All posts by Cort Johnson

Ian Lipkin on Long Hauling with the Coronavirus, a Possible B-cell Subset, and Protein Biomarkers for ME/CFS

Dr. Ian Lipkin, known to much of the world as the “virus hunter”, has throughout his career developed new technologies for discovering viruses and has uncovered many new viruses. Recently, Lipkin uncovered the apparent cause of a puzzling and devastating disease affecting children called acute flaccid myelitis (AFM).  He’s helped to uncover several potential subsets in ME/CFS including Dr. Peterson’s “atypical subset” and a gut subset. Dr. Lipkin leads the NIH funded Center for Solutions for ME/CFS at Columbia University’s Center for Infection and Immunity (CII).  He, Dr. Mady Hornig and their colleagues there have contributed important insights into our understanding of ME.

Simmaron Research has had a special collaboration with Lipkin and CII over the years, especially through its signature studies on spinal fluid of ME/CFS patients.  The Simmaron Research Foundation has collaborated with Dr. Lipkin and/or Hornig on 7 peer reviewed publications.  Dr. Hornig, one of the co-authors of the proteome study, is a member of the Simmaron Research Foundations Scientific Advisory Board.

Between the coronavirus pandemic and publication of groundbreaking proteomics results, there was a lot to discuss with Dr. Lipkin.

Coronarvirus

Ian lipkin coronavirus

A sick Ian Lipkin talking to Dr. Oz in March. He has not fully recovered from the virus.

It’s not surprising that Ian Lipkin, one of the top virologists in the world, has been featured again and again in media stories about the coronavirus. Lipkin was hailed for flying to China in 2003 while it was in the midst of the first coronavirus outbreak (SARS) and playing a key role in helping the Chinese build a pathogen response system. Lipkin quickly flew to China during the present Sars-Cov-2 outbreak, and then, ironically, became infected with the virus in March while back in New York City.

I asked him a series of questions, including how he was doing almost six months later. Ian Lipkin, unfortunately, has joined the long-hauler community. Fortunately for him and us, his cognitive faculties have not been affected.

I have not recovered completely. My capacity for exercise is reduced. Fortunately, there is no cognitive impairment. The experience has given me a deeper appreciation for the challenges faced by people with ME/CFS. However, my level of disability does not compare with what many people with ME/CFS suffer.

Q: what can the U.S. expect from the coronavirus over the fall/winter?

I am concerned that we will see a surge in disease as people move indoors and schools and businesses re-open. Until vaccines are readily available it will continue to be important to maintain physical distancing and to wear masks. These are are the best tools we have for reducing virus transmission.

Q:  KCRW reported that you’ve seen many COVID-19 patients with long term fatigue. The COVID-19 long haulers obviously present a real opportunity to catch a post-infectious illness in its tracks. A year from now do you believe we are going to have some answers to how these mysterious post-infectious illnesses occur?

It is too early to know how the fatigue associated with COVID-19 relates to ME/CFS. Some COVID-19 survivors have severe lung and/or heart damage that is clearly different from what is observed in ME/CFS. I nonetheless think we need to be open to the possibility that COVID-19 may provide clues that will help us understand and develop new approaches to ME/CFS.

Q: A vaccine or rather vaccines are coming. I’m sure much will depend on how effective the vaccines are, but do you have any idea what percentage of the US population needs to be vaccinated to really stop the virus?

This point is controversial. Most of my colleagues who model the spread of COVID-19 have estimates in the range of 60-80%.

Q: As bad as the coronavirus has been, it could have been much worse. A highly contagious and highly deadly virus could have produced a disaster unlike anything we could imagine. Are you seeing signs that the U.S., China and other countries are bulking up their pathogen detection capabilities?

China has been building capacity for infectious disease surveillance since 2003 when SARS devastated its health care system and economy. There is nonetheless room for improvement in both China and the US. I am strongly advocating for GIDEoN, a global surveillance system, where countries commit to sharing information. This is our best hope for preventing future pandemics.

Q: You were just starting or about to start a study using the same Serochip analysis on people with ME/CFS that you used to understand acute flaccid myelitis – a mysterious illness affecting young children –  which had defied attempts to understand it. The Serochip analysis could uncover a pathogen or pathogens which initiated ME/CFS or an autoimmune reaction underway.  What is the status of that study, and how has the coronavirus shutdown affected your ME/CFS work?

The pandemic did force us to temporarily table this work. Only last week, we began analyzing samples from Derya Unematz of the Jackson Laboratories using the SeroChip.

Lipkin Brings Disease Busting Technology to ME/CFS

The Proteomics Paper

Proteomics has kind of been the lost “omics” field in ME/CFS. Genomics (the study of genes), transcriptomics (the study of gene expression), metabolomics (the study of metabolites) and even epigenomics (the study of epigenetic modifications of the genome) have all had their moments but proteomics (the study of proteins) has  been mostly left behind.

Only four proteomic ME/CFS studies have been done – none of which, interestingly, has been done on the blood.  The first on cerebrospinal fluid (CSF) occurred back in 2005, the second in 2011 (CSF), one seven years ago in 2013 (saliva), and one in 2016 (saliva). Each has had interesting results. The last study – a saliva study – pointed a finger at mitochondrial proteins. (Update – two proteomics studies were recently published: a New Zealand study using PBMC’s and an Australian study examining immortalized lymphocytes.)

Proteomics has the potential to reveal much. Genes, after all, code for proteins, and it’s the proteins that do the actual work of the cell. Because they play that crucial role, proteomics has particularly been used to identify biomarkers, produce diagnostic tests, and drug targets.

Studying proteins, however, is in some ways more difficult that studying genes. Genes, at least, are constant and unchanging. Their expression may be modified but they themselves remain the same. Proteins, on the other hand, change from cell to cell and in the same cell over time. Many of them undergo processes such as phosphorylation and ubiquination that modify their structure.

Assessing proteomics, then, is a potentially very fruitful but nonetheless complex endeavor.

The Study

Plasma proteomic profiling suggests an association between antigen driven clonal B cell expansion and ME/CFS, Milica Milivojevic , Xiaoyu Che , Lucinda Bateman, Aaron Cheng, Benjamin A. Garcia, Mady Hornig, Manuel Huber, Nancy G. Klimas, Bohyun Lee, Hyoungjoo Lee, Susan Levine, Jose G. Montoya, Daniel L. Peterson, Anthony L. Komaroff, W. Ian Lipkin. Plos One : July 21, 2020. https://doi.org/10.1371/journal.pone.0236148

Our work, whilst exploratory in nature, shows that the plasma proteome is a viable and untapped source of potential biomarkers in ME/CFS, and can provide insight into disease pathophysiology. The authors

This present study – using “ultra-performance liquid chromatography-tandem mass spectrometry” – is the first done on plasma. It assessed the plasma of 50 ME/CFS cases and 50 controls from the practices of ME/CFS experts (Dr. Peterson, Dr. Klimas, Dr. Bateman, Dr. Levine) across the country. Various self-report questionnaires were used including one to assess if the symptoms of irritable bowel syndrome (IBS) were present.

immunoglobulin

A subset of patients appeared to have high levels of an immunoglobulin that has been linked to disease before.

The team at CII ploughed through hundreds of proteins. While a linear model didn’t pick up any proteins, a linear plus quadratic model appears to have struck proteomic gold – at least for a subset of patients. Twelve ME/CFS patients had “extremely high” levels of a protein called IGHV3-23/30 – an immunoglobulin protein.

