All posts tagged IBS

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

Looking for clues to the cause of chronic fatigue syndrome (ME/CFS), Ian Lipkin has, over the years, poked his fingers into a number of different areas. His 2012 XMRV study showed that the virus was not infecting people with ME/CFS. (It was a contaminant). His pathogen studies (unpublished) found no evidence of a viral infection in ME/CFS.

Subsets

Lipkin may have uncovered more potential subsets than any other researcher and has long emphasized the need to break ME/CFS up into its constituent parts.

lipkin subsets ME/CFS

Lipkin believes identifying subsets is critical to the progress in this field

Lipkin and Mady Hornig’s 2015 cytokine study  which found the immune system going gangbusters early in ME/CFS but then pooping out, exhausted, later identified two possible subsets (early and long duration patients.) Lipkin then teamed with the Simmaron Research Institute to document similar findings in chronic fatigue syndrome (ME/CFS) patients’ spinal fluid.  Dr. Peterson, Lipkin and the Simmaron Research Institute then uncovered an atypical ME/CFS subset (the “Peterson subset”.)

In an email Lipkin emphasized the critical need to identify the subsets he believes must be present in this disease.

ME/CFS is not a single disorder and is unlikely to have  single cause or a single treatment. As we learn more about ME/CFS, we are beginning to define subtypes. This is critical to understanding how people become ill and developing practical solutions for management. The challenge is not unique to ME/CFS. It is representative of the Precision Medicine initiative that is sweeping clinical medicine and public health. Just as there is no one cause or cure for all cancers, all forms of heart disease, or all infections, there will be more than one path to ME/CFS and more than one treatment strategy.

Over the past couple of years Lipkin – who has been intensely interested in the role that gut bacteria plays in this illness – has been digging into an ME/CFS plus irritable bowel subset. We’ve learned in the past ten years just how influential the gut is. Gut bacteria and the metabolites they produce don’t stop at the gut. If they leak out of the gut they can directly affect the immune and central nervous system functioning. Some of the metabolites showing up in ME/CFS metabolomic studies originate in the gut.

Last year Lipkin’s group published the most comprehensive gut bacteria study in ME/CFS yet done, which incorporated immune and clinical findings. This year he repeated the gut bacterial analysis and added metabolomics  and clinical findings to the mix. The man clearly likes large, complex studies.

The 2017 Gut Study

The large 2017 Nagy-Szakal/Lipkin gut study was notable for it’s size (n=100) and it’s breadth – it included patients from no less than six ME/CFS practitioners including Dr. Peterson. It found, amongst other things, increased levels of bacteria from a family (Clostridiaceae) known for its abundance of toxic and disease causing bacteria.

One of the few gut studies that’s actually been able to identify individual bacterial species, the study found increased abundances of several bacterial species (Faecalibacterium & Coprococcus spp.) that have been associated in other studies with IBS-like symptoms, including colonic pain, bloating, and GI discomfort.

Using a type of data analysis called topological data analysis (TDA) which is able to incorporate metagenomic, metabolic pathway, immune and clinical data, the Lipkin group found that the presence of irritable bowel syndrome (IBS) was having a major effect on disease severity, gut microbiota, and immune profiles.

That finding led the Lipkin group to split the ME/CFS patient cohort into ME/CFS with IBS and ME/CFS without IBS subsets and examine the differences in microbiota (gut bacteria).

gut bacteria ME/CFS

The gut bacteria in the ME/CFS plus IBS subset was different from the ME/CFS only group and the healthy controls

The results were astonishing. A dissimilarity measure found that gut bacteria differed as much between the ME/CFS + IBS patients and the ME/CFS – IBS patients as between the ME/CFS group as a whole and the healthy controls. That analysis suggested that the guts of the ME/CFS patients with and without IBS featured significantly different bacteria.

The cytokine data in the study did not add to the analysis but the microbiome analysis revealed a number of interesting possibilities,

Metabolic pathway analyses revealed the ME/CFS + IBS and the ME/CFS – IBS groups differed in some important ways. Both groups featured enriched metabolic pathways that produced Vit. B6, but an important part of the energy production process (the pyrimidine ribonucleoside degradation pathway) was enriched in the ME/CFS only group. That same pathway was hit hard in the ME/CFS plus IBS group.

