Post Lyme Disease and Chronic Fatigue Syndrome (ME/CFS) - Are They The Same?

Post treatment Lyme disease syndrome (PTLSD) occurs when someone is treated for Lyme disease but never recovers. This mysterious illness has all sorts of possible interconnections with chronic fatigue syndrome (ME/CFS). Symptomatically it's quite similar, and of course, as so often occurs in ME/CFS, it's triggered by an infectious event, from which one never recovers.The list of possible infectious triggers for chronic fatigue syndrome is a long one (Epstein-Barr virus, parvovirus-B, enteroviruses, Giardia, Ross River virus and others). (With the Simmaron Research Foundation involved in a study looking at the incidence of insect borne diseases in ME/CFS more infectious triggers may be added to the list.)Some think Borrelia burgdorferi - the pathogen causing Lyme disease - should be on that list. Lyme disease is transmitted by a tick carrying the Borrelia burgdorferi bacteria. Early on the bacteria can cause a red spreading rash and fever, muscle aches, headaches, fatigue etc. If untreated it can cause some horrific problems but even if treated it can cause lifelong problems in some.That suggests that a problem with the immune response may be involved. Like ME/CFS the symptoms of post treatment Lyme disease syndrome (PTLSD) very much look like immune symptoms. Typically when researchers assess immune functioning they measure cytokines and other immune factors but these researchers and others like them are more and more taking a different route.Cytokines can help us understand what's happening in the immune system but they don't tell us what is causing the problem. Examining the genes that turn on those cytokines (and many other genes) might. At the very least it provides researchers with a much wider inquiry.  The upside to this kind of inquiry is lots of information - and so is the downside; researchers have to filter through that information to figure out what is relevant and what is not - not an easy task.It is a task, though, that more and more researchers inside and outside the chronic fatigue syndrome field are embracing.  In this case a look at the gene expression of people who came down with Lyme disease and then were treated for it proved to be quite illuminating.

The Study

Using "next-generation" techniques this study examined the gene expression of the PBMC's in the blood

1. just after people got Lyme disease
2. three weeks after they get treated for it
3. and then six months later.

This same kind of study has been done twice in ME/CFS to mixed results. In this case the results were exciting enough for the Director of the NIH, Francis Collins, to devoted one of his recent blogs to it.Longitudinal Transcriptome Analysis Reveals a Sustained Differential Gene Expression Signature in Patients Treated for Acute Lyme Disease. Jerome Bouqueta, Mark J. Soloskib, Andrea Sweic, Chris Cheadleb, Scot Federmana, Jean-Noel Billaudd, Alison W. Rebmanb, Beniwende Kabrea, Richard Halpertd, Meher Boorgulab. MBio. 2016 Feb 12;7(1):e00100-16. doi: 10.1128/mBio.00100-16.

The Results

The study revealed the startling fact that even after antibiotic treatment almost half the patients (13/29) had lingering effects (new-onset fatigue, widespread musculoskeletal pain involving ≥3 joints, and/or cognitive dysfunction) from the infection six months later. Four met the new criteria for post-treatment Lyme Disease Syndrome (PTLDS). (See the new criteria which is similar to some ME/CFS and FM criteria - here. )The infection initially caused a massive change in gene expression involving over 1200 genes. Surprisingly three weeks of antibiotic treatment, which presumably had wiped out the bacteria, the gene expression was still greatly altered with over 1,000 genes acting up (or down) in the Lyme disease patients.A pathway analysis indicated that the types of genes one would expect to get involved with an infection did; the inflammatory, immune cell trafficking, and hematologic system pathways were all upregulated.The big surprise, though, came in the last blood draw which showed that six months after treatment the gene expression of the Lyme patients (well and ill) and the healthy controls was still quite different.  The researchers clearly expected that six months after the antibiotic treatment, with many former Lyme patients fully recovered, that they would look, once again, like the healthy controls but they didn't.Some important immune genes had been turned off; genes associated with the toll-like receptors which alert the body to a pathogen, for instance, were no longer activated. Almost 700 other genes, however, were still significantly upregulated or downregulated in the Lyme disease patients.This suggests, as we've seen before, that significant infectious events can have long term consequences.The gene expression analysis, unfortunately, provided no clues why some people with Lyme disease recovered after antibiotic treatment while others remained ill. That was probably due to the fact that only four Lyme patients meet the criteria for post treatment Lyme disease syndrome (PTLDS); i.e. the sample size was very small and that small sample size brings up a question.

A Missing Group?

Where to draw the line symptomatically between a disease and non-disease state has dogged ME/CFS researchers since the disease began. A more stringent criteria has the benefit of ensuring that a more ill patient group is identified but it can also cut out those who are still ill. That may have happened with this Lyme study.In the beginning of the article, the authors asserted that Lyme patients who remained ill after antibiotic treatment were a) a minority and b) unusual. They stated that these patients tended to have more severe symptoms in the beginning, had greater spread of the pathogen through their body, and had had delayed antibiotic treatment. The vast majority of Lyme patients (about 90%) who were treated appropriately with antibiotics, on the other hand, tended to "recover rapidly and completely". This study, however, found that almost half (13/29) the Lyme disease patients, all of whom were presumably appropriately treated with antibiotics, said some of their symptoms persisted at six months.  Because they didn't meet the PTLDS criteria they weren't included in the analysis between recovered and non-recovered patients. (Apparently they were included in the recovered group.)Nor would they be included as post-Lyme disease patients by a doctor using the PTLDS criteria, and might very well be considered depressed, malingerers or whatever. This not to say the PTLDS criteria is a bad one; it's designed to produce a group of quite sick post Lyme patients for studies, but that criteria - particularly any criteria based on symptoms - is going to have problems.