Immunoglobulins refer to antibodies produced by B cells which bind to pathogens, neutralize toxins, regulate immune system functioning and help kill cells infected with bugs.  The immunoglobulin system wards off infections but when it goes wrong it can produce autoimmune diseases and contribute to cancer.

The region of the genome IGHV3-23/30 comes from is associated with Non-Hodgkins lymphoma’s (NHL), Waldenstrom’s macroglobulinemia, anti-myelin associated glycoprotein neuropathy and monoclonal gammopathy. The lymphomas have been linked to a bacterial driven immune response or an autoimmune response. One study has suggested an increased risk of NHL in ME/CFS.

So, why did massive amounts of one particular immunoglobulin appear to be present in about a quarter of the ME/CFS patients? The authors speculated that an antigen – something that was activating the immune system – was driving the expansion of a set of B-cells associated with these immunoglobulins.  They suggested that identifying that antigen or the use of kinase inhibitors that could effect the functioning of IGH3-23/30 could be helpful in these patients.

If this finding holds up, it should be noted that dozens of kinase inhibitors are available or are under development for the treatment of cancer and inflammatory diseases.

Additionally, another immunoglobulin  IGKV3(D)-11 was significantly associated with ME/CFS patients without IBS.  Increased levels of this immunoglobulin, interestingly, enough have shown up with IGH3-30 in response to a cytomegalovirus (CMV) or Streptococcus pneumoniae infection.

Every study Lipkin does seems to further differentiate ME/CFS patients with IBS from those without and this study was no exception. In the past he’s found different set of metabolites and distinctive gut flora in this group. This time the ME/CFS+IBS group was distinguished by a protein –  IGLC7 – another B-cell associated immunoglobulin protein – this time associated with antibody regulation.

Biomarkers

IGF-1

The low levels of IGF-1 found in ME/CFS have also been found in infection, trauma and aging

Next the group looked for a biomarker. Biomarker identification is a burgeoning field in proteomics. Just in the past couple of weeks, studies have used proteomics to  determine how sick a COVID-19 patient is likely to become, how sick people with bacterial infections will get, which athletes will have more trouble recovering from a concussion and potential protein biomarkers in type II diabetes.

Using a variety of techniques the Lipkin group attempted to identify proteins that have high diagnostic efficacy using “Area under the curve” (AUC) analyses. These analyses identify how well a result identifies a patient group. A value of 0 indicates a perfectly inaccurate test and a value of 1 reflects a perfectly accurate test; i.e. every patient is correctly identified.

Eight plasma proteins with high AUC’s (up to .838) were identified. While no particular pathways were distinguished, a strong focus on the immune dysregulation with several proteins involved in B-cell regulation was seen throughout.

  • cathelicidin antimicrobial peptide (CAMP) – an antimicrobial peptide increased during both bacterial and viral infections, high CAMP levels have been found in several autoimmune/inflammatory diseases
  • Ig lambda variable region 1–47 (IGLV1-47) – associated with B cells and decreased in ME/CFS
  • Fc receptor-like protein 3 (FCRL3) – found in low levels in ME/CFS FCRL3 has been shown to inhibit B-cell signaling. Reduced levels of this and IGLVI-47 suggest problems with B-cell regulation may be present in ME/CFS.
  • leucin-rich glycoprotein 1 (LRG1) – lower levels of this pro-inflammatory protein could reflect problems with neutrophil functioning which have cropped up in ME/CFS in the past
  • gelsolin (GSN) – decreased levels of this actin scavenger could result in inflammation and oxidative stress. Lower serum GWN levels have been found in inflammatory conditions
  • cartilage acidic protein 1 (CRTAC1) – the presence of a connective tissue protein is intriguing
  • insulin-like growth factor 1 (IGF1) – The low levels found in ME/CFS are interesting given that low levels of IGF1 have been associated with infection, trauma, and aging. This protein has shown up in ME/CFS before.
  • IGF-binding protein acid labile subunit (IGFALS) – an IGFI binder low levels were also found in ME/CFS

Breaking Up ME/CFS?

Next – in a step which showed how serious Lipkin is about assessing the possible differences between the IBS+ and IBS- group, they attempted to see if they could use proteomics to differentiate the ME/CFS+IBS group from the ME/CFS group.

Five proteins (LRG1, CRTAC1, IGLC7, KNG1, PON3) differentiated the ME/CFS-IBS group. One of them in particular (KNG1), with it’s impact on inflammation (bradykinin), blood vessels and pain, appears to fit ME/CFS well.

gut flora

One group of ME/CFS patients may have gotten the illness via the gut. It’s possible that rebalancing the gut flora could help.

Six proteins differentiated the ME/CFS+IBS group (IGF1, CRTAC1, and CAMP, SERPINA3, ITIH2, IGHV1-18), with B-cells, inflammation and oxidative stress providing a familiar theme.  Very high levels of CAMP – an antimicrobial peptide found in several autoimmune diseases and in the mucosa of inflammatory bowel disease (IBD) – particularly distinguished the ME/CFS+IBS group. IBD is a broad term used to describe diseases like ulcerative colitis and Crohn’s disease.

The authors speculated that gut dysbiosis (dysregulated gut flora) results in increased inflammation and gut permeability resulting in higher plasma levels of CAMP and a protein named PIGR. That was encouraging given that it should (hopefully) be possible at some point to repopulate the gut with a better floral mix.

Despite the fact that Lipkin found gut dysbiosis in all ME/CFS patients, he found a distinctive gut flora in ME/CFS+IBS vs ME/CFS-IBS patients. He also found dysregulated metabolic pathways that were common to both groups. With the two groups sharing some similarities and differences, it’s not clear how closely allied these two groups are.

For those thinking the gut couldn’t possibly be a major issue, Lipkin found in a separate study that the severity of symptoms such as pain, fatigue, and reduced motivation were correlated with distinct gut species and the metabolic pathways they impacted.

“The Subset Maker”: Lipkin Chronic Fatigue Syndrome Study Highlights Energy Issues In Gut Subset

I asked Lipkin about the two ME/CFS groups:

Q: Your work has now shown a divergence between ME/CFS+IBS and ME/CFS-IBS patients with regards to metabolites, the microbiome and now proteins.  Some commonalities between these two groups have been seen but also some distinct differences. How close would you speculate the two groups are? Is IBS a kind of add-on to the general group of ME/CFS patients, or are ME/CFS with IBS patients fundamentally different?

There are many paths to ME/CFS. One is associated with intestinal dysbiosis and may respond to dietary and pre- and probiotic interventions.

I also asked Lipkin about the overall study results:

Q: This was an exploratory study. Besides the IgG finding, it uncovered a set of potential biomarkers that might differentiate the ME/CFS group as a whole and between ME/CFS+IBS and ME/CFS-IBS patients. Were the results good enough to pull for a larger study, and how much larger would a proteomics study need to be to produce really robust results?

As you note, this was an exploratory study. We will need to examine samples from a minimum of another 100 people with ME/CFS and 100 matched controls. The results are nonetheless intriguing and support the hypothesis that at least some patients have immunological abnormalities.

The study was funded by an NIH grant and the Solve ME/CFS Initiative.