Plus, the abnormalities found in the urea cycle, which is closely linked to aerobic energy production (Krebs or TCA cycle)  occurred mostly in the ME/CFS + IBS group.

The data suggested that people with ME/CFS and IBS group had different bacterial gut makeups and might have more problems with energy production than people with ME/CFS, and it set the stage for Lipkin’s next effort.

The 2018 Gut and Metabolomics Study

Sci Rep. 2018 Jul 3;8(1):10056. doi: 10.1038/s41598-018-28477-9.Insights into myalgic encephalomyelitis/chronic fatigue syndrome phenotypes through comprehensive metabolomics.  Nagy-Szakal D1, Barupal DK2, Lee B1, Che X1, Williams BL1, Kahn EJR1, Ukaigwe JE1, Bateman L3, Klimas NG4,5, Komaroff AL6, Levine S7, Montoya JG8, Peterson DL9, Levin B10, Hornig M1, Fiehn O11, Lipkin WI12.

After striking that rich vein, the Lipkin group expanded their research effort – incorporating metabolomics for the first time into their studies. (Lipkin and the Simmaron Research Foundation are also currently engaged in the first metabolomics spinal fluid study.) Once again incorporating a wide variety of doctors from different locations (Peterson, Bateman, Klimas, Levine, Montoya) and using a fairly large sample set (n=100) Nagy-Szakal/Lipkin, the Lipkin group fused together blood metabolomic, fecal bacterial metagenomic, and clinical data to paint a new picture of ME/CFS.

The study represented the first attempt to meld two potentially important fields in ME/CFS – metabolomics and gut microbiome findings- together.  Lipkin and Hornig have proposed that the gut issues play an important role in ME/CFS, and several studies have found evidence of dysbiosis (pro-inflammatory gut bacteria) in ME/CFS.  Unutmaz is chasing down a T-cell gut connection, and past studies have suggested that bacterial leakage from the gut could help explain at least some of the post-exertional malaise present.

Given the group’s past gut findings – that significant differences in gut bacteria, immune profiles and possibly energy production exist between ME/CFS + IBS patients and ME/CFS patients without IBS, it made sense for the Lipkin group to once again split the ME/CFS group into subsets with and without IBS and analyze the heck out of them.

Study Results

Energy Production Problems Highlighted

The study confirmed past general findings of decreased levels of phospholipids and sphingomyelins – two important findings by Naviaux- and increased levels of triglycerides (TG’s). (Triglycerides have been associated with metabolic problems and hypothyroidism.)

That both the ME/CFS + IBS group and the ME/CFS without IBS group had reduced levels of metabolites associated with the choline-carnitine energy pathway suggested that both groups had similar core metabolic problems.  (Carnitine participates in the TCA cycle, ATP production and energy metabolism).

More Was Better

The Lipkin group’s decision to integrate metabolomics, microbiome and clinical data worked. Not only did incorporating all this data together illuminate a possibly important subset – the ME/CFS IBS subset – but it also allowed the group to better differentiate ME/CFS patients from controls. It suggested that studies which combine multisystemic data together will do a better job in describing this multisystemic disease.

As with the 2017 study, having or not having IBS was the biggest driver in determining the kind of bacterial profile (and bacterial metabolic pathways) present. This time the study found that the metabolomics of the ME/CFS + IBS group were significantly different from the ME/CFS only group as well. That suggested these two subsets of ME/CFS patients might be quite different indeed.

In contrast to Naviaux, the study did not find a “consistent decrease” in ceramide metabolites – the most commonly disrupted metabolite Naviaux found in his ME/CFS group.  When Lipkin controlled for IBS, he found increased levels of ceramides in the ME/CFS plus IBS group but decreased levels of ceramides in the ME/CFS only group. That suggested that key metabolites in ME/CFS might be different in these two ME/CFS subsets.