Disease Similarities

The study indicated that the gene expression responses to an infection can vary dramatically  and in unexpected ways. The researchers compared their gene expression results to those of five other infections.Early in the disease, for instance, Lyme disease looks more like viral influenza than other bacterial infections such as Staphylococcus aureus, Streptococcus pneumoniae, and Escherichia coli. (Even with influenza, though, the response at the gene level is far different with the two infections sharing just 35% of activated/downregulated genes.)All five of the infections analyzed did trigger the upregulation of two immune pathways (TREM1,TLR) involved with infection but interferon signaling pathways - often believed to be active in viral infections - were upregulated only in Lyme disease and influenza.Genes identified with activated B-cell pathways were prominently featured in the early phases of all the infections except for Lyme disease.Plus, Lyme disease was the only disease to exhibit a down-regulated EIF-2a (cellular stress response) pathway. Because that pathway was down-regulated at all three blood draws it could play a major role in Lyme. The fact that the same pathway is down-regulated in lupus suggests Lyme disease could have something in common with autoimmune disorders and the authors suggested a lupus treatment might be helpful in Lyme. )The takeaway message is that the body's response to an infection is probably unique to that infection. That suggests that the many infections that trigger ME/CFS may produce very different gene expression responses - and that many different pathways to ME/CFS may exist. Whether they all merge upstream at some point to produce ME/CFS or if a bunch of entirely different pathways to ME/CFS exist is a question that can't be answered at this time.

The Chronic Fatigue Syndrome (ME/CFS) Connection

At the gene expression levels Lyme disease appears, at this point, anyway, to be little like ME/CFS. While some similar pathways were seen in the two diseases in the end only 18% of the same genes and about a third of the same pathways showed up in both diseases.At this point Lyme disease looks much more like lupus (60% of pathways in common) than ME/CFS, and the authors suggested that circulating immune complexes might be a tie that binds those two diseases together.I found two ME/CFS studies with a similar design; each assessed gene expression during an infection and then afterwards and then determined if the results varied between those who recovered and those who got ME/CFS.An early small Lloyd study (2007)  found significant gene expression differences in those who developed ME/CFS after infectious mononucleosis compared to those who recovered. A 2011 gene expression study (n=36) by the same group, however, that compared ME/CFS patients with infectious onset (EBV, Ross-River, Coxiella virus) and healthy controls over time, found so little difference over time between still sick and recovered patients the papers ended stating that "further investigation of the peripheral blood transcriptome is not warranted."Some researchers beg to differ. Five years later with several groups (Ron Davis - Open Medicine Foundation, Derya Unutmaz - Bateman-Horne Center,  Lipkin/Hornig - Center For Infection and Immunity, Nath - Intramural NIH Study and Dr. Montoya - Stanford ME/CFS Initiative) are mounting major efforts to understand the ME/CFS "transcriptome" and other "omes" using better techniques.Unutmaz, for instance, proposes to use gene expression and other technologies to uncover immune subsets that he believes will irrevocably alter how ME/CFS is viewed and studied. Some time ago, he threw some samples from the Solve ME/CFS Biobank into his big immune machine. The data that popped out was enticing enough for him to spend a considerable amount of time working up an NIH grant proposal. That work paid off and he recently scored a major grant from the NIH.While the Lyme disease study didn't help researchers understand what goes awry in people who are still sick after getting an infection (and after being treated for it) - which is what we really want to know - a larger study is underway to determine that.  Researchers were also working on identifying 50-100 genes they hoped could finally produce a early diagnostic test for Lyme disease.The study demonstrated the power of this technology to reveal new things about disease. Several things popped out in this study that weren't expected:

• Every infection probably triggers a unique response
• a Lyme infection may irrevocably change how our genes are expressing themselves (even after treatment)
• Early in the course of the disease Lyme looks more like viral influenza than other bacterial infections
• Lyme disease has some important similarities to lupus and rheumatoid arthritis that could suggest new treatment possibilities
• That some commonalities exist between ME/CFS and Lyme disease but the diseases appear more different than similar

Seeing gene expression differences emerging between different infections suggests this work provides a kind of precision that we very much want to see.  That precision, though, requires an enormous amount of data, and with that ironically, can come some muddiness.  Where gene expression has generally let us down in ME/CFS has been the difficulty of  consistently identifying the specific genes on which the disease may turn.Hopefully the more powerful machines and analytic techniques being used by ME/CFS researchers will help provide the diagnostic biomarkers and new treatment options that other research efforts have not been able to. If this study is any indication, as researchers dig more deeply into the molecular underpinnings of ME/CFS, we'll probably be in for some surprises.