Conclusion

Ian Lipkin, Mady Hornig, and the CII team produced the first proteomics study done on plasma in ME/CFS, in collaboration with clinical experts including Dr. Peterson and Simmaron. Since proteins do the work in cells they represent a particularly direct way of getting a biological snapshot of what’s happening in a disease.  Because proteins change over time and from cell to cell, and can be affected by different processes, proteomics studies are complex endeavors. Proteomics has, however, been used successfully many times to uncover biomarkers.

A linear plus quadratic approach in this preliminary study uncovered a possible subset of patients with high levels of an immunoglobulin (antibody) which suggested that B-cells in this group of patients have responded to a pathogen or are engaged in an autoimmune reaction. Validating this finding could open to the door to use of kinase inhibitors in ME/CFS.

A search for a biomarker yielded eight possibilities, most of which were involved in the immune response – and some of which were associated with B-cells.

While some similarities were seen, this study also added to a string of studies which suggest that ME/CFS+IBS patients have different proteomic, metabolomic and transcriptomic profiles; i.e. that they differ biologically in significant ways. Very high levels of one protein (CAMP) suggested that an autoimmune process may be underway, and that ME/CFS+IBS patients may have something in common with people with inflammatory bowel disease. The authors proposed that gut dysbiosis (altered gut flora) in these patients was resulting in increased gut permeability (leaky gut) and inflammation.

The authors warned that larger studies are needed to validate the findings in this study. With a B-cell subset of patients appearing, eight candidate protein biomarkers showing up, and with ME+IBS patients being further differentiated from ME/CFS-IBS patients, one would hope, though, that this study proves to be a stepping stone to a much bigger study.

This study furthers Simmaron’s work to collaborate in scientific investigations that have the potential to identify immune-based biomarkers and characterize ME/CFS subsets, so we can discover effective treatments for patients.

Old Drug Points To a New Way To Knock the Epstein-Barr Virus Down

A recent study suggested that Epstein-Barr reactivation might be present in substantial number of people with ME/CFS.  Anti-herpesvirus drug protocols in ME/CFS, however, tend to last very long and aren’t always successful.  The same drugs have been used for decades. That, however, could be changing, though.

Some studies remind us to always be ready for surprises – to not think that we know so much. The body is always throwing us curveballs and it turns out that sometimes drug companies can as well. The spironolactone saga in EBV reminds us that important answers to ME/CFS and other diseases might not need to come from some sophisticated R&D drug program but might literally, right now, be found down the aisles of a pharmacy.

EBV Reactivation

The goal – find a new drug that could stop EBV from reactivating.

Sankar Swaminathan MD, Chief of the Division of Infectious Diseases at the University of Utah, has been publishing on Epstein-Barr virus  for almost 20 years. Besides infectious mononucleosis – a common trigger for ME/CFS – EBV has been associated with autoimmune diseases and a host of cancers.

Four years ago, Swaminathan and colleagues went on a search to find a drug not to kill EBV – the bug is too firmly embedded in our cells to hope for that – but to stop it from reactivating. It’s when EBV awakens from its latent state and begins reactivating that it becomes the most dangerous. If Swaminathan could stop EBV from doing that he would have achieved a momentous goal.

He had an important clue. He knew that EBV (and other herpesviruses) produced a protein called SM that played a critical role in the early stages of EBV reactivation. He also knew that current slate of herpesvirus drugs left SM untouched – suggesting the protein presented a new possibility for a new herpesvirus drug.

The Study

Verma D, Thompson J, Swaminathan S. Spironolactone blocks Epstein-Barr virus production by inhibiting EBV SM protein function. Proc Natl Acad Sci U S A. 2016;113(13):3609-3614. doi:10.1073/pnas.1523686113

“It’s remarkable that a drug we have used safely in the clinic for over 50 years is also an effective EBV inhibitor. It goes to show how basic research can reveal things we would never have found otherwise”  Swaminathan

His team found a way to target the protein, and then created an assay that allowed them to screen compounds for antiviral activity.

Then came the surprise – spironolactone – a 50 year old drug knocked EBV down. The drug not only stopped EBV from forming the capsid or top layer of EBV that it needs to replicate, but it also blocked the expression of genes the virus used to replicate as well.

aldactone - spironolactone

No one suspected that a kidney drug of all things might hold the key to beating EBV. (Aldactone – brand name for spironolactone)

Spironolactone, though, has never been known as a antiviral. Far from it – it’s a mineralocorticoid receptor antagonist used to treat kidney disease, heart failure and edema.

The researchers found that its mineralocorticoid antagonist properties weren’t suppressing EBV – something else was.  Although, the researchers were unsure just how it was doing it, it was clear the drug doing something to EBV that no other drug had done. It had the potential to open a new era of more effective herpesvirus treatments.

Spironolactone, itself wasn’t the answer. While it’s been used for decades it can have significant side-effects. Besides some potentially toxic effects, it also increases the secretion of salts – something that salt craving ME/CFS patients might not find so beneficial.

The authors suggested that spirolactone’s most important role lay not in the drug itself, but in its ability to pointing to how produce more effective herpesvirus drugs. Noting that the current basket of anti-herpesvirus drugs suffers from problems with side effects and increasing rates of drug resistance, they suggested spirolactone be used “as the template for development of antiherpesvirus drugs”.

“We think there is great potential to modify this molecule so that it can work as an antiviral without having undesired side effects,” Swaminathan.

First, though, they would have to find out how Spironolactone was doing what it was doing.

Mystery Solved –  and the Hunt for a Better Anti-Herpesvirus Drug Begins 

Dinesh Verma 1Trenton Mel Church 1Sankar Swaminathan 2 3Epstein-Barr Virus Co-Opts TFIIH Component XPB to Specifically Activate Essential Viral Lytic Promoters Proc Natl Acad Sci U S A. 2020 Jun 9;117(23):13044-13055. doi: 10.1073/pnas.2000625117. Epub 2020 May 20.

“These findings pave the way for development of antiherpesvirus drugs with new mechanisms of action” Verma et. Al.

Four years later – and at about the same time that an ME/CFS study found direct evidence of EBV reactivation in about a quarter of patients –  the mystery of how a kidney drug came to beat back EBV was solved.

Active Epstein-Barr Infections Found in Large ME/CFS Study

Spironolactone, it turns out, stops or inhibits the transcriptions of 15 genes the virus needs to replicate. The researchers knew that SM – the protein which had lead to the discovery of spironolactone – enhances the activation of those genes. What they didn’t know is that the SM protein does that by ferrying another protein called XPB to EBV’s DNA, at which point XPB turns on the genes that begin EBV’s replication process.

EBV virions

EBV virions (circles). An XPB directed drug might be able to keep EBV under wraps.

XPB, then, provided a new, earlier, possibly more effective target for shutting down EBV. The University of Utah researchers are now trying to find new drugs that target XPB with the goal of keeping EBV and other herpesviruses in their latent states.

Spironolactone, then, didn’t turn out to be the EBV inhibitor the medical world is looking for. The 50 year old kidney drug did, however, provided the clue they needed to start developing a new generation of more effective anti-herpesvirus drug.

The Spironolactone saga shows that  answers to medical issues can come from unexpected places – including old, old drugs – that no one would think to explore.

Novel assays – like the one developed by the University of Utah team – and new data mining techniques will undoubtedly provide surprising new insights in the years to come. Some answers to ME/CFS and other diseases could be in plain sight – if only we can see them.

Active Epstein-Barr Infections Found in Large ME/CFS Study

“EBV is an important factor for the development of the disease” in at least a subset of patients.  The authors

A new study is revitalizing a long simmering question about the role of Epstein Barr Virus and other herpesviruses in ME/CFS.

herpesviruses ME/CFS

Herpesviruses have been studied in ME/CFS for decades. Few studies, though, have looked for direct evidence of active infection.

Herpesviruses just never seem to go away, in the ME/CFS field. They’ve been studied on and off for decades in chronic fatigue syndrome (ME/CFS) and yet the research keeps coming.

Why? For one reason, reactivated latent viruses are too juicy a possibility for an illness that often starts with an infection. ME/CFS also produces symptoms similar to those  produced by “sickness behavior”: a process initiated by the brain that’s designed to keep us in bed to stop spreading an infection. Plus enough positive study results have kept the herpesvirus theme alive in ME/CFS.  While negative studies can be found, too many positive studies have kept this inquiry from fading.

The Study

And now we have another positive result. A Bulgarian team (on behalf of the European Network on ME/CFS (EUROMENE)) assessed the prevalence of latent and active Epstein-Barr, cytomegalovirus and human herpes virus 6 in 108 ME/CFS patients and healthy controls (58 ME/CFS; 50 healthy controls).

Besides being larger than many past studies, this study went a step further than most past studies. Most studies have relied on more indirect measures such as antibody tests that assess whether an immune response has been raised to determine whether active herpesvirus infections are present. This study, though, assessed antibodies and used a process called PCR to directly look for signs of herpesviruses (herpesvirus DNA) in the plasma.

While several EBV antibody studies have had conflicting results, I was able to find only published two studies that have assessed active EBV infections using PCR. Neither found evidence of active herpesvirus infections in ME/CFS. One, however, was very small (n=20) and the other was 20 years old.  In 2013, though, Ian Lipkin reported in a CDC talk that he failed to find direct evidence of herpesvirus infection in almost 300 people with ME/CFS.

Foremost Virus Hunter Finds Biomarkers, Few Viruses in Big Chronic Fatigue Syndrome Study

If pathogens are in a latent state they should remain in the cells and not be present in the blood. Almost all of us carry latent or inactive herpesvirus infections in our cells. They are not a cause for alarm. Active herpesvirus infections, in which the pathogen is actively replicating and spreading from cell to cell through the blood, are another matter.

Results

The study did not find evidence of increased active cytomegalovirus or HHV-6 infections in the ME/CFS group.  Two findings, however, suggested that active EBV infections – perhaps similar to those found in infectious mononucleosis/glandular – were significantly more prevalent in the ME/CFS group.

Cell infected with herpesviruses

A cell infected with herpesviruses (green dots) (from National Cancer Institute)

Almost 25% of the plasma samples from ME/CFS patients were positive for EBV DNA.  Almost 2/3rds of those patients also had high levels of antibodies (EBV‐CA IgG class antibodies) that have been linked with active infections.  (This type of antibody latches onto an antigen on the capsid or shell of the virus. These particular antibodies fade quickly after the virus is vanquished from the blood.)

The study didn’t find evidence of active HHV-6 or CMV infections. (Some researchers, however, believe that a smoldering infection that this type of research wouldn’t detect may present in a subset of ME/CFS patients. Also low level HHV-6 infections in the organs may not  show up in the blood.  Nor did the study assess the early EBV proteins that Williams at Ohio State University has been finding in ME/CFS.)

Using both serological tests and PCR, this study provided a robust finding of an active EBV infection in about 20% of the ME/CFS patients tested. The authors asserted that this finding indicated “EBV is an important factor for the development of the disease” in at least a subset of patients.

The EBV ME/CFS Saga Continues

There’s plenty of reason to be concerned about an active EBV infection. Researchers are continuing to explore the role EBV plays 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.

 

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

The EBV saga in ME/CFS is littered with interesting and sometimes conflicting findings. We know that EBV – the main pathogen associated with infectious mononucleosis/glandular fever – is a common trigger for ME/CFS. Several studies also suggest that immune response to EBV may be lacking in some patients; i.e. some people with ME/CFS appear to have trouble fighting it off.  Some studies have found a paltry antibody response to the virus. Other studies, however, have found no evidence of an immune hole.

Over the past decade Ariza and Williams at Ohio State University have methodically been making the case that a smoldering EBV infection is producing fatigue and other symptoms in a subset of people with ME/CFS. A recent study suggested that smoldering infection could be producing neuroinflammation.

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

The Autoimmune Virus?

On a broader front, a 2018 study which the lead researcher called “a capstone to a career in medical research” suggested that EBV is a kind of autoimmune accelerator that is turning on genes associated with autoimmune disease – an interesting finding given the possibility of an autoimmune subset in ME/CFS.   Two gene expression studies done ten years ago suggested that EBV was turning on/off multiple genes in ME/CFS patients cells.

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

 

This Euromene study was too small (n=108) to be definitive, but the dual testing approach (PCR and serology) provided confidence in its results. Clearly, the EBV story in ME/CFS – like the EBV story in so many diseases – is not over.  If an active EBV infection is present in a significant subset of patients the next question is what to do about it.

With regards to that question, a recent study has produced some potentially very good news on the treatment front. That blog is coming up next.

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

The Blood Vessel Crunch: A Unifying Hypothesis for ME/CFS

This is another hypothesis paper that gives one hope – and makes one wonder if the authors might have a handle on what’s happening with chronic fatigue syndrome (ME/CFS). The paper proposes that a tantalizingly simple problem – an autoimmune attack on just one receptor – out of hundreds of potential receptors –  could be causing virtually all the symptoms of ME/CFS.

B2AdR

Could an autoimmune process attacking the B2 adrenergic receptor be causing the symptoms of ME/CFS?

Receptors dotting the surface of a cell don’t seem impressive, but they’re actually the key to the activity of our cells. Lock onto a receptor and you make the cell change. Most drugs don’t target cells – they target the receptors on cells.

Could just one messed up receptor, though, produce the symptoms of ME/CFS? If it’s an important enough receptor found in enough places – yes, it can, and the receptor in question in this paper –  the beta-2 adrenergic receptor or B2AdR is indeed a heavy duty receptor.

Found in the blood vessels in the brain, the skeletal muscles and the heart, it is a downstream mediator of the sympathetic nervous system (fight or flight system)  which among other things, controls blood flows.

The evidence for B2AdR dysfunction in ME/CFS is building. It’s not overwhelming – it’s not a done deal, but it’s pointing in a very intriguing direction.

One study from a Simmaron collaborator has found elevated levels of B2AdR autoantibodies (antibodies that attack the receptor) in ME/CFS and another is believed on the way. Small mutations in the genes that produce the receptors have been found as well. Plus, similar mutations have been associated with a kind of mild ME/CFS-like state as well. Finally, Scheibenbogen’s work suggests that ß2AdR autoantibodies stimulate the ß2R signaling, but in a subset of ME/CFS patients their functioning has been blunted.

Simmaron Research collaborated with Carmen Scheibenbogen in a pilot study of B2AdR autoantibodies in ME/CFS by contributing patient samples and funding in 2018.

Unifying Hypothesis?

That was enough evidence for Klaus Wirth MD and Carmen Scheibenbogen MD in Germany to believe they had to get the word out and in doing so built a grand, indeed a “Unifying” hypothesis of ME/CFS.

A Unifying Hypothesis of the Pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Recognitions from the finding of autoantibodies against ß2-adrenergic receptors. Klaus Wirtha, Carmen Scheibenbogen, Autoimmunity Reviews, 2020

Numerous documented problems in ME/CFS including low heart rate variability, chronotropic incompetence (inability of the heart rate to increase appropriately during exercise), something called QTc shortening (shortened ventricular repolarization)

The ß2AdR’s in the blood vessels play an important role in opening or dilating the blood vessels  enough during exercise to accommodate up to 20-fold increases in blood flows muscles will see.  In order to do that the blood vessels release a wide variety of vasodilators such as adenosine, ATP, prostaglandins, (PGEs), prostacylin (PCI), bradykinin (BK) and protons.

scheibenbogen

Carmen Scheibenbogen has been studying autoantibodies in ME/CFS for several years

During exercise the body also needs to send blood to the active areas and shunt it away from non-exercising areas. The arteries clamp down to send the blood forcefully to the small blood vessels in the muscles which in turn must open to receive and use the large quantities of blood they need. This process of clamping down on the blood vessels in one end and opening them up on the other is called “functional sympatholysis”.

The authors believe that the heightened sympathetic nervous system activity clamps down hard on the arteries. Meanwhile the B2AdR dysfunction impairs the ability of the small blood vessels to dilate. This dysbalance between vasoconstrictor and vasodilator forces – with the vasoconstrictors winning – triggers the release of  painful vasodilating substances in an attempt to open the blood vessels. The entire process is, in turn, enhanced by the metabolic/energetic problems in the muscles.

In what appears to be a rough blood vessel equivalent  (i.e. leaky small blood vessel syndrome?) this enormous production of vasodilators leak into the interstitial spaces found between the blood vessels, the lymph and the cells.  This happens because one of them, bradykinin,  also happens to be pretty good at enhancing microvascular (small blood vessel) permeability. So now you have some potent peptides in a place they shouldn’t be – which is always a recipe for problems.

Throw that together with a balky energy production system in the muscles and you have a three way mess. The muscles aren’t, in what appears to be a low oxygen (hypoxic) environment, producing enough energy. The bigger blood vessels, on the other hand, are clamped down tight. The small blood vessels stuck in the middle pump out scads of vasodilators which, when they leak out into the tissues exact a price.

This process occurs in dysmenorrhea (menstrual cramps) when tissues in a hypoxic (low oxygen) and hyper-contracted uterus pour vasodilators into the blood causing fatigue, flu-like symptoms, fever, pain and even the sleep disturbances. (Dysmennorhea or endometriosis has been found increased in ME/CFS.)

The situation is a little different in ME/CFS – the authors believe it’s the blood vessels that are in a hypercontractile state – not the muscles. In fact, with the vasodilators pouring out, the authors don’t believe the muscles in ME/CFS are necessarily in a strongly hypoxic state at all.

If a hypercontractile or hypoxic uterus sounds bad, though, consider what hypoxic, hypercontractile blood vessels in the skeletal muscles across the body might be like – maybe something like ME/CFS.

Weird Cardiovascular Findings

The authors propose that  ß2AdR dysfunction could also be responsible for the weird cardiovascular situation found in ME/CFS. Calling the cardiovascular findings in ME/CFS “unique and not found in any other condition or disease”, the authors listed them: hypovolemia (low blood volume), reduced preload (reduced blood flows to the heart), low cardiac output at rest, small hearts, and the kicker – the low renin-angiotensin-aldosterone system (RAAS) activity.

A big and never answered – and rarely asked – question about ME/CFS is: why is the blood volume low? That brings up another more recently asked but similar question:  why are low venous blood flows to the heart consistently found as well? In other words, where the heck has the missing blood gone?

RAAS - Wikimedia

An underactive RAAS system in ME/CFS is a mystery given the low blood volume present. The authors have an idea why.

It’s a big question. For one thing, low blood volume alone could cause the sympathetic nervous system to go onto hyperdrive and put the vagus nerve (the rest and digest system) to sleep.

The real mystery, though, involves what’s going on with the renin-angiotensin-aldosterone system (RAAS) in ME/CFS. Low blood volumes should automatically activate that system to increase the blood volumes, but paradoxically, instead of being increased, RAAS activity appears to be reduced in this disease.

Because, as noted above, low blood volume sends the sympathetic nervous system into overdrive, the inability of the RAAS to do its job could play a major role in ME/CFS. For some reason the RAAS has hardly ever been looked into in this disease.

Wirth and Scheibenbogen have certainly been looking. They turned, once again, to a vasodilator – bradykinin – for a possible answer. While bradykinin attempts to open the blood vessels, it may also be inhibiting RAAS activity and blood volume enhancement at the same time.

The Spillover Effect

The authors don’t believe that these problems are just happening in the muscles. They believe that just about every symptom in ME/CFS could be caused when vasodilatory substances spill over into the general circulation, around the muscles, the lymph nodes, the gut and the bladder.

Provided that enough of these vasodilatory substances were present, every stress on the cardiovascular system could result in fatigue, pain, flu-like systems etc.

Even mental stress, they believe, could cause pain by triggering the sympathetic nervous system to clamp down further on the blood vessels of the skeletal muscles, causing them to emit vasodilators in an attempt to get more blood, and producing pain, flu-like symptoms, etc. For me, personally, this could explain the muscle pain and flu-like symptoms I often experience simply sitting in a chair while doing mental work.

bradykinin

The authors focused on bradykinin – a vasodilator which can also cause pain and increase vascular permeability

The chief vasodilator  – bradykinin – a seemingly all purpose peptide, could also open the blood-brain barrier, and contribute to the intracranial hypertension, small fiber neuropathy, sleep apnea and sleep problems present. Given the low blood volume and preload failure predicted by the spillover of vasodilatory substances, orthostatic intolerance (trouble standing) would be a natural outcome.

An add-on factor in ME/CFS may be a dysfunction of the endothelial cells lining the blood vessels. Autoantibodies to B2AdR receptors could be keeping the blood vessels in ME/CFS from dilating enough.

The chronicity of it all could play a role as well. Given enough cardiovascular stress the B2AdR receptors will simply disappear.

A local TV report triggered Klaus Wirth's interest in ME/CFS

A local TV report triggered Klaus Wirth’s interest in ME/CFS

Mystery Man

But what about Klaus Wirth? We’ve never heard his name before, yet here he is the co-author of a major hypothesis paper on ME/CFS. Wirth, it turns out, an experimental pharmacologist focused on cardiovascular research in Sanofi-Aventis Deutschland in Frankfurt.

During his investigations into small blood vessel diseases he realized how important activation of the beta adrenergic receptors were for blood flows through both the small and large blood vessels. In 2018 his work suggested that beta adrenergic activation plays a vital role in brain blood flows.

Then in March 2018 he happened to turn on a TV show:

In March 2018 I saw a short report on our local TV on a father whose son was bedridden by ME/CFS. He was interviewed for his activities in politics to enhance funding for ME/CFS research. I had no idea of what ME/CFS was and I made a Google search that evening. Next day I went into pubmed. The second abstract I saw was that of Carmen’s group on autoantibodies against ß2-adrenergic receptors. I immediately felt that there might a problem with cerebral and skeletal muscle perfusion and a fundamental and underlying cardiovascular problem. Although I immediately felt that I might be able to understand the pathophysiology it was very tiring to put the pieces of this puzzle together. It took us 1-1.5 years.

Conclusion

Given the vast reach of the cardiovascular system it’s a natural place to look for a cause of ME/CFS, but nobody has looked at it in ME/CFS patients in quite this way before. Banking on studies showing that autoantibodies to the B2AdR receptors are present in a significant subset of ME/CFS patients, the authors draw a vast model of cardiovascular dysfunction which could produce many, if not all, of the symptoms of ME/CFS.

At its core the hypothesis is simple – there’s an imbalance between vasoconstriction and vasodilation in the blood vessels. It starts with a vasoconstriction crunch produced by an overactivated sympathetic nervous system. Damage to BSAdR receptors leaves the small blood vessels near the muscles struggling to open up enough to get the blood they need. With limited blood flows, and with the energy deprived muscles screaming for more blood, the authors envision pain and fatigue provoking vasodilators pouring out in an attempt to open up those blood vessels.

So many vasodilators pour out that they get into the general circulation and leak into the interstitial spaces – the spaces between the blood vessels, the lymph and the tissues – causing pain, fatigue and other symptoms – as well as low blood volume, preload failure and sympathetic nervous system hyperactivity.

One vasodilator, bradykinin, may be responsible for a host of effects including the inability of the renin-angiotensin-aldosterone system to increase blood volume to the proper levels, intracranial hypertension, small fiber neuropathy, sleep apnea and sleep problems.

It’s a grand, unifying hypothesis, indeed. The authors, in fact, see three mechanisms by which these beta adrenergic receptors could be damaged in ME/CFS:  autoantibodies (autoimmune attack), polymorphisms (e.g. mutations) in the gene that produces the receptor, and desensitization to chronic cardiovascular stress. Plus, problems with the endothelium (smooth muscle cells lining the blood vessels) or another form of vascular dysfunction could also strongly contribute.

Stay tuned. A second hypothesis paper focusing on the energy problems in the muscles is coming.

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.

Simmaron Celebrates Ten years of Innovative ME/CFS Research

March 4, 2020

“We envision a world where ME/CFS is treatable and well-understood. To get there, we are scientifically redefining ME/CFS.” The Simmaron Research Foundation

Dr. PetersonIt’s been ten years since the Simmaron Research Foundation for ME/CFS opened its doors. Dr. Daniel Peterson, one of its founders, was restless. Ever since people with a strange, debilitating illness began knocking on his door in the Incline Village outbreak in the mid-1980’s, he’d been focused on ME/CFS. Since then he’d been patiently collecting data and samples – including precious spinal fluid samples – and biding his time until the researchers were ready – and now he thought they were.

With the formation of the Simmaron Research Foundation, Peterson was given the opportunity to put his experience and samples to the test. It turned out that the ME/CFS research community was very interested in what he had to offer.

Research

A Special Partnership

Since its founding, the Simmaron Research Foundation has enjoyed a special relationship with Dr. Mady Hornig and internationally renowned virologist Dr. Ian Lipkin at the Colombia Center for Infection and Immunity. Dr. Lipkin’s interest in chronic fatigue syndrome (ME/CFS) – which began with Dr. Peterson – dates back to 1984. Dr. Lipkin talked about that and his search for more resources in a 2014 video.

 

Simmaron’s Signature Research Effort:

The Cerebral Spinal Fluid Studies

Simmaron’s signature research effort over the past ten years has involved the most intense and potentially difference-making exploration of the spinal fluid yet done in ME/CFS. Bathing the brain, the cerebral spinal fluid provides a unique access to an organ many believe plays a central role in ME/CFS.

Dr. Peterson’s dogged accumulation of cerebral spinal fluid samples over the years paid off in two unique studies. With recent studies providing more evidence of neuroinflammation in ME/CFS, Simmaron’s early decision to commit a substantial amount of resources to spinal fluid investigations is looking prescient indeed.

A gateway to the brain - the cerebral spinal fluid

Simmaron’s signature research efforts have focused on the cerebral spinal fluid – the gateway to the brain.

The first study published in 2017 assessed more cytokines, used more sophisticated statistical analyses (logistic regression/network analysis) and was larger (n=91) than past ME/CFS spinal fluid studies.

The studies started with a collection of samples from many of Dr. Peterson’s sickest patients, which Dr. Hornig called “unparalleled” in their breadth and rigor.

Simmaron sent off two sets of spinal fluid samples – one to Mady Hornig and Ian Lipkin at the Center for Infection and Immunity (CII) for a pathogen and cytokine study and another smaller set to Griffith University researchers in Australia to assess for immune abnormalities.

The CII added a set of multiple sclerosis patients to the mix to produce one of the most interesting studies in years. Few studies had compared MS and ME/CFS patients, and none had assessed the crucial immune factors present in the spinal fluid.

The cytokine levels in both the ME/CFS and the MS patients differed widely from those of the healthy controls. Interestingly, both ME/CFS and MS patients demonstrated reduced cytokine levels – a fascinating finding given the similar finding in the blood for longer duration ME/CFS patients. That finding prompted Dr. Hornig to speculate that, “I think what we’re seeing is an immune system exhaustion over time.”

Despite both diseases demonstrating the same general trend towards immune exhaustion, they differed markedly in the cytokines affected. The cytokines highlighted in ME/CFS suggested an allergic type of reaction – similar to that found in central nervous system infections – was present.  Cognitive decline and aging – two themes in ME/CFS research – as well as reduced neuron production were also highlighted.

The fact that the alterations in the immune factors in ME/CFS were almost as extreme as those found in multiple sclerosis – a disorder characterized by severe central nervous system dysfunction –  suggested that a significant pathological process was indeed occurring in the central nervous systems of ME/CFS patients.

A Hunch Pays Off – The Peterson Subset

“Dr. Peterson’s clinical acumen, his long-term follow up of this patient population and his attentiveness to the full range of complex, serious medical disorders that might develop. The classical group had been followed for similar lengths of time but had not developed these more severe, serious comorbidities.” Mady Hornig

Next, Simmaron and the CII turned to an unusual subset of patients. Dr. Peterson has long asserted that a classical (infectious onset) subset of patients is present in ME/CFS, and is different from what he called a “complex atypical” subset of patients.

Dr. Peterson’s believed his typical “classical” ME/CFS patients came down with a flu-like illness from which they never recovered. His atypical patients, on the other hand, tended to be sicker, have more cognitive problems, have more severe comorbid diseases (autoimmune diseases, cancer), tended to have unusually severe neurological symptoms (such as seizures), and had experienced things like blood transfusions, exposure to infectious agents during international travel, etc.

Many of these illnesses appeared long after the ME/CFS diagnosis. In fact, at the time of diagnosis Peterson reported that the atypical patients looked like a typical ME/CFS patient but felt that some other underlying central nervous system process was underway.

Peterson subset

Dr. Peterson’s intuition that the atypical patients were fundamentally different saved the spinal fluid study – and pointed to a new subset.

Dr. Peterson was so sure, in fact, that an atypical subset of ME/CFS was present – and probably bollixing up study results – that he requested that the group be assessed apart from the other patients in the first Simmaron/CII spinal fluid study. Peterson’s intuition turned out to be correct: the atypical group affected the results so thoroughly that it had to be removed from the first study.

The next study compared the atypical and typical patients. Using Peterson’s spinal fluid samples, The Center for Infection and Immunity (CII) at Columbia found that the “Peterson Subset” displayed a markedly different pattern of immune results: something quite different was going on in their central nervous systems.

Given how sick the atypical patients were, one might have expected their immune factors to be even more reduced, but instead they were increased. In stark contrast to the classical patients, the atypical patients had higher levels of virtually all the immune factors assessed.

Their immune presentation over time differed as well. Almost half their immune factors were lower early in the illness but as the illness proceeded, in contrast to the typical patients, the atypical groups’ immune systems actually revved up again.

Since the higher levels of cytokines in the atypical group would have negated the lower levels of cytokines in the “classical” patients, Peterson’s request that the atypical patients be set aside saved the biggest CSF study in ME/CFS history from a null result. Given the size and expense of the study, that negative result would have dampened interest in the immune aspects of the CSF in ME/CFS for years.

The study demonstrated how critical it is for savvy ME/CFS experts to work hand in hand with research teams to explore ME/CFS – and put the research field on the alert for the apparently very biologically different atypical patients.

The Gut

Since its inception, Simmaron has collaborated with the Columbia Center for Infection and Immunity on several gut studies, including, in 2017, the first study to characterize ME/CFS patients gut flora all the way down to the species level. Prior to this study, ME/CFS gut studies had identified genera, each of which contain many different species, some with very different characteristics. This time, Ian Lipkin used a new approach called metagenomic sequencing to get at the actual players in the gut – the bacterial species.

Simmaron collaborated with the Columbia Center for Infection and Immunity to produce the first study to describe the bacterial species present in ME/CFS patient’s guts.

For the first time, the gut flora of ME/CFS patients with and without irritable bowel syndrome (IBS) was assessed, as well.

Such dramatic differences in bacterial species showed up between the two groups that the researchers were able to distinguish the two simply by comparing their gut flora.

In 2018, Dr. Peterson participated in another innovative CII gut study. Melding together gut flora and metabolomic findings for the first time, Nagy-Syzkal and Lipkin found that ME/CFS and ME/CFS-IBS patients again displayed significantly different gut flora as well as metabolomic signatures.

While problems with fatty acid metabolism were present in both groups, the study found that ME/CFS patients with IBS had additional problems with ATP production and the urea cycle. Plus, the findings suggested high loads of bacterial toxins could be triggering IBS, and pathogens in the gut could be triggering ME/CFS in both groups. On the treatment end, the study findings suggested SMAse blockers might be helpful if the findings are validated.

For all the focus on metabolomics in ME/CFS, a gut microbiome analysis was better able to distinguish ME/CFS patients from healthy controls than a metabolomic analysis. That surprising finding suggested the gut may play a bigger role than we’ve thought in this disease.

Natural Killer (NK) Cells

Dr. Peterson was the co-author of the first NK study, over thirty years ago, to find deficient NK cell functioning in chronic fatigue syndrome (ME/CFS). Following a year-long collaboration between Dr. Peterson and Griffith University in Australia, Griffith found reduced natural killer cell functioning at all time points – indicating that NK problems in ME/CFS are consistent and pervasive.

Peterson’s next Griffith University collaboration found that small bits of mutated RNAs called miRNAs may be contributing to the problems with cytotoxic NK and T-cells in ME/CFS.

Immunology Workshop

In 2014, Simmaron hosted the first ever Immunology Workshop at the IACFS/ME International Conference:

Validating Treatment Successes

Making more effective treatments available for ME/CFS patients has been a goal of Dr. Peterson’s for years. Dr. Peterson’s focus on and his creative approach to infectious onset patients, in particular, has resulted in using and documenting treatments that other doctors might not try.

Dr. Peterson has reported that almost 30% of his patients test positive for active HHV-6 or human cytomegalovirus (HCMV) (via PCR, rapid culture, antigenemia), and a whopping 50% test positive for active Epstein-Barr virus (EBNA) infection.

Simmaron’s core work includes efforts to analyze the effects of little used immune treatments such as Cidofovir (Vistide), Ampligen and IVIG on ME/CFS with a goal of publishing treatment data.

Vistide

In 2013, Dr. Peterson reported on the results of the first retrospective analysis of Vistide’s effectiveness in ME/CFS. Few ME/CFS experts use Vistide but Peterson found that 70% of 65 patients treated from 2005-2012 for HHV6 and/or HCMV infection were either full (able to return to work) or partial (significant increase in functionality) responders; a very high rate of success in an illness characterized by a poor response to treatments.

Only 30% of Vistide recipients did not have a significantly positive response to the drug, and no serious side effects were seen; ironically the minor side effects seen were attributed to a drug, Probocenid, that’s used to ensure that Vistide is absorbed into patients’ systems effectively.

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

Ampligen 

In 2018, Simmaron and Dr. Peterson reached out to Maureen Hanson and the CDC to help with a project to assess the effectiveness of Ampligen. To this day, Ampligen still remains the only drug the FDA has assessed for ME/CFS. With no Ampligen trials forthcoming Peterson searched for ways to provide a boost for a drug he knows from long experience that can work very well.

Simmaron’s collaboration with Maureen Hanson and the CDC seeks to show why Ampligen is effective in ME/CFS

The novel project took advantage of a year-long lapse in Ampligen availability to assess changes in immune and other factors and symptoms at three time points: (1) while Dr. Peterson’s patients were on Ampligen; (2) when they were off Ampligen; and (3) when they went back on Ampligen.

The extensive testing included NK cell function, cytokine expression, multiple symptom surveys, an exercise tolerance test and Cornell-designed research protocols.  Besides demonstrating how Ampligen works, the study could begin to uncover which subsets of patients it works in.

Gunnar Gottschalk presented preliminary results from “The Workshop for Young Investigators” at the NIH’s ME/CFS Conference in 2019. He reported finding “significant and sustained clinical reduction(s) in both the physical and neurological symptoms following Rintatolimod (Ampligen®)”, including improvements in physical functioning, pain and energy after 6 months of treatment.

An analysis of the biological data is underway.

Next Up For Simmaron

Simmaron’s highest priority is publishing data on ME/CFS subsets and effective treatments – two factors which experience has shown are inextricably linked to one another. Simmaron believes the hidden subsets in ME/CFS have the potential to cloud or nullify the results of biomarker and research efforts as well as treatment trials. On the flip side, elucidating those subsets could produce breakthrough results. To this end, Simmaron’s work is strategically focused on helping the field break out of that conundrum.

Expanded Treatment / Subset Effort

Simmaron

The Simmaron Research Foundation is committed to scientifically redefining how ME/CFS is understood and treated.

Simmaron recently began fundraising for an expanded effort to analyze data from Dr. Peterson’s patients who’ve responded to treatments like Ampligen®, IVIG and cidofovir, as well as amino acid infusions, saline, etc. The goal of these studies is to biologically identify which patients respond to which treatments, and build a scientific roadmap for getting a first medication approved by the FDA for ME/CFS.

Maureen Hanson, PhD of Cornell, is leading the scientific arm of the study, the U.S. Centers for Disease Control is doing statistical analysis; and Dr. Peterson will provide the patients and the treatments.

Simmaron believes the rigorous data analysis being used in these efforts can provide a building block for designing rigorous placebo-controlled trials that have a stronger chance of approval, and ultimately attract pharmaceutical companies to the disease.

Spinal Fluid Study – Round Three

The second phase of the Simmaron/Columbia spinal fluid study now in progress expands the prior studies, and breaks new ground by including a metabolomics analysis. Metabolomics – the study of metabolic by-products – has suggested that a hypometabolic state akin to hibernation may be present in ME/CFS.  This study should shed light on both the metabolic and immune underpinnings of the neuroinflammation believed present in ME/CFS.

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

Finally Found – A Natural Killer Cell Enhancer for ME/CFS?

For several years now, researchers at the National Centre for Neuroimmunology and Emerging Diseases (NCNED) at Griffith University in Australia have been leading the research on natural killer (NK) cells in chronic fatigue syndrome (ME/CFS). In fact, they recently published an overview on NK cells and ME/CFS.

natural killer cell failure ME/CFS

The natural killer cells in ME/CFS are pretty much a failure at killing infected cells.

NK cells play a critical role in the innate immune response which kicks in first to fight off an infection.  NK cells do just what their name implies: after alerting the immune system that trouble is ahead, they jump in and kill as many infected and damaged (cancer) cells as possible. The goal? To keep a pathogen in check long enough for big guns of the adaptive immune system (T and B cells) to rev up and ultimately destroy the invader.

For some time now, the Griffith group has focused on an unusual subject for ME/CFS –  ion channels – the very, very small channels in our neurons and cells – which play a big, big role in nerve and cell activation. Ion channels are getting a lot of interest in pain research but except for the Griffith team – not so much in ME/CFS.

The problem with NK cells in ME/CFS is that they’re just not killing very well. When given the chance to wipe out some infected cells, they pretty much poop out – not good news for anyone wanting to quickly knock down infections or remove cancerous cells.

NK cells, like many cells, require intracellular calcium to function properly, the levels of which are regulated, at least in part, by the ion channels the Griffith group is studying. These TRPM ion  channels are found in a wide variety of cells and tissues, and play a particularly important role in  sensory processing – a big concern in ME/CFS.

The ion channel that the Griffith group has been particularly interested in – TRPM member 3(TRPM3) – appears to be a jack of all trades. The fact that it can be activated by everything from temperature, natural chemicals, and toxins to synthetic compounds suggests it plays a fundamental role in the body, and, indeed, TRPM3 dysfunction has been implicated in inflammatory and neuropathic pain disorders.

Ion Channels and ME/CFS

The Griffith group’s findings in ME/CFS stretch back almost four years. In 2016, they showed that both TRPM3 and intracellular concentrations of calcium were reduced in the NK cells of ME/CFS patients. These findings suggested that in ME/CFS, the signal to kill  the pathogens wasn’t getting through to the NK cells.

That same year, Griffith introduced a potential explanation: the genes that governed TRP ion channel functioning – in particular, TRPM3 ion channel functioning – were loaded with mutations in ME/CFS. That same year, the group reported they’d found similar mutations in the B cells of ME/CFS patients.

ion channel issues

The ion channel / Ca mobilization issues in ME/CFS (From Impaired calcium mobilization in natural killer cells paper_

2017 brought another study validating the TRPM3 channel reductions. Further testing indicated something had gone wrong with the TRPM3 receptors themselves. When stimulation tests found a reduction in Ca2+ mobilization was occurring, the researchers proposed something startling: that TRPM3 channels across the body could be malfunctioning.

“As TRPM3 receptors are expressed throughout the human body, the current findings suggest that impaired TRPM3 function may play a significant role in the multisystemic pathomechanism of CFS/ME.”

Given how ubiquitous TRPM ion channels are, the loss of them body-wide could be responsible for many of the multitudinous symptoms associated with ME/CFS.

2018 and 2019 brought further validation of their previous findings (in small studies).  Just this month, the group published evidence that a related ion channel, TRPM2 – perhaps in a compensatory response – is over-expressed on ME/CFS patients’ NK cells. Despite its increased levels, it too was not functioning well.

Then in October of this year came a potential fix for the NK cell problem in ME/CFS.

Front. Immunol., 31 October 2019 Naltrexone Restores Impaired Transient Receptor Potential Melastatin 3 Ion Channel Function in Natural Killer Cells From Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients, Helene Cabanas1,2,3*Katsuhiko Muraki3,4,  Donald Staines1,2,3 and  Sonya Marshall-Gradisnik1,2, https://doi.org/10.3389/fimmu.2019.02545

Naltrexone hydrochloride (NTX) is best known in its low dose form in ME/CFS. It was referred to in this paper, though, simply as naltrexone. NTX in its normal dose functions as an opioid antagonist which reverses the effects of opioids. While it’s doing that, it also happens to activate the same TRPM3 channels that have been found inhibited in ME/CFS.

The Australian researchers used something called a whole cell patch clamp technique to assess the functioning of NK cells from people with ME/CFS. This technique, which was developed in the 1970’s/80’s, enabled researchers to assess the functioning of single ion channels on cells for the first time. (It also won its creators the Nobel Prize.)

The study again found that low levels of TPRM3 channels were present in ME/CFS.  It showed that stimulating the NK cells from healthy controls worked – the NK cells sprang into action. The NK cells from the ME/CFS patients responded to the stimulation by remain dead as a door nail. That stimulation test suggested that whatever TPRM3 channels were present simply weren’t working.

ME/CFS patients, then, appeared to have two problems: they were losing TRPM3 ion channels and those that were still present were not working well.

Incubating the healthy controls’ NK cells in naltrexone had no effect on them, but the ME/CFS patients’ NK cells responded dramatically: they now appeared to be acting normally.

Besides presenting a possible treatment for the NK dysfunction in ME/CFS, the finding suggested the Griffith researchers’ original hypothesis could be correct: the mysterious NK cell dysfunction problem could derive from problems with the TPRM3 ions.

Sonya Marshall-Gradisnuk was enthusiastic about her team’s results

This was a laboratory study – a proof of concept study. It’s a long way from testing naltrexone in humans but it did hold out the potential of a treatment for the low NK functioning in ME/CFS.

Given that NK cells ferret out infected and cancerous cells and remove them, getting the NK cells functioning properly again in ME/CFS would be a big step forward.

The leader of the group, Sonya Marshall-Gradisnik, was clearly enthusiastic:

“This world-first discovery suggests new potential pharmaco-therapeutic interventions in ME/CFS.”  Professor Sonya Marshall-Gradisnik

Opioid Drugs and Immunosuppression

The study also raised the question of what effects opioid drugs could be having on the immune systems of people with ME/CFS. No studies have attempted to assess that issue, but this study and others suggests it could be negative.

Opioid drugs have been found to impair the functioning of macrophages, natural killer cells and T‐cells and weaken the gut barrier.  A 2013 review asserted that, given the prevalence of opioid use, “opioid-mediated immune suppression presents a serious concern in our society today”.

The effects of opioids are complex, however. Immune cells also secrete endogenous opioid peptides which relieve inflammatory and neuropathic pain.

Conclusion

 

breakthrough

A breakthrough for ME/CFS? Time will tell.

The studies have generally been small, but the results have been consistently positive. They suggest that poorly functioning TRPM3 and perhaps related ion channels could be causing the reduced NK cell cytotoxicity commonly found in ME/CFS. This study found that the opioid antagonist Naltrexone was able to reverse the TRPM3 and calcium mobilization problems in ME/CFS patients’ NK cells.

Reversing the poor NK cell cytotoxicity functioning to normal would be a major step forward. Further studies will be needed, however, to determine if the results seen in the laboratory apply to people with ME/CFS – which is often a perilous step. I couldn’t find any clue as to what the effective dose would be or whether the low dose form of naltrexone might help.

It bears mentioning that the Griffith group has evidence that another ion channel may not be working properly in ME/CFS, that these channels are widespread throughout the body, and a systemic dysfunction with them, if present, could cause many problems.

 

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