The Core Problem in Chronic Fatigue Syndrome Identified? Naviaux’s Metabolomics Study Breaks Fresh Ground

Bacterial Toxins Highlighted

Nagy/Lipkin suggested that increased levels of bacterial toxins (IBS connection) in ME/CFS may be triggering an enzyme called sphingomyelinase to produce the ceramides which then may damage the gut lining and possibly interfere with energy production.

gut metabolomics ME/CFS

The metabolomic analysis suggest unique metabolic problems may be present in the ME/CFS plus IBS group

Ceramides are waxy fats that figure in a number of processes that may be important in ME/CFS. Not only can they produce many free radicals (reactive oxygen species) that can damage the gut lining (the IBS connection), they can also interfere with electron transport (the energy connection) as well as contribute to insulin and leptin resistance (metabolism issues).

The authors also proposed that the higher mannitol levels found in the ME/CFS could reflect the breakdown of two important barriers in the body: the gut barrier and the blood-brain barrier.

Several studies suggest a breach in the gut barrier could be contributing to systemic inflammation in ME/CFS, and one suggests that exercise may further widen that breach. Several researchers, including Jarred Younger and Avindra Nath, have also postulated that the suspected neuroinflammation in ME/CFS results from immune cells entering the brain through a weakened blood-brain barrier.

The Gut Shines in Distinguishing ME/CFS Patients From Healthy Controls

Interestingly, for all the focus on metabolomics, a network analysis using differences in gut bacterial abundance was better able to distinguish ME/CFS patients from healthy controls than did metabolomic results.

That suggested that gut bacterial differences may be more prominent than metabolomics differences in ME/CFS patients. That was a surprise, and we’ll see how this all turns out. It stands to reason that the closer we get to the core of the problem, the more striking the differences we’ll see between healthy people and people with ME/CFS.  (Will the gut play a bigger role than we thought?)

Possible Treatment Options

The group suggested that their findings, if validated, could present some possible treatment options. They included using SMAse blockers to reduce ceramide levels and giving carnitine supplementation to increase the low levels of metabolites in the choline-carnitine pathway.  One open-label study found that carnitine supplementation helped over half of ME/CFS patients.

Given the unrevealing cytokine data from Lipkin’s cytokine data and his recent turn to metabolomics I asked Lipkin how important a role cytokines were likely to play in future ME/CFS research and treatment. Lipkin felt they may yet play an important role in ME/CFS indeed:

“Cytokine disturbances can result in fatigue, cognitive and other disturbances. The observation that other biomarkers such as metagenomic or metabolomic profiles are highly associated with disease does not diminish their (cytokines) importance. There may be people who would benefit from drugs, including antibody therapies, that modulate cytokine responses.”

Scheibenbogen is pursuing antibody therapies in ME/CFS, and Nancy Klimas is reportedly using Enbrel (etanercept) – a cytokine (TNF) blocker – plus mifepristone in her Gulf War Illness trial. Other biologics are available and more are coming on the market.  Recent findings in POTS suggest that antibody drugs will probably play an important role in that disease as well.

Since the study also found that taking Vit. B supplements was associated with higher levels of pantothenic acid and lower fatigue scores, taking Vit. B supplements may be a good idea.

The 5-MT Question

Decreased levels of 5-MT, a metabolite associated with tryptophan, serotonin and melatonin metabolism could reflect problems with serotonin/melatonin conversion. This finding, however, was confounded by the high use of antidepressants (50% of the ME/CFS group) which could have produced the decrease.

Correlation studies do suggest, though, that low 5-MT levels could contribute to problems with cognition, sleep and fatigue. Larger studies are needed to determine if the low 5-MT levels are associated with those symptoms in ME/CFS – and if they are – if it might be beneficial to modulate that pathway using drugs in ME/CFS.

Next Up for the Simmaron Research Foundation and Ian Lipkin

The next phase in the Simmaron Research Foundation’s ongoing collaboration with Ian Lipkin is an expanded study which will, for the first time in ME/CFS, analyze the metabolomics of ME/CFS patients cerebral spinal fluid. The study, which will also include immune analyses is the third Simmaron/Lipkin CSF study to date. The first two studies found dramatic evidence of immune activation and the presence of a potential new subset.

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

Lipkin also reported rapid progress from his new NIH research center and a new collaborative effort with ME/CFS researcher and NIH ME/CFS research center leader Derya Unutmaz. The idea of two top labs in the country collaborating in a complementary fashion is an exciting one – one we will hopefully see much more of in this field.

Lipkin and Unutmaz are merging their respective strengths in a collaboration – something we could use much more of in ME/CFS.

We are completing analysis of saliva, blood, and feces for bacteria, viruses and fungi from ME/CFS and control subjects using powerful new sequencing methods. This will be the largest and most comprehensive study to date on the microbiome in ME/CFS. We will soon begin metabolomic, proteomic, and transcriptomic analyses of ME/CFS and control subjects before and after exercise. We are deeply grateful to the patients who are contributing to this work despite the implications for their health. They are true heroes.

We have begun a new collaboration with Derya Unutmaz and Jackson Laboratories that builds on the complementary expertise of our teams in cellular immunology and molecular microbiology and biochemistry.

Dana March and Tony Komaroff are building an app to help ME/CFS subjects and their caregivers track their status. We have had great support in this effort from people in the community.

Conclusions

In the past three years Lipkin’s identified three potential subsets (early/late duration patients, the “Peterson subset”, ME/CFS + IBS subset) and his explorations into the ME/CFS IBS subset continues to reap dividends.

Lipkin has been a vocal advocate for ME/CFS

Dr. Ian Lipkin, Center for Infection and Immunity, Columbia University

His metabolomic study found signs of energy production problems in all ME/CFS patients, but when Lipkin separated out the ME/CFS + IBS patients, he found altered, even at times opposite metabolic findings that could suggest a different source of fatigue was present in the ME/CFS + IBS patients. His earlier study suggested more severe energy production problems may be present in ME/CFS patients with IBS.

The importance of the gut bacteria in ME/CFS perhaps rose to a new level of significance when a network analysis found larger differences in gut bacteria than metabolites. Lipkin’s ability to better differentiate ME/CFS patients from healthy controls using gut bacteria, metabolomic and clinical data suggests that large studies which tie together multiple systems will be the most helpful.

In short, the latest study from the Lipkin group indicates that the gut does matter in ME/CFS and that in those with gut problems it may matter more than we think.

The Simmaron Research Foundation and Lipkin are employing metabolomics in the study of cerebral spinal fluid for the first time, and Lipkin has launched a new collaborative ME/CFS effort with fellow NIH ME/CFS Research Center leader Derya Unutmaz.

 

Even “Minor” Infections Can Cause Chronic Fatigue Syndrome (ME/CFS)

Giardia hasn’t historically ranked high as a potential cause of chronic fatigue syndrome (ME/CFS). Some anecdotal reports suggest that a Giardia outbreak may have occurred prior to the Incline Village ME/CFS outbreak in the 1980’s. More recently, Corinne Blandino’s severe, decades long case of ME/CFS – which originated with an exposure to Giardia at work – demonstrated how devastating a case of Giardia triggered ME/CFS can be.

Giardia long lasting effects

Giardia is thought of as a minor infection – but it can have long lasting effects.

It wasn’t until city in Norway got exposed to Giardia in 2004, however, that Giardia, a protozoa, became one of the pathogens definitively linked with chronic fatigue syndrome (ME/CFS). Large studies (n=1254) examining the aftermath of the outbreak in a public water system in Bergen found that five years later, almost 50% of those originally infected still had symptoms of irritable bowel syndrome and/or chronic fatigue (post-infectious chronic fatigue).

“Other patients suffer a severe, long lasting illness, for which treatment is ineffectual, and even after the parasite has finally been eliminated, some sequelae persist, affecting quality of life and continuing to cause the patient discomfort or pain” (LJ Robertson et al, 2010)

Five percent suffered from fatigue severe enough for them to lose employment or be unable to continue their education. Interestingly, all had taken anti-parasitic drugs and all had apparently cleared the pathogen from their systems.  Five years later, 30% were deemed to have an ME/CFS-like illness and almost 40% had irritable bowel syndrome  (IBS).

“Minor” Infection – Sometimes Serious Results

By all accounts Giardia shouldn’t be doing this. Giardia is not normally considered a serious infection. Most people have some diarrhea and pass the bug quickly – and if they don’t, antibiotics are usually (but not always) effective. Giardia, seemingly, produces the kind of “minor” infection that our medical system doesn’t spend much time on.

The Mayo Clinic reports that Giardia infection (giardiasis) is one of the most common causes of waterborne illness in the United States. The parasites are found in backcountry streams and lakes throughout the U.S., but can also be found in municipal water supplies, swimming pools, whirlpool spas and wells. Giardia infection can be transmitted through food and person-to-person contact.

Research studies are slowly revealing that the effects of even vanquished Giardia infections can be long lasting for some. The Mayo Clinic reports that intestinal problems such as lactose intolerance  may be present long after the parasites are gone. (Even though half a dozen studies have been published on the Bergen outbreak, Mayo fails to note that long term issues with fatigue and pain (or ME/CFS) may result).

The Bergen studies indicate, however, that this rather common infection worldwide can cause long term and even at times debilitating fatigue as well. The takeaway lesson from the Bergen studies is that one doesn’t need to have mono, Ross-River virus or Valley fever or any of several serious infections to get seriously afflicted. As Dr. Chia has been saying about enteroviruses for years, any minor infection has the potential to cause ME/CFS in the right person.

The Galland-Giardia Chronic Fatigue Syndrome (ME/CFS) Connection

The Norwegians wrongly reported that they were the first to associate fatigue with Giardia infections, but they couldn’t be blamed for thinking so. Way back in 1989, an integrative doctor named Dr. Galland suggested that Giardia infections were associated with ME/CFS. That year, Galland reported at a scientific conference that Giardia might be more common in ME/CFS than expected. Using a new test, Galland found active Giardia infection in 46 per cent of his chronic fatigue syndrome (ME/CFS) patients. (Galland noted that many of his patients may have picked up the bug during travel to foreign countries).

In 1990 Galland published a paper “Giardia lamblia infection as a cause of chronic fatigue.” in the Journal of Nutritional Medicine. (The paper never appeared on PubMed, the main English research database, apparently because of the journal it was published in. Citations from present and past journals devoted to ME/CFS have never appeared in PubMed either.)

chronic fatigue - giardia

Galland found the most devastating long term symptom after a Giardi infection was not gut pain but fatigue

Interestingly, given the involvement of a pathogenic gut protazoan, the patients’ gut symptoms were relatively minor; it was their fatigue, muscle pain, muscle weakness, flu-like feelings, sweats and enlarged lymph nodes that stood out. Galland reported that treating the infection alleviated the fatigue in over 80% of his patients and removed the digestive complaints in 90%. In 1998 Galland reported that one outbreak of Giardia, in Placerville, California, “was followed by an epidemic of Chronic Fatigue Syndrome, which swept through the town’s residents”.

Galland found that a longer than usual treatment regimen was often necessary to clear the body of the bug. Instead of the normal five-day treatment, his average treatment regimen lasted three weeks and could extend to eight.  He has also reported treatment successes involving other parasites (Entamoeba hystolytica, Cyrptosporidium) and other diseases such as rheumatoid arthritis.

In 2011, Galland hadn’t let up on the ME/CFS/giardia/intestinal parasite angle, reporting that a woman with severe fatigue and dizziness (but not many gut symptoms) who had tested positive for Giardia slowly recovered under his anti-parasitic protocol. Citing a Johns Hopkins study indicating that 20 percent of healthy controls had antibodies to Giardia, Galland suggested that Giardia infections were much more common, particularly in small town water systems (such as Incline Village?), than previously suspected.

Giardia is probably not a common cause of ME/CFS: Dr. Peterson said he regularly tests for it but rarely finds it – but because it is usually treatable, it’s a test that probably everyone, particularly those who got ill after foreign travel, should get.

The biggest question for the ME/CFS community (and the Lyme community), though, is why, as with other infections, some people who get enough treatment to make the pathogen disappear are still ill.

Back to the Norwegians

Galland may have generated some buzz in integrative medicine circles, but it took the Norwegian researchers to get Giardia and ME/CFS on the map in the research world. Tests revealing increased numbers of cytotoxic (i.e. killer) T-cells indicated an immune system on the alert for a pathogen.  (Similar findings occur in herpesvirus and cytomegalovirus infections, infectious mononucleosis, etc.)

With the Norwegian studies indicating that depression and anxiety weren’t the culprits in the ME/CFS outbreak, several hypotheses popped up:

  • The Sneaky Pathogen theory – The pathogen wasn’t gone at all, it was laying low. Poor immune surveillance was allowing low, undetectable levels of the bug to produce low-grade inflammation that was causing fatigue, abdominal distress and other symptoms.
  • The Hit and Run Gut Attack Theory #1 – Before it was overcome, the water-borne pathogen permanently damaged the lining of the intestines causing problems with gut permeability, hypersensitivity, bacterial overgrowth, immune reactions (fatigue, etc.) and irritable bowel syndrome.
  • The Hit and Run Gut Attack Theory #2 – the pathogen triggered the activation of mast cells in the gut causing fatigue, hypersensitivity, IBS and other symptoms.

The Latest Study

Giardia-specific cellular immune responses in post-giardiasis chronic fatigue syndrome, Kurt Hanevik1, 2Email authorView ORCID ID profile, Einar Kristoffersen1, 3, Kristine Mørch1, 2, Kristin Paulsen Rye1, Steinar Sørnes1, Staffan Svärd4, Øystein Bruserud1 and Nina Langeland1, 2 BMC Immunology 201718:5 DOI: 10.1186/s12865-017-0190-3

The latest Norwegian study attempted to explain the lingering fatigue and other problems by testing immune responses (T-cell proliferation assay, T cell activation and cytokine release analysis) to Giardia in 20 Giardia exposed fatigued individuals, 10 Giardia exposed non-fatigued individuals and 10 healthy unexposed individuals were recruited as controls.

The study did not find increased immune responses to Giardia (including T-cell activation or cytokine responses) in the post-infectious Giardia group. The still ill Giardia patients did, however, have higher levels of a key immune marker called sCD40L implicated in inflammation and in severe symptom flares in ME/CFS patients after exercise.

giardia question chronic fatigue syndrome

No one knows why 5-10% of the post-giardiasis patients are still sick

Why these patients – five years after their Giardia infection was resolved – are still ill remains a mystery, but the link between Giardia infections and subsequent chronic illnesses is growing.  A higher incidence of Giardia infection was recently found in lupus. Just this year, a study found an association between Giardia infection and the subsequent development of arthritis.  A 4,000 person study recently confirmed an association between Giardia infection and the development of irritable bowel syndrome.  That study’s findings were buttressed by an earlier study indicating that Giardia induces gut hypersensitivity in rats long after the parasite had been cleared.

How Giardia is setting some people up for subsequent illnesses such as ME/CFS, arthritis, lupus or IBS isn’t entirely clear.  It is clear, though, that particularly virulent strains of Giardia that cause more damage might be involved.  Giardiasis can damage the microvilli of the intestines and promote inflammation. Eight months after the apparent resolution of Giardia, signs of gut inflammation were present in almost 50% of the Bergen cohort. (That high number suggested that the Bergen cohort may have been hit by a particularly virulent strain of Giardia.)  Protracted levels of gut inflammation resulting in systemic inflammation – as some suspect is present in ME/CFS – could explain the fatigue and other problems that remained.

“Host responses” may be important as well. Reduced levels of gut arginine at the time of infection may result in more gut damage. Although T-cells are the big guns in the immune response to pathogens, one study suggested that one’s gut microbiome makeup played a bigger factor in preventing/allowing a serious infection to occur.

Some findings in the Norwegian Giardia outbreak mirror others seen in post-infectious ME/CFS illness states. Greater illness severity, whether characterized by increased symptom severity, more time spent in bed and/or a more difficult time ridding the body of the infection have been found to predispose people with infectious mononucleosis or giardiasis to coming down with ME/CFS.  Being female is another risk factor.

Prior illnesses may make a difference as well. Prior gut symptoms increased the risk of fