied psychological distress” Moldofsky, a sleep researcher, dug deeper.

After assessing their physical and mood symptoms, Moldofsky put post-SARS survivors through a sleep study.

Results 

Moldofsky found, as he suspected, that the post-SARS patients looked very much like ME/CFS and FM patients. Along with the disabling fatigue and pain came non-refreshing sleep, more arousals at night and the mysterious alpha-wave intrusions that often disrupted sleep in the two diseases. Moldofsky also found a delayed entry into REM sleep and increased stage 2 NREM sleep.

One difference did stand out – the post-SARS patients experienced more fatigue and less pain than the FM patients did; i.e. they looked a bit more like chronic fatigue syndrome patients than FM patients.

Moldofsky came up with two possible explanations for the long term disability he saw: psychological trauma from the illness and the direct effects of the virus itself.

Noting that studies indicated the virus is able to spread throughout the brain including the hypothalamus, Moldofsky proposed the virus had produced a chronic neuroinflammatory state affecting sleep, pain sensitivity and energy levels. That hypothesis, of course, is identical to similar ones proposed for ME/CFS and fibromyalgia.

Ending the paper Moldofsky asserted that:

“A longer term, large scale study is needed to establish the contribution of epidemic and pandemic viral disease to the disordered sleep, chronic fatigue and somatic symptoms of chronic fatigue/fibromyalgia syndrome.”

While the 1918 flu pandemic involved the flu – not SARS-CoV-2 –  recovery was so often contracted that it spawned a syndrome known at the time as “encephalitis lethargica”.

The Present SARS Pandemic

That study has never been done, and now here we are with another potential nervous system infecting coronavirus.

SARS-CoV-2 virions

COVID-19 presents a unique opportunity to catch the emergence of post-infectious illness in its tracks.

Avindra Nath at the NIH reported that the virus can cause multiple central nervous system problems (dizziness, headache, impaired consciousness, epilepsy, meningitis, encephalitis as well as delirium, hallucinations, mood disorders, hypomania, anxiety, depression). (It can also hit the peripheral nervous system causing loss of smell, taste problems, neuralgia and muscle injury.)

According to one report, Nath stated that patients with multiple sclerosis, myasthenia gravis, dermatomyositis who are on immunotherapy are at higher risk of developing corona infection.

Severe Infections Found in Younger People

The virus’s lethality for older people is well-known but less well-known are the devastating effects it can have on the young and healthy. While they’re not dying at the rate of the elderly, younger people appear to be being hospitalized at a torrid clip.

Governor Cuomo recently reported that over 50% of coronavirus hospitalizations in New York City are between 18 and 49 years of age.

With models predicting millions may fall ill in the U.S. alone, the emerging SARS-CoV-2 cohort presents an immense opportunity to understand chronic post-infectious illnesses that will (hopefully) not come again.

Since studies indicate that the severity of illness greatly increases the risk of coming down with a post-infectious illness, the high numbers of younger people being hospitalized for COVID-19 suggests considerable numbers of people in the prime of their lives may have an ME/CFS-like illness in their future.

Opportunity Knocks

It’s possible that post-SARS illness cohort will be so large, affect so many younger people, and cause such losses in economic productivity that the NIH and other research institutions will, this time, focus considerable resources on the post-infectious consequences of having a severe infection.

The Dubbo studies and others have invariably found that the type of infection (bacterial or viral), the type of tissue it primarily infects (respiratory system, gut, brain) doesn’t matter. For the most part, after a period of time, the post-infectious illness patients look like each other: they look like ME/CFS/FM patients.

Using post-infectious ME/CFS patients to help understand what post-SARS patients will be going through seems to make perfect sense as well. Avindra Nath’s small, but comprehensively studied, ME/CFS group in the NIH’s intramural study, could provide clues for post-SARS studies.  Expanding Nath’s ME/CFS cohort and using the study to help understand the massive hit SARS-CoV-2 is likely to produce, not today, not tomorrow, not in three months, but in the years to follow would make perfect sense.

Even more impactful would be rigorously following and studying the mass post-COVID-19 cohort that will emerge in order to understand how post-infectious diseases emerge and how to treat them.

Avindra Nath reported that “a lot of people have been asking about post-viral syndromes”, that it would be good to follow the many “postviral immune mediated diseases” (including ME/CFS), and that attempts are being made “to develop nationwide databases”.

Vicky Whittemore reported that the NIH has recognized a huge problem may be brewing, and that an opportunity exists to learn about post-infectious illnesses. She started talking about post-COVID-19 infection illnesses (e.g. sequelae) with Joe Breen and others at NIAID a couple of weeks ago, and have heard from several researchers who are interested.

Whittemore suggested that everyone who tests positive for COVID-19 get on a COVID-19 registry and she mentioned this one. (There may be others.)

It’s possible that ME/CFS holds clues to what hundreds of thousands of people may be experiencing over the next year and onwards. It’s clear that those having difficulty recovering from COVID-19 will hold clues to what has been happening with us as well. A vigorous research effort to understand their plight should provide a boon for us all.

The dark cloud that is the coronavirus could produce a silver lining after all.

Lipkin Brings Disease Busting Technology to ME/CFS

Our biggest weapon in the battle against chronic fatigue syndrome (ME/CFS) has to be the almost dizzying emergence of new technologies being developed. ME/CFS may not have much money, but somehow it’s attracted several pioneers in the medical technology field.

Dr. Ian Lipkin specializes in creating new technologies, one of which he will soon bring to bear on ME/CFS

Ian Lipkin (Columbia), Ron Davis (Stanford), Gordon Broderick (Rochester), and Travis Craddock (Nova Southeastern) aren’t just using the latest technologies – they’re actually creating them. Lipkin, the Director of the Center for Infection and Immunity at Columbia University, and a longtime Simmaron Research Foundation collaborator, is internationally known for his ability to create new molecular diagnostic techniques.

Lipkin developed MassTag-PCR, the GreeneChip system, and was the first to use next generation sequencing technology to identify pathogens. The 1,500 or so pathogens Lipkin identified include the West Nile Virus, numerous tick-borne agents, Lujo virus, MERS-CoV, and Tilapia Lake Virus to name a few. He also played a critical role in battling the SARS epidemic in China.

Lipkin, who has worked with Dr. Dan Peterson for many years, has a long collaborative research history with ME/CFS. Since September 2017, Lipkin has been the Director for the Center for Solutions for ME/CFS (CfS for ME/CFS) at Columbia University funded by the NIH.

Mystery Disease Strikes Children

Lipkin made news recently with his discovery of the apparent cause of a puzzling and devastating disease mostly affecting children called acute flaccid myelitis (AFM). The way the disease develops bears some interesting similarities with ME/CFS.

Several striking bits of evidence suggest a pathogen might be involved. The bug is not new – it first showed up in 1962 – and usually causes nothing more than a respiratory infection  – but in rare cases (600 cases in the U.S. since 2014) it can be devastating.

A spike in AFM incidence in the U.S. in 2014 suggested a virus might have become more prominent.  The fact that most infections appear during late summer and fall as pathogens start to sweep the U.S., plus a CDC report which indicated that the disease almost always followed a respiratory infection, turned a big spotlight on pathogens.

Lastly, symptom onset was abrupt and the disease produced polio-like symptoms such as difficulty moving the eyes, drooping eyelids, facial droop, facial weakness, difficulty swallowing, slurred speech, sudden arm or leg weakness (paralysis). The difficulty breathing that caused some children to be placed on ventilators brought back memories of the iron lung which kept people with polio alive in the early 20th century.

With that the hunt was on for an enterovirus – the cause of polio and a sometimes conjectured cause of ME/CFS. Although attempts to snag the intruder in the cerebral spinal fluid proved fruitless, it wasn’t for lack of trying. The CDC created a task force (which included Avindra Nath, the lead investigator of the NIH intramural study on ME/CFS) and embarked on a cerebral spinal fluid (CSF) study that included over 500 people.

Lipkin Tries New Tack

Lipkin proposed a low viral load, a hit and run virus, and technical issues might be bollixing up the PCR search in AFM, and turned to a much more powerful new technology developed by his team called VirCapSeq-VERT, as well as the use of peptide arrays that looked for immunological responses to pathogens. (VirCapSeq-VERT with its ability to detect novel and mutated viruses is like PCR on steroids.)

The peptide arrays proved the trick. Lipkin found antibodies to EV peptides present in almost 80% of the study participants’ CSF, and zeroed in on a specific enterovirus called EV-D68.  Since then a separate study has confirmed his finding. Now some researchers are calling acute flaccid myelitis “the new polio“.

Lipkin on Acute Flaccid Myelitis

ME/CFS Next

Lipkin will begin testing people with ME/CFS shortly

Lipkin will soon begin testing ME/CFS samples

The question now is whether Lipkin can do the same thing for ME/CFS. A VirScan analysis funded by Solve ME failed to produce results; however, that method may not have had the specificity needed to find the footprints of an infectious agent. Lipkin and his colleague Dr. Nischay Mishra are using the same Serochip method they used to solve AFM, to begin an intensive search for an immunological response to a pathogen (viruses, bacteria, endogenous retroviruses, fungi) in ME/CFS.

The Serochip will scan through up to 6 million peptides (small amino acid chains) in an attempt to uncover a hidden pathogen that has been, or still is, tweaking ME/CFS patients’ immune systems. The work could also uncover an autoimmune reaction.

ME/CFS with its multiple subsets is likely far more complex than AFM, but if Lipkin can find a distinct immune signature or more likely distinct immune signatures in ME/CFS, he might be able to break another mysterious, pathogen triggered disease wide open.

Lipkin and his team will begin testing the blood or spinal fluid of ME/CFS patients in early 2020.

Click on the stories below for a look back at Simmaron’s collaborative work with Dr. Lipkin.

Ian Lipkin & Simmaron to Collaborate in New NIH ME/CFS Research Center

Peterson’s Atypical Subset Opens New View of ME/CFS in Columbia/Simmaron Publication

Simmaron’s Spinal Fluid Study Finds Dramatic Differences in Chronic Fatigue Syndrome

Researchers Closing in on Definitive Lyme Tests As NIH Amps Up Lyme Efforts

It wasn’t until 1983 that Borrelia burgdorfii, a bacteria carried by the black-legged or deer ticks, was identified as the cause of Lyme disease. That didn’t mean a good diagnostic test has been available – far from it.

None of the currently available tests (PCR, antibodies) are anything near definitive. PCR tests often fail when they simply miss the low numbers of bacteria present. The most commonly used tests, antibody tests, on the other hand, don’t begin to be accurate until a month or more into the disease.

That’s not a good scenario for a person bitten by a tick who needs a quick regimen of antibiotics to ward off the potential joint, connective tissue, heart and nervous system complications that can occur, 20-30% of whom never get the infamous Lyme rash. Public health authorities estimate that as many 300,000 people are exposed to Lyme disease every year – but only 30,000 cases are reported.

Lyme disease

Lyme disease has been a scourge for decades, but doctors still use tests developed in the 1990’s.

The current tests are so problematic that health officials in areas with high rates of Lyme disease often simply provide prophylactic doses of antibiotics to anyone exposed to a tick who comes down with a fever, headache, etc.

Plus people who remain ill after treatment, or who are diagnosed using controversial tests, can be given long term courses of antibiotics long term which carry their own risks. The number one thing that’s wanted and needed in the Lyme world is an effective diagnostic test. The good news is that one may be on the horizon.

The current slate of antibody tests were agreed upon back in 1993 at the Dearborn Conference when our understanding of Lyme disease was in its infancy. Twenty three years later, experts experienced in the clinical and laboratory aspects of Lyme and other infectious diseases met at the Cold Spring Harbor to discuss better Lyme diagnostic tests.

That meeting and discussions afterward laid the basis for a 2019 Viewpoint article in the Journal of Clinical Infectious Diseases with the provocative title, “Direct Diagnostic Tests for Lyme Disease“.

Direct Diagnostic Tests for Lyme Disease

Direct Diagnostic Tests for Lyme Disease Steven E Schutzer Barbara A Body Jeff Boyle Bernard M Branson Raymond J Dattwyler Erol Fikrig Noel J Gerald Maria Gomes-SoleckiMartin Kintrup Michel Ledizet … Show more Clinical Infectious Diseases, Volume 68, Issue 6, 15 March 2019, Pages 1052–1057, https://doi.org/10.1093/cid/ciy614

The Viewpoint effort was lead by Stephen Schutzer – an immunologist and sometime ME/CFS researcher – who in 2011 used an analysis of proteins in the cerebral spinal fluid to distinguish post-treatment Lyme disease from chronic fatigue syndrome (ME/CFS).

The authors got right to the point: the serologic tests presently used, they wrote, “cannot distinguish active infection, past infection, or reinfection”. “Reliable direct-detection methods, on the other hand, now appear achievable”.

It should be noted that the scientific advances allowing such statements to be made provide hope not just for Lyme disease patients but for those with other difficult-to-detect infections. Reliable diagnostic tests have recently been developed quickly for a number of newly emerging diseases such as Middle East respiratory syndrome – coronavirus, Zika infection, and even 2 newly recognized tick-borne borrelia infections (Borrelia mayonii, Borrelia miyamotoi).

B. burgdorfii is a different case, however. Three factors in its makeup (low bacterial load, high antigenic diversity and a wacky genome) have made it particularly difficult to capture.

Antigen Capture

Instead of directly looking for the bacteria itself, it’s possible to look for the antigens (proteins) the bacteria sloughs off into the blood, urine, etc. Past antigen capture efforts have been thrown off by the high antigenic variability found in the Lyme bacteria but new developments in mass spectrometry, and antigen enrichment and stabilization are making antigen capture a real possibility for capturing B. burgdorfii. 

A Better PCR

B burgdorfii

Three aspects of B. burgdorfii make it difficult to find.

B. burgdorfii’s second trick for evading capture – low bacterial loads in the blood – have made it difficult to capture by PCR.  Enter high-throughput sequencing techniques that have been developed to scan larger blood samples. Frequently used to detect exotic infections, the authors asserted these techniques can “be applied successfully to Lyme disease diagnostics”.

They know – because they’ve done them. These tests, which are 200 times more sensitive than normal PCR, may just be the tip of the iceberg, though. Adding other measures to their Lyme test kit allowed the authors to increase the sensitivity of their PCR a jaw-dropping 16,000 fold – enabling them to catch many more cases of Lyme disease than had been previously detected.

Instead of the .5 ml of plasma usually taken, the authors took 1.25 ml of whole blood, used a technique to amplify the bacteria present, and then used multiple primers.

Next Generation Sequencing

B. burgdorfii’s third evasive maneuver – its complex and unusual genome consisting of high levels of circular plasmids – has enabled it to evade capture in the past, but the development of a new technique (“long-read sequencing”) has allowed Pacific Bioscience to uncover hallmark sequences of the bug’s genome that can conceivably be targeted in diagnostic tests.

Serology Not Dead Yet

Serological testing, which relies on assessing the immune response to the bug, has a couple of problems, but doctors are familiar with serological testing and it may be cheaper and easier to use than other techniques. Improved serological testing could clearly provide a boon as well.

Just a week ago, a biomedical engineering group from Columbia published a study using a new serological test which purportedly can diagnose a Lyme infection in just 15 minutes. This test which uses “microfluidics” was much more effective than the standard tests at diagnosing early infections. The test needs to be further refined and tested, but the early results were good.

Effective Lyme Test Now Technically Possible

The advances enabled the authors to assert that “the goal of an active-infection diagnostic test is now technically achievable”. Note the word “technically”. We’re not there yet.

Understanding the full breadth of B. burgdorfii’s genetic diversity, creating better genomic databases, optimizing sample collection procedures and other issues need to be resolved for that to happen. That’s all a matter of funding; i.e. the political will to get the Lyme (and other tick-borne illnesses) under control.

New NIH Emphasis on Lyme Disease 

Finally, in a last bit of good news – the NIH will be ploughing more resources into Lyme research over the next five years.

Lyme disease has differed little from ME/CFS, fibromyalgia and others in its neglect at the NIH, and new NIH emphasis on Lyme was the result of years of advocacy work. In some ways, ME/CFS advocacy is on a parallel track – it’s just a few years behind. A Congressional Lyme Disease Caucus,led by two Lyme champions, and that was officially formed in 2013, paved the way.

Lyme strategic plan

Years of advocacy paid off when the NIH published a strategic plan for Lyme. The NIH is now working on a strategic plan for ME/CFS.

The 2016 21st Century Cures Act mandated the establishment of the Tick-Borne Diseases Working Group the NIH. In 2018, that group produced a report outlining recommendations for research which included increasing funding, improving diagnostics and, more importantly, developing a strategic plan.

That plan was recently published, and when it was, Rep. Chris Smith, one of the leaders of the Lyme Caucus, and a long time advocate for more Lyme research, reported advocacy efforts had paid off:

“After lagging for decades, NIH is all in for researching Lyme and other tick-borne diseases to better diagnose and treat those suffering from this horrific disease. This is great news for patients and Lyme-literate doctors who will now have serious, federal partners working aggressively to improve strategies for the detection, treatment, and one day, prevention of Lyme.”

That plan includes a number of intriguing focii, including determining the cause of an ME/CFS-like disease (post-treatment Lyme disease syndrome), better understanding the only known food allergy that can be induced by an insect bite (alpha gal syndrome), and developing rapid and direct detection diagnostic tests as well as vaccines and immune-based treatments.

Lyme isn’t the only neglected disease benefiting from effective advocacy. The money the HEAL project is pumping into efforts at the NIH to fight the opioid epidemic and create better pain drugs resulted from a public outcry. ME/CFS, with its ramp-up of advocacy efforts, and the NIH’s work on a strategic plan, is hopefully following a similar path as Lyme disease.

See- Did a Pivotal Moment for ME/CFS Just Happen?

Smith is not nearly done with Lyme advocacy. His next trick is a bill (TICK Act (HR 3073) that would create a national strategy to prevent and treat Lyme and similar diseases.

Conclusion

Rapidly decreasing technological costs are helping the search for better diagnostic tests. More work needs to be done, though, to validate a test and bring it to market.

The takeaway message from the Direct Diagnosis paper is that we now have the technology needed to develop a reliable, effective test for Lyme disease. Such a test would identify many people who don’t know they have the disease and stop unneeded treatment in those who don’t have it. It should also help us understand what’s going on in those who have been treated and remain ill (post-treatment Lyme Disease).

The missing element has been the political will to comprehensively tackle the disease and provide the necessary research funding.

That appears to be changing as well. Years of advocacy paid off with the recent production of a strategic plan to comprehensively fight Lyme disease. The NIH’s new emphasis should further advance the development of better diagnostic tests and, hopefully create new treatment possibilities. With ME/CFS on a similar path with it’s own strategic plan being developed, it’ll be illuminating to see how much Lyme disease funding shoots up over the next couple of years.

More on Lyme Disease From Simmaron

Post Treatment Lyme Disease Unmasked? Immune Hole in the Illness Identified

The Epstein-Barr Virus – Could it be Causing Neuroinflammation in ME/CFS?

EBV has been a virus of interest since almost day one in chronic fatigue syndrome (ME/CFS). In fact, at one point, EBV was such a hot topic that ME/CFS was called for a time “chronic Epstein-Barr virus” disease.

Virion EBV

Epstein-Barr virus virions (circular centers). Virions are the form of the virus which infects other cells. EBV dUTPase is released when the process of creating virions is aborted…

While studies have generally failed to find evidence of EBV reactivation, EBV has never fallen out of the picture with ME/CFS and for good reason. For one, it’s entirely possible that researchers were looking in the wrong place to determine if EBV is an issue in this disease.  For another, EBV infection in adolescence or later and the infectious mononucleosis (glandular fever) it produces, is a common trigger in ME/CFS, and is a proven risk factor for multiple sclerosis.

Besides ME/CFS, researchers are continuing to assess the role EBV may play in many serious illnesses including multiple sclerosis (MS), systemic lupus erythematosus (SLE), Guillain-Barre Syndrome, several cancers,  rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), inflammatory bowel disease (IBD), celiac disease, schizophrenia, and others.

Neuroinflammation, of course, is a hot, hot (pun intended) topic in both ME/CFS and fibromyalgia. Recent studies suggest neuroinflammation is present in both diseases and major studies are underway to validate that finding.

Nobody until now, though has attempted to complete the circle, and bring that “original gangster” in ME/CFS – Epstein Barr Virus – and the new guy in town – neuroinflammation – together.  Could EBV be causing or contributing to the neuroinflammation present in the disease?

Some History

Over 10 years of work by an Ohio State University team lead by Maria Ariza and Marshall Williams has been turning the EBV question in ME/CFS on its head. High levels of EBV, they believe, are not the problem in ME/CFS at all. In fact, their studies suggest that EBV may be at its most dangerous in ME/CFS not when it reactivates – but when it fails to reactivate properly.

dTUPase model

The Ohio State University dUTPase continuing NIH grant is in its 9th year.

By the time the impaired immune systems of people with ME/CFS have started knocking down EBV’s attempt at reactivation, the bug has already produced a potentially pathogenic protein called dUTPase. The Ohio State University researchers believe this protein may be wreaking havoc in a large subset of people with ME/CFS.

With the NIH supporting them every step of the way – their continuing grant on dUTPase is now in its 9th year – the evidence that this protein is contributing to ME/CFS (and other diseases) has continued to build.

In 2012, the group found evidence that the immune systems of people in a large subset of ME/CFS patients were indeed battling this protein. Just a year later they showed that even when viral loads of EBV were low, dUTPase could still be triggering a significant pro-inflammatory response. That finding suggested that failed prior attempts to link EBV reactivation to ME/CFS were barking up the wrong tree.

Two years later, they demonstrated that dUTPase was able to make its way into exosomes (now a major topic of interest in ME/CFS), cross the blood-brain barrier, produce major immune effects, and perhaps even promote further EBV infections.

Then a 2017 study added another herpesvirus long suspected in ME/CFS – HHV-6 – to the mix. That study found antibodies to dUTPases produced by both EBV and HHV-6 in almost fifty percent of the ME/CFS patients.  That suggested that the two herpesviruses might even be reactivating each other – a feature found in some very immune suppressed states including organ transplant patients and drug induced hypersensitivity syndrome.

Then again, really significant immune suppression in ME/CFS may not be a surprise. Up to 75% of ME/CFS patients were found to have low numbers of the B-cells designed to keep EBV in check in a recent study.

If the immune system wasn’t having enough trouble, in 2017 the first evidence of an autoimmune process involving EBV dUTPase was found in ME/CFS. Autoantibodies to the human dUTPases (humans produce a dUTPase as well) were found in ME/CFS – at much higher levels than in healthy controls (39% vs. 5%). That suggested that the immune response to EBV and HHV-6 dUTPase may have gone awry in some people with ME/CFS. Their bodies were now attacking their own human dUTPase.

The 2019 Study

In the present study we provide further evidence…. (that) dUTPase protein…could contribute to the development of a neuroinflammatory microenvironment in the brain(s) (of a subset of ME/CFS patients.)  The authors

Epstein-Barr Virus dUTPase Induces Neuroinflammatory Mediators: Implications for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Marshall V. Williams PhD; Brandon Cox ; William P. Lafuse PhD; and Maria Eugenia Ariza, PhD. Clinical Therapeutics March 2019

In 2019, the team took another step. In an earlier study they’d demonstrated that the EBV dUTPase protein could be causing or contributing to the symptoms present in ME/CFS. Since many of these symptoms can be produced by the brain, they next asked if the enzyme could be affecting the integrity of the blood-brain barrier (BBB) and other aspects of neuroinflammation.

There’s a pretty good reason to believe this might be the case. EBV, after all, has been associated with some pretty nasty neurological diseases. The virus loves to hang out in nerve cells and astrocytes, is a risk factor for M.S. and has, in fact, been found scattered throughout the astrocytes and microglial cells in MS patients’ brains.

The Ohio State University researchers plopped the dUTPase protein into a variety of cells and then determined how it affected the expression of genes that play an important role in maintaining the blood brain barrier (BBB) and the functioning of various brain cells (cerebral microvascular endothelial cells, astrocytes, microglia cells).

The big bug’s dUTPase protein turned out to be quite adept at tweaking genes and proteins associated with the BBB and neuroinflammation. It turned on 12 of 15 genes and 32 of the 100 proteins examined in vitro (in the lab) and 34 of the 84 genes examined in mice.

The fact that these genes play a role in BBB integrity/function, fatigue, pain synapses and their functioning as well as tryptophan, dopamine, and serotonin metabolism suggested that this enzyme, in or out of the brain, could conceivably cause widespread problems.

How the Blood-Brain Barrier Works

 

 

All in all, the protein appeared to be doing its best to find a way to get EBV into the brain. That’s perhaps not a surprise given how much EBV loves to hang out in neurons. As EBV dUTPase was down regulating the expression of genes dedicated to producing a tight BBB it was “strongly” inducing the expression of two cytokines (IL-6 and IL-1β) known to disrupt The BBB.

If EBV dUTPase gets inside the brain, it seems almost guaranteed to cause neuroinflammation.  Studies indicate it can trigger microglial cells and astrocytes (star-shaped immune cells in the brain) to produce potent pro-inflammatory cytokines (IL-6, IL-1β and TNF-α). It also prompts astrocytes to produce a substance (PTGS2/COX-2) associated with neuroninflammatory toxicity. Plus it’s able to alter the expression of genes associated with pain (GPR8451 and GCH152) and fatigue (TBC1D153) to boot.

In mice, it altered the expression of genes associated with cognition (synaptic plasticity, learning and memory).  One of the more intriguing findings, given the possible disruption of the kynurenine pathway in ME/CFS, was the protein’s potential to increase synthesis of a potent neurotoxin called quinolinic acid. Genes associated with the metabolism of two of the major neurotransmitters in the brain, dopamine, and serotonin, were also affected.

EBV dUTPase neuroinflammation

If EBV dUTPase has indeed been able to get into ME/CFS patient’s brains it seems almost guaranteed to cause neuroinflammation

All in all, EBV dUTPase is not a protein anyone wants hanging out in their head. It is, however, a protein that could potentially produce a lot of the problems found in ME/CFS.  This study demonstrated that the protein appears to have the capability to make its way to ME/CFS patient’s brains. Determining if it has will take further investigations, however.

It should be noted that the protein and its antibodies (or the autoantibodies to the human dUTPase) are not found in everyone with ME/CFS but the potential subset – ranging from 30% to 60% of those tested so far, is pretty darn large.

Plus, the virus is heavily implicated in the stress response. If you feel like your nervous system is over-reacting to, well, anything (or everything), EBV and this protein could be a factor. Of all the viruses, EBV and the herpesviruses love most to come out and play when one’s system is stressed.

In fact, Ron Glaser, one of the initiators of the EBV dUTPase research effort, demonstrated back in 1991 that EBV thrives in situations of psychological stress. Given the enormous stress people with ME/CFS are under, and the affects the illness has on both axes of the stress response, it makes sense that the virus might be continually trying to reactivate – and spilling it’s toxic protein into the bloodstreams of some people with this disease.

A Good-bye to a Pioneer

Ron Glaser

Glaser was shocked he couldn’t get his ME/CFS grant applications funded at the NIH

Ron Glaser was something of a legend in his own time. With his doctorate in pathology, his EBV citations alone total over 100. All told he published over 300 papers. Glaser co-founded Institute for Behavioral Medicine Research, which under his leadership brought in over 140 million in grant money over 20 years. At one point he was one of the world’s most cited authors.

His memorials mention his impact on the psychoneuroimmunological (PNI) field, his enthusiasm, (and the red and white Corvette he loved). What they don’t mention is that this leader also devoted time to a much neglected field called chronic fatigue syndrome. Glaser, in fact, took the time out of his busy schedule to sit on the now disbanded federal advisory committee for ME/CFS (CFSAC).

I vividly remember talking to him. He was not a man to mince words. An accomplished researcher with a long history of grant success, Glaser was first shocked, and then very angry at the rejections piling up for his ME/CFS grant applications. He just couldn’t understand it. Never in his decades of work had he experienced such a thing.

Stating, ironically, he couldn’t stand the stress (he did look like he was about to burst a blood vessel), he eventually moved on, but not before making his experiences perfectly clear to the federal advisory committee and everyone around him.

Glaser was not happy at not being able to work more in ME/CFS, but the work he did did not go for naught. Glaser first published on EBV dUTPase in 1985 and on EBV and ME/CFS in 1988 and his work lives on in Ariza and William’s studies on ME/CFS today. Check out a memorium to Ron here. 

Marshall Williams – On the Continuing Hunt for EBV dUTPase in ME/CFS

What about the connection between this protein and the presence of infectious mononucleosis/glandular fever in ME/CFS? Do we have any idea if the enzyme is more likely to be found in people who’s disease was triggered by IM or who had an acute, flu-like onset?

That is an excellent question. We are in the process of trying to obtain longitudinal serum samples from an IM cohort who developed CFS as well as age matched patients who had IM but never developed CFS. Hopefully, that may address this question.

EBV dUTPase exosomes

When EBV (lytic) replication is aborted it tosses EBV dUTPase into exosomes (circles with red marks) which, after binding to TLR receptors on immune cells, tells those cells to turn on proinflammatory and other genes (from Ariza, Williams and Glazer -https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0069827)

This study demonstrated that this enzyme has the potential to disrupt the BBB and enter the brain – and as added bonus – perhaps helps get EBV into the brain. Is there any way to tell if this has actually happened in ME/CFS?

Not really at this point but maybe in the future. Screening CSF from ME/CFS patients for antibodies to the EBV-dUTPase or HHV-6 dUTPase might suggest potentially the presence of these viruses in the brain.

Exosome research is heating up in ME/CFS. Some anecdotal reports show that exosomes in the blood may be affecting energy metabolism and other functions. Could herpesvirus dUTPases be involved? Is there any more information on exosomes and EBV dUTPases?

We have not looked at energy metabolism but there are some reports in the literature that some herpesviruses including EBV and HHV-6 alter mitochondrial function. There is information concerning EBV products in exosomes but most of these have focused on proteins/microRNAs involved with latency.

What is next for your team? 

We are in the process of submitting a manuscript detailing a mechanism(s) by which the EBV-dUTPase and to a lesser extent the HHV-6 dUTPase alter germinal center function, which could contribute to autoimmunity in CFS patients. We will be continuing these studies as well as those regarding neuroinflammation. (B-cells manufacture autoantibodies in the germinal centers found in the lymph nodes and spleen)

Epstein-Barr Virus May Be Turning On Pathogenic Genes in ME/CFS

If there was ever a “prodigal virus” in ME/CFS it would surely be the Epstein-barr virus (EBV). Since the first EBV ME/CFS study 1984 no less than 51 ME/CFS or post-infectious viral studies have featured either Epstein-Barr virus or infectious mononucleosis in their titles. (That leaves out a considerable number of viral and immunological studies which didn’t put EBV in their titles.) While hypotheses of chronic viral reactivation in ME/CFS have lost favor the virus is too complex, too fascinating, and simply too problematic for it not to continue to be studied.

EBV budding out of B-cell

A B-cell with EBV budding out of it

A PubMed search brings up over 500 EBV citations associated with multiple sclerosis and over 30,000 citations associated with the virus.  To get an indication of how broad EBV research continues to be – one of the latest  EBV studies determined if the stress of space flights results in increased levels of EBV reactivation in astronauts. (It did and they advised astronauts to stay away from immunocompromised individuals upon return home…)

The research community clearly continues to find EBV – one of the few viruses our bodies are unable to kick out – a fascinating and important topic. Check out the first in  a series of two blogs on EBV’s possible contributions to ME/CFS.

The Review

In his EBV and ME/CFS review longtime ME/CFS researcher Jonathan Kerr digs down into some past ME/CFS EBV findings which recent understanding of EBV is shedding some new light.

Kerr notes that psychological stress is associated with EBV reactivation and maintaining that state of psychological stress can result in prolonged states of EBV reactivation and diseases such as ME/CFS, nasopharyngeal cancer and post-transplant lymphoproliferative disorder (PTLD).

Many studies have found that stress triggers the release of glucocorticoids which tell the pathogen that the coast is clear and it’s time to start growing the family and producing more virions.

Whether or not the original ME/CFS trigger is associated with increased levels of  psychological stress, the dysfunctions found in both stress response axes (HPA axis, autonomic nervous system) post-ME/CFS suggests that psychological stress could  possibly give a bug like EBV a leg up in diseases like ME/CFS. Plus, other studies have found evidence of an immune hole which could give EBV an extra foothold in ME/CFS.

In the U.S., Ariza and Williams have shown that attempts at EBV replication in ME/CFS can trigger the production of an enzyme called EBV dUTPase which, among other things, results in the production of pro-inflammatory cytokines which may produce fatigue, pain, flu-like symptoms, etc.

Kerr’s group in the U.K., though, has taken a different tack.

The 2008 Study

Assessing the expression of 88 genes Kerr suspected were playing a role in ME/CFS, his group was able to separate healthy controls from ME/CFS patients, and then break those ME/CFS patients into 7 subsets in 2008. No less than 12 of the genes his group assessed were known to be associated with EBV.

Finding such a huge split in gene expression between ME/CFS patients and healthy controls, and then being able to split up the ME/CFS group into gene expression subsets with unique symptom profiles, was striking.

One of the genes which stuck out back then is called Epstein-Barr Virus (EBV) induced gene 2 (EBI2). While EBI2 sounds like it comes from EBV, it’s a human gene. As EBV begins to reactivate it induces the expression of this gene, which regulates B-cell functioning, T-cell mediated antibody responses, and inflammation.

Kerr’s 2008 study suggested the gene was working overtime in 55% of ME/CFS patients. In another analysis, EBI2 was upregulated in 38% of 31 patients vs zero of 40 healthy controls.

The 2010 Study

A larger (n=117 ME/CFS patients) 2010 study analyzed antibodies associated with EBV in eight gene expression subsets. As before, twelve of these genes were known to be associated with Epstein-barr virus (EBV)

EBV Gene 2 expression

Greatly increased expression of the EBV Induced Gene 2 was found in the ME/CFS group

One subset – subset D – stood out in its severity. This group of patients, all females, demonstrated a consistency of the worst kind, posting the lowest functional scores  in no less than five of SF-36 functional domains (physical role, vitality, general health, bodily pain, and total score) and experiencing high rates of muscle pain and sleep issues.

They also led the pack in the expression of  EBV associated genes. Their EB12 genes were turned on and pumping away at higher levels of activity than in any of the other groups. So were all the other 11 associated EBV genes.

In other words, this appeared to be a highly afflicted EBV ME/CFS subset.  EBV may be involved in other subsets, but it appeared to be wreaking special havoc in this one.

Interestingly, the abnormal antibody (EBNA IgG) result found indicated the antibody was not elevated but was reduced. Since antibodies play a key role in immune clearance, the low levels suggested an immune deficit could be present.  For one, they suggested EBV was probably more often found in its latent state in this group.

EBV is found in two forms: its lytic form occurs mostly in epithelial cells, and its latent form in B-cells.  The low levels of EBNA IgG appear to suggest, if I have it right, that EBV is able to survive in B-cells longer, giving it more time, one would think, to possibly tweak those B-cells more. That’s an interesting finding given the role B-cells play in autoimmunity.

Nine Years Later – Science Marches On

Nine years ago, not much was known about EB12 but science has been moving on. EB12 is now recognized as a “critical regulator of the immune response”. It ordinarily plays a valuable role in the interaction between B and T-cell and the antibody response.

Gene expression

Jonathan Kerr believes EBV may be causing a gene to over express itself in ME/CFS

As one might suspect, though, EBV activation of this gene is not associated with good outcomes.  Increased EBI2 expression appears to dysregulate the delicate immune response – increasing B-cell activity (and therefore the risk of autoimmunity)  – while inhibiting T-cell activity – and potentially suppressing the immune system’s ability to deter pathogens and knock out cancerous cells. Kerr pointed out that EBI2 could also be contributing to the reduced cerebral perfusion, gray matter reduction and white matter hyper intensities found in both multiple sclerosis and ME/CFS.

Given the findings of the past 11 years, Kerr suggested that the EB12 gene deserves a deeper look in this disease.  The possibility that a severely ill EBV subset – characterized by a hyperactivation of the EBI2 gene – is present, is, of course enticing. Given that ME/CFS often has an infectious trigger, a special EBV subset makes perfect sense, and if it is present, it may offer some unforseen opportunities.

One of the advantages of having an upregulated gene that’s been implicated in a bunch of nasty diseases is possible increased interest from big pharma. If the EBI2 gene is wreaking havoc in some of the more severely ill ME/CFS patients, help may be at hand in the future.  Kerr pointed to two EBI2 modulators  (GSK682753A, NIBR189) currently under development.

Kerr acknowledged several caveats to his hypothesis. His findings need to be validated by other laboratories using other sets of ME/CFS patients. He noted that finding EBV antibodies in ME/CFS does not in any way indicate that the bug is causing ME/CFS – that is still in doubt. His hypothesis – that EBI2 upregulation is playing an important role in a subset of ME/CFS patients –  is unproven at this point.

It’s a hypothesis though, which is consistent with the data presented thus far and could account for “many of the immune and neurological abnormalities” found in a group of patients.

East African Disease Informs Nath’s Search for the Cause of ME/CFS

Could a disease found in the remote villages of East Africa end up being a model for chronic fatigue syndrome (ME/CFS)?

Ugandan Village

Ugandan Village (from the NIH)

Dr. Avindra Nath – the leader of the NIH Intramural study on ME/CFS –  thinks perhaps so. He’s not daunted by mysterious diseases and nor should he be. Just a couple of years ago his NIH team was able – by bringing new technology to bear – to unravel a mysterious disease plaguing children in Africa. Using a much larger array of tests he’s hoping to do the same in ME/CFS.

Nath became acquainted with “nodding syndrome” at a meeting in Uganda in 2012. This strange and often devastating disease, found in the remote regions of Uganda, Tanzania and South Sudan, causes children’s heads to periodically nod  and can produce seizures, mild to severe cognitive impairment, muteness, gait problems, paralysis and often death. Brain scans have shown significant brain atrophy.

Studies suggested that the disease was linked to a parasite, Onchocerca volvulus, carried by the black fly, but numerous efforts to find the parasite in the brain or cerebral spinal fluid failed.  Attempts to tie it to immune factors including autoantibodies, as well as genetics, toxins, nutritional factors, and others came to naught as well.

Like ME/CFS the speculation regarding the cause of nodding syndrome has been rife with possible connections to autism spectrum disorder, Alzheimer’s, poor nutrition, PTSD and others being put forth. Ugandan psychiatrists have even proposed that the disease is a form of “Developmental Trauma Disorder” brought on by the war.

Enter Nath, Tory Johnson, a former postdoc fellow of his, and Thomas Nutman, a National Institute of Allergy and Infectious Disease (NIAID) researcher.  Suspecting the problem was autoimmunity, they brought out one of their big guns – a kind of protein chip technology that allowed them to screen for thousands of antibodies at once.

The results were tantalizing. The levels of four antibodies were 100 fold higher in the sick children compared to the healthy children.  Further testing revealed that two of these antibodies were more reactive or active in the sick children. They ended up focusing on one antibody found in both the blood and cerebral spinal fluid.

This antibody – which was linked to the leiomodin-1 protein  – reacted 33,000 times more strongly in the children with nodding syndrome.  Interestingly, both groups – the sick and the healthy children – carried the antibodies, but they were elevated in the sick children.

Leiomodin-1 staining neurons

Staining reveals Leiomodin-1 antibody (green) interacts with human neurons

After finding this link, they deepened their search. The leiomodin-1 protein had been found primarily in smooth muscle tissue and the thyroid, but if it was causing the neurodegenerative symptoms it had to be in the brain as well. Further testing, including immunostaining human neurons, indicated that protein was indeed found in parts of the brain imaging studies had indicated were associated with nodding syndrome.

Having established a putative link between the antibody and the disease (that it was found in and could potentially affect the brain) the next step was to demonstrate that the antibody could indeed be causing the disease. Subjecting cultured human neurons to the antibody showed that the antibodies could indeed be damaging the childrens’ neurons.

Getting at the source of the antibody was next. The authors hypothesized that an immune attack against the parasitic worm had gone awry and was attacking the ill childrens’ neurons. This could only happen, though, if the parasitic worm and human neurons shared genetic sequences that could cause the immune system to mistakenly attack human neurons. Studies confirmed that a very short sequence of the parasite’s tropomyosin gene was quite similar to a sequence expressed in human neurons.

autoimmune responses ME/CFS

Nath believes the infections may have triggered a variety of autoimmune responses targeting the brain in ME/CFS

With that, the circle was closed. They had identified an antibody, shown it was in the brains of the sick children, showed that it could do damage to the neurons that were damaged in the children, and demonstrated similar genetic sequences were present in the parasite and humans.

There was still the nagging issue of antibody prevalence, though.  Only slightly over 50% of the sick children had antibodies to leiomodin-1. If the antibody to leiomodin-1 was causing the disease in these children, what was causing the disease in the others?

Nath et al proposed that the parasite triggers a different immune response in different children.  Some of the children developed autoantibodies that damaged neurons in their CNS  – and produced nodding syndrome (which is now understood to be a form of autoimmune epilepsy).

This syndrome is likely not a disease mediated by a single immune specificity. We speculate that nodding syndrome may not be a single antibody syndrome.  Nath et al.

Citing test results which showed a range of elevated autoantibodies in the sick children, they suggested that some children with nodding syndrome have developed antibodies to  neuronal proteins other than leiomodin-1.

A Model for Chronic Fatigue Syndrome (ME/CFS)?

Nath reported that his approach to ME/CFS has been shaped by his experiences with nodding syndrome. He suspects the infectious onset that so many people with this disease experienced triggered their immune system to accidentally produce autoantibodies that are attacking their central nervous system or other parts of the body.

If suspect antibodies show up, future research efforts will presumably proceed down the same pathway as they did in Nodding Disease: first they will identify the proteins the antibodies are attacking, and then they will determine where those proteins are found, and demonstrate experimentally that the antibodies are likely doing damage.

Nath and his compatriots uncovered the antibody connection to nodding disease seven years ago – a long time in this age of fast moving medical technology. Nath reported he’ll be using a newer approach involving mass spectrometry, or phage display, in ME/CFS which will allow him to “probe almost infinite numbers of proteins/peptides”.

Seven years ago, extensive testing had failed to find a culprit leaving the cause of nodding syndrome a complete mystery. In 2017 Nath et. al. produced a clear pathway that explains about 50% of nodding syndrome victims.

Technology Paves the Way

Note that the breakthrough didn’t come from the slow accumulation of results over decades; –  it occurred very quickly and simply required the right technology being applied to the disease. When that happened, a cause of the disease became clear, and researchers simply proceeded down established pathways to prove  it.

Nath and the NIH are looking at much more than antibodies in their intramural study, and ME/CFS, with its multiplicity of triggers, is likely to be more complex than nodding syndrome. The same principle, though, – a variety of autoimmune processes produced by an infectious trigger – may apply.

Dr. Nath appears to have gotten at a cause of one mysterious disease. May he be as successful with this one.

Check out an interview with Dr. Nath

Dr Nath Talks on the ME/CFS NIH Intramural Study

The NIH’s Accelerating Research on ME/CFS Conference

Because of a death in the family, Brian Wallitt will be presenting in Dr. Nath’s place at the NIH conference. Dr. Nath reported that Wallit will present on the high rate of rare diseases found during the first half of the study and some other data but will not present statistical analyses. With just half of the projected participants having finished the first part of a two-part study, the lack of statistical analyses is not really a surprise.

Brian Wallitt will be presenting at 10:00 AM EST on April 5th (day two) of the Accelerating Research on ME/CFS conference – the first NIH sponsored research conference on the disease since 2011. Check out the agenda here.

Learn more about the NIH Conference below.

NIH Brings in New Faces and Looks to the Future in Accelerating ME/CFS Research Conference

Catching ME/CFS in the Act: The Collaborative on Fatigue Following Infection (COFFI)

It sounds like a great idea – combine all the post-infectious fatigue studies together into one database in order to find answers to one of the biggest questions in ME/CFS – why do some people stay ill after an infection while others recover?

infection - chronic fatigue

Every major infection has provoked a similar response – a significant number of people become chronically ill.

COFFI (Collaborative on Fatigue Following Infection) incorporates no less than 9 studies that have examined post-infective fatigue or illness. The Dubbo study – pioneered by Andrew Lloyd and funded by Australian Health Agencies and the Centers for Disease Control (CDC) in the U.S., still in some ways the best study – started it all off.

The most dramatic conclusion of the first Dubbo study was that somewhere around 10% of people exposed to a serious infection remained ill six months later. Remarkably, the kind of infection – viral or bacterial – didn’t matter. It seemed that being exposed to any serious infection left one at risk for a prolonged fatiguing illness.

Since the Dubbo studies began, eight other post-infectious cohort studies have finished up or are underway. The largest of these are the four Chicago cohort studies (about 1000 participants) under the direction of Ben Katz and Lenny Jason, which have been examining infectious mononucleosis college students for almost ten years. There’s also campylobacter gastroenteritis (n=600), Legionnaires disease (n=190), and Ross River Virus (n=60) cohorts. All told, about 3000 people have participated in 9 studies which have examined people who failed to recover from an infection.

COFFI believes that susceptible individuals develop prolonged fatigue after infection because of biological (immune system, autonomic nervous system, etc.), behavioral and/or environmental effects, which produce alterations in neurobehavioural, cardiovascular and/or immunological systems. The goal of the collaborative is to elucidate what went wrong in those with post-viral (and bacterial) illnesses.

On the face of it, the collaboration holds great promise. How better, after all, to learn about how an illness develops than to capture it in its earliest stages?

The Post-Infectious Illness Group

Different flavors of post-infectious illness exist. One set involving diseases like acute disseminated encephalomyelitis and Guillain-Barre Syndrome produces very dramatic symptoms (paralysis, coma) and is studied. The other produces less dramatic symptoms (fatigue, cognitive problems, PEM) etc., but despite the tremendous functional hits seen, has mostly skated under the scientific establishment’s radar.

The studies that have emerged in the second group look like the kind of studies you would expect from a niche topic. They tend to be underfunded, focus on more easily and cheaply assessed factors, are often light on biological analyses, and sometimes focus on behavioral factors.

Nevertheless, some foundational findings have emerged. First – any serious infection is going to incapacitate a significant subset of those afflicted. The results have been remarkably consistent across types of infectious onset, with most showing from 9-13% of those encountering a serious infection of any type are still ill at six months and 7-9% remain ill a year later.

That’s obviously not a small number of people.

Lloyd, the senior author of the collaborative, has enrolled a mishmash of partners. They include biologically oriented members (Ben Katz, Renee Taylor, Ute Vollmer-Conna, Knut-Arne Wensaas, Jeannine L.A. Hautvast), some in-betweener’s (Brun Wyller, Dedra Buchwald, Renee Taylor) and some behaviorists (Peter White, Esther Crawley, Gabrielle Murphy, Rona Moss-Morris).

The Epidemiological Efforts

Giardia

The Bergen Giardia studies demonstrate the funding woes present in this field. They’ve succeeded in documenting high rates of ME/CFS, chronic fatigue and/or irritable bowel syndrome (IBS) years after an extended Giardia outbreak in Norway.  The studies have established that the outbreak has had a significant health impact on a substantial number of people – an important finding for sure – but it’s been unable, until recently, to delve into any biological factors. (A genetic study is underway.)

The Biopsychosocial Efforts

Moss-Morris’s work shows that cognitive behavioral therapy (CBT) has moved into clearly defined biological illnesses such as MS and renal disease. She’s managed to study the behavioral aspects of fatigue and/or conducted CBT trials in no less than five diseases – ME/CFS, IBS, multiple sclerosis, renal disease and cancer. (The MS CBT trial was deemed successful.)

Moss-Morris assessed epidemiological and biopsychosocial factors in people who became ill following a campylobacter infection (food poisoning). Ironically, that study suggested that those who tried hardest to ignore or push past their illness (e.g. who felt “I must not let this get the better of me” and who engaged in all-or-nothing behavior) were most likely to get ill. (So much for the malingering hypothesis).

chaos

The biopsychological studies have failed to provide consistent theme

Psychologist Peter White must have been chagrined to find that his Bart cohort failed to indicate that mood disorders or negative life events contributed to a “fatigue syndrome” after an infection.

The results of Buchwald’s 2000 infectious mononucleosis study must have flummoxed everyone.

It suggested that a greater number of life events more than six months before the illness began and increased family support were predictive of those who remained ill.

The Q fever studies ended up with a similarly hard to understand mix of factors. Female gender, being younger, having a pre-existing health condition, and being hospitalized in the previous 3 months might make some sense, but why would consuming no alcohol and using medication contribute to a prolonged illness?

The Qure study found that long-term doxycycline treatment utterly failed to move the needle on the illness; i.e. a persistent bug is not responsible.  CBT, on the other hand, improved fatigue and symptoms somewhat but completely failed in the most important measure – improving functionality. (By reducing stress, behavioral therapies should provide some symptom reduction…)

The lack of a recognizable theme suggests that the biopsychosocial results are not getting at the root of anything.  If the goal is illness eradication, researchers need to dig into the biology, and biological efforts have indeed achieved better results.

Biological Efforts

The studies that have dug deeper into biology appear to have been more successful.  Blood tests in the Dubbo studies suggested that pathogen persistence was not the issue: in every case the pathogen appeared, at least, to have been vanquished.

The results of the Qure study on the effectiveness of long-term doxycycline treatment in those with prolonged Q fever suggested the same: it found that the standard treatment for the disease had no effect at all on those who remained ill.

Nor did immune activation over time – as measured by cytokine levels – appear to cause disease persistence in the Dubbo group.

The only risk factors identified occurred early in the illness. Higher levels of cytokines and symptom severity early in the illness appeared to set the stage for a prolonged illness. This suggested that the bug – whichever bug it was – did its damage early and then disappeared.

Genetic studies then suggested a reason why. Immune gene polymorphisms were found in this group which predisposed them to a heightened immune response when confronted with a pathogen.  With three studies confirming and extending that finding, it seems solid. It appears that people with polymorphisms in specific immune genes that heighten the inflammatory response are more likely to become and stay ill.

consistency

The biological studies have provided a more consistent theme of immune activation and autonomic nervous system activation.

The ongoing Chicago infectious mononucleosis studies have dug a bit deeper biologically and uncovered some interesting findings.  Autonomic symptoms and early illness severity were predictive of a prolonged illness (while perceived stress, stressful life events, family stress, difficulty functioning and attending school, and psychiatric disorders were not).

Six months of illness resulted in lower oxygen consumption and reduced peak oxygen pulse; i.e. problems utilizing oxygen – something that Hanson’s latest metabolomic study and others suggested may be happening. (The authors called this “reduced fitness” and “efficiency of exercise.”).  Plus, a network analysis was able to diagnose 80% of ill patients using immune factors, and at six months autonomic nervous symptoms stood out. The analysis suggested a powerful pro-inflammatory immune state persisted for as long as 24 months after the initial onset.

The new “Dubbo studies” (“The Sydney Infectious Outcomes Study (SIOS)) have found an early reduction in heart rate variability, suggesting autonomic nervous system involvement.

In contrast to the biopsychosocial-oriented studies, a theme may be emerging in the biological studies: immune activation and autonomic nervous system problems early, resulting possibly in problems with oxygen utilization, with autonomic nervous system problems persisting.

Wyller’s Weird Results Or Why a Poor Study is Worse Than No Study at All

Many of the post-infective studies have been confined to charting epidemiological factors. Only the initial Dubbo study and the Katz/Taylor Chicago studies have tried to dig deeply at all into biological factors. Even then the scope of the studies has been limited.

Brun Wyller’s CEBA studies (Chronic Fatigue Following Acute Epstein-Barr Virus Infection in Adolescents) appeared at first glance, to fix that. The three studies analyzed 149 factors including early illness severity, immune factors, neuroendocrine stress response, cognitive functioning, emotional disturbances, genetics/ epigenetics of candidate genes, personality traits, and critical life events during and after infectious mononucleosis (IM).

Steps Per Day

The first CEBA study (Lifestyle factors during acute Epstein Barr virus infection in adolescents predict physical activity six months later) assessed the effects of the 149 factors on the number of steps taken per day at six months in 200 individuals. None of the markers of infection or immune response studied affected activity levels.  (Nor did any psychological factors).

Instead, three factors – none of which showed up previously in the post-infectious studies – did. Baseline physical activity (steps per day), substance use (alcohol and illicit drugs), and human growth hormone were associated with reduced steps per day after six months. (Notice the opposing substance use results: low alcohol use was a risk factor for post-Q fever illness, while increased alcohol/substance use was a risk factor for post-infectious mononucleosis illness).

The results suggested that sedentary individuals with low HGH levels who were abusing alcohol/drugs and who became ill with IM are predisposed to be, guess what, more sedentary than usual six months after coming down with infectious mononucleosis.

That’s among the most underwhelming and just weird results I’ve ever seen, and one wonders why Wyller bothered to publish it.

Predictors of Chronic Fatigue

Predictors of chronic fatigue in adolescents six months after acute Epstein-Barr virus infection: A prospective cohort study.

Another study of Wyller’s cohort charted biological factors against fatigue at six months. The main finding that a bunch of symptoms (sensory sensitivity, pain severity, functional impairment, negative emotions) were associated with increased fatigue simply stated the obvious. The more fatigued a person was, the more negative emotions they had (what a surprise!), the more functionally limited they were (!!!!), and the more pain they were in (stunning!), etc.

The fact that viral load had no predictive value was in line with past studies. The slightly increased plasma C-reactive protein found (Wyller suggested it was caused by negative life events) and reduced plasma vitamin B12 levels were the only two biological factors that stood out.  Neither will move this field forward significantly.

Predictable Results?

So how did Wyller get such pitiful results?

It turned out the study was not as comprehensive as the 149 factors made it appear to be, and was rudimentary to boot.  Included in that 149 factor set were standard blood tests, demographic results, psychological testing, etc.

Wyller testing ME/CFS

Wyller’s testing regimen made a biological result unlikely.

Wyller used a Fatigue Scale – the Chalder Fatigue Scale – believed be problematic in ME/CFS.  His immune tests mostly consisted of immune cell counts which have historically not been particularly effective.  Natural killer cell cytotoxicity – which has consistently been found to be low in ME/CFS – was not done.

The one stressor used – during the autonomic nervous system testing (deep breathing while supine and during 3 minutes of standing) – was too mild (at least a 10 minute tilt table test is needed to diagnose POTS).

While changes in heart rate and blood pressure have been found in ME/CFS, heart rate variability is a more discerning factor and has been more commonly assessed and found altered in ME/CFS – but was not used in Wyller’s study. The cortisol blood test Wyller used has not been found effective in ME/CFS. (Blood cortisol awakening response and morning saliva cortisol tests (not done) have been more effective).

All in all, the study – with its lack of a significant stressor, its limited testing protocol and the use of measures which have not proved useful in ME/CFS – appears to have been almost doomed to failure.  One wonders why Wyller expected to find anything at all, and the results probably could have been predicted.

They also, not surprisingly, opened the door wide open to a biopsychosocial interpretation of ME/CFS that Wyller walked right through.  Wyller reported that,

“Taken together, the results seem to support a biopsychosocial rather than a biomedical perspective on the development of chronic fatigue and CFS.”

Lenny Jason’s Chicago Studies

The next Chicago studies, led by Lenny Jason, will examine many more biological factors in its next iteration. Unlike the Dubbo, Giardia, Wyller’s studies and others, Jason’s samples predate the illness onset, giving him the potential to uncover biological risk factors present before a person became ill.

He has blood samples from over 4,000 students, 4-5% of whom contracted infectious mononucleosis, which they are following. Papers should start appearing this spring/summer. As of October 2018, Jason was still in the process of applying for grants to study blood and saliva factors. They hope to study autonomic functioning, cytokine, metabolomic and saliva biological risk factors.

Jason’s preservation of his samples in a deep freeze means they’ll be able to be assessed as we learn more about ME/CFS over time.  They provide the potential for uncovering perhaps the greatest mystery of all in ME/CFS – what was going on before ME/CFS actually hit that put one at risk for it?

Conclusion

Time will tell if the The Collaborative on Fatigue Following Infection (COFFI) will help, hurt or do anything at all. If the embarrassingly rudimentary website with its weird ads is any indication, the group may not amount to much.

Wyller’s efforts indicate that rudimentary, poorly targeted efforts can do more harm than good if the authors decide to default to a historical norm: if you can’t find something biological, a biopsychosocial explanation must apply.  His results and other biopsychosocial study results are so bizarre, though, that one wonders if anyone will take them seriously.

trigger - post-infectious fatigue

The post-infectious studies have the possibility of catching the disease in the act.

The biological efforts are another story. These cohorts offer the enticing possibility of catching the disease in the act as it first manifests itself. The first post-infectious fatigue studies – the Dubbo studies – are still some of the best, and outlined some findings that have continued to stand: illness severity is a major risk factor and the bugs that triggered the illness in the first place don’t appear to play a role in prolonging it. The early cytokine and genetic results fit that picture: they suggest a stronger than usual early immune response may set the stage for ME/CFS.

Incorporating more sophisticated tests, the Chicago infectious immune studies add the possibility of long-term autonomic nervous system problems, further suggest immune issues play a role and, intriguingly, provide the first signs of impaired energy production during exercise.

Jason, if he can get the money to test his samples, has the opportunity, with his metabolomic, autonomic nervous system and immune testing, to provide more insights into how this illness got started in the first place and why it remains. Plus, his frozen samples provide the opportunity for future researchers to dig even deeper into these questions. They should prove invaluable.

 

 

Immune Factor May Jump Start Chronic Fatigue Syndrome (ME/CFS)

December 31, 2018

“For the first time, we have shown that people who are prone to develop a CFS-like illness have an overactive immune system, both before and during a challenge to the immune system. Our findings suggest that people who have an exaggerated immune response to a trigger may be more at risk of developing CFS.” Alice Russell

This British study is interesting in so many ways. Most importantly, it draws a link between an overactive immune system and CFS-like chronic illness in Hepatitis C patients who were studied before and after treatment with an immune stimulant. The authors believe it may tell us why some people come down with chronic fatigue syndrome (ME/CFS) after an infection. If so the Brits have found the first predictive blood factor for ME/CFS.

Psychoneuroendocrinology. 2018 Dec 14. pii: S0306-4530(18)30196-3. doi: 10.1016/j.psyneuen.2018.11.032. Persistent fatigue induced by interferon-alpha: a novel, inflammation-based, proxy model of chronic fatigue syndrome. Russell A1, Hepgul N2, Nikkheslat N3, Borsini A4, Zajkowska Z5, Moll N6, Forton D7, Agarwal K8, Chalder T9, Mondelli V10, Hotopf M11, Cleare A12, Murphy G13, Foster G14, Wong T15, Schütze GA16, Schwarz MJ17, Harrison N18, Zunszain PA19, Pariante CM20.

It is interesting in one way, because it comes out of King’s College London – the longtime home of Simon Wessely, the British psychologist who developed the cognitive behavioral therapy (CBT) and graded exercise therapy (GET) approach to chronic fatigue syndrome (ME/CFS). Wessely, a leader of the biopsychosocial approach to ME/CFS, championed the idea that psychological and social factors largely perpetuate ME/CFS.  Psychiatrists Trudy Chalder and Mathew Holtorf also hail from King’s College.  (Anthony Cleare, another psychiatrist from King’s College, has done substantial research into the HPA axis in ME/CFS over the past 20 years. Cleare’s 1995 paper used cortisol tests to differentiate ME/CFS from depression.)

Kings College Medicine

King’s College London has been the home of several prominent pyschiatrists studying ME/CFS (By Stephen Craven, CC BY-SA 2.0, https://commons.wikimedia.org/w/index.php?curid=13848828)

Six years ago Medical Express reported that the PACE Trial – which Kings College researchers participated in – proved that CBT/GET practices “provide good value for the money“. Three years ago Queen Mary College of London and King’s College London dug their feet in to prevent the release of the raw PACE data.  It was King’s College that called the attempt to get the data “vexatious,” which in legal terms basically means without merit. The PACE findings are now in the throws of being discredited.

The study is also interesting because it was funded by the Medical Research Council (MRC), a United Kingdom based governmental agency that funds medical research. The MRC, which helped fund the PACE trial, has been a mixed bag. Funded studies on ethnicity, risk factors (biopsychosocial risk factors) and CBT speak to a strong behavioral thrust. However, the MRC has also funded studies on the mitochondria, the autonomic nervous system and now on an immunological model of ME/CFS.

A new generation of psychiatrists from King’s College appear to be taking a different tack. Carmine Pariante, who has focused for years on the physiological roots of depression, has been using hepatitis C patients to try and understand how immune mediated fatigue and depression arise.

A Model for ME/CFS?

It turns out that when hepatitis C patients are given interferon-alpha (IFN-a) about a third of them develop severe fatigue and/or become depressed. The realization that an immune activating drug was causing fatigue and depression in those who were not fatigued or depressed before was a revelation to the medical community. That led to the idea of sickness behavior, which posits that during an infection, the brain and immune system induce symptoms (flu-like symptoms) that force individuals to isolate themselves, stopping the spread of the infection.

trigger ME/CFS

Did high IL-10 levels jump start ME/CFS?

Since many people with chronic fatigue syndrome (ME/CFS) are by definition caught in a chronic case of “sickness behavior” (a chronic illness state triggered by an infectious event), hepatitis C patients provide the possibility of real insights into ME/CFS.  If researchers can determine how immune activation triggers flu-like symptoms and/or depression in people being treated for hepatitis, they may get clues to what is going on with ME/CFS.

In an action that proved enormously helpful, the group took baseline measures of immune activation prior to the introduction of the interferon drug, and then afterwards. They also assessed psychological factors and metabolites associated with the kynurenine system.

THE STUDY

Psychological Factors Play No Role

In a finding that must have disappointed Trudy Chalder and Mathew Hotopf – who were also part of the study – psychological factors struck out on all counts. Neither a history of depression, stressful life events in the prior six months or early life trauma had any effect on  those who became ill following the IFN-a administration.

Cytokines Not Perpetuating Fatigue

Cytokines weren’t, strictly speaking, perpetuating fatigue in the ill hepatitis C group either. The cytokine levels in both the recovered and the still fatigued hepatitis C patient were similar.

They may, however, have triggered it.

Possible Predisposing Factor Identified

The hepatitis patients who came down with severe fatigue demonstrated increased IL-10 and IL-6 levels early on – very early on.  In fact, hepatitis C patients who became ill had high IL-10 levels BEFORE they received the drug. High levels of IL-6, a pro-inflammatory cytokine which has been associated with fatigue, were found early in the illness.

IL-10

High Il-10 levels at baseline may be a biological risk factor for coming down with ME/CFS.

The researchers speculated that patients’ immune systems were primed to take off prior to their receiving the drug – and it was this immune priming which lead them to become ill after taking the drug.

Six months later their IL-10 levels, interestingly, were normal – suggesting that IL-10 had done it’s work quickly and then faded into the background, leaving behind a chronic state of fatigue.

The beauty of this study is that it identifies possibly the earliest blood factor yet – increased IL-10 levels – that may set someone on the path to developing ME/CFS.

While the authors didn’t attempt to explain how these factors produce ME/CFS, some possibilities immediately present themselves. Higher than normal IL-10 levels could suppress one’s ability to quickly clear an infection.  High IL-10 levels and several IL-10 polymorphisms have also been associated with the development of lupus, an autoimmune disorder.

Andrew Miller of Emory University has some ideas of his own.

Miller Time

Andrew Miller, PhD also believes that the ‘sickness behavior’ he finds in hepatitis C patients given IFN-a is similar to what’s happening in ME/CFS.  Miller, however, came to that conclusion, by looking at the brain.

He found reduced activation of the striatum – a part of the basal ganglia that produces dopamine – in fatigued hepatitis C patients and people with ME/CFS. This finding suggested that reduced dopamine levels in ME/CFS may be producing problems with motor activation (physical activity) and fatigue. Indeed, primate studies indicate that immune activation in the presence of low dopamine levels results in enormous fatigue, motor slowing, and depression.

Unrewarding Reward: The Basal Ganglia, Inflammation and Fatigue In Chronic Fatigue Syndrome

Another study, taking a deeper look at what happens to a brain on IFN-a, found it took just four hours for IFN-a to produce microstructural changes in the left striatum – changes that were “strikingly correlated” with the development of fatigue. The authors reported that increased levels of lactate and altered pH – two problems found in ME/CFS –  may set the stage for these microstructural abnormalities.

Microstructural Havoc: The Immune System, Fatigue and the Brain – An ME/CFS and FM Scenario

Immune Hypersensitivity Syndrome?

This presents the possibility that infection-produced inflammation could knock out dopamine production permanently, leaving behind – and this may be the important part – a hypersensitized reaction to inflammation. Miller believes that dopamine deprivation causes the basal ganglia to over-respond to inflammatory signals, resulting in the fatigue and other symptoms associated with “sickness behavior”.

That sickness behavior includes mood changes. The British group found that a “biological sensitivity”, or over-reaction to IFN-a, predicted who would come down with depression while on the drug.

When Anthony Cleare of King’s College trashed Montoya’s cytokine findings last year because they didn’t show cytokine elevations, he missed the point that Montoya’s results may have pointed to a possible exquisite sensitization to cytokines in ME/CFS.

Conclusion

It was very good to see an MRC-funded physiological study pan out and get such abundant media coverage.  Thankfully, Lenny Jason is in a good position to follow up on this study result to see if IL-10 is indeed raised in young people who fail to recover from infectious mononucleosis. If that pans out, the first predisposing factor for ME/CFS in the blood will have been found.

That finding will then give us an entry point to determining how ME/CFS comes about. Avindra Nath’s and Derya Unutmaz’s studies of short-duration post-infectious ME/CFS patients would hopefully be able to piggyback on the British finding and begin to unravel the genesis of ME/CFS.

The basal ganglia/hepatitis connection is fascinating because it suggests that the Brits’ hypothesis, that fatigued hepatitis C patients present a good model for ME/CFS, may be correct. Andrew Miller’s and other studies suggests that the brain changes in ME/CFS replicate those of the fatigued hepatitis C patients. Interestingly, they affect the basal ganglia – a part of the brain involved in motor activation (physical movement), learning, cognition and fatigue.

Miller’s hypothesis that inflammation may knock out dopamine production in the basal ganglia resulting in a hypersensitization to immune signals in ME/CFS is compelling. Neuroinflammation has been linked to microglial activation and reduced dopamine levels.  Plus two studies have found reduced basal ganglia activation in FM. One study suggested the basal ganglia could be causing the movement problems in FM.

Spinning Fibromyalgia: Brain Findings Suggest Dopamine May Be Key

Given that the basal ganglia affects movement, fatigue and reward, it would seem to present a rich vein for ME/CFS researchers to mine.  In other fields, researchers would probably be vigorously digging away at a vein with this much potential ore in it, but in ME/CFS researchers are just scratching the surface. Getting  more out of the research community will require that the federal government fulfill its promise to invigorate this field.

In the meantime, it’s good to see the MRC and the Brits, psychiatrists most of them (!), make good on a physiological study, hopefully set the stage for more to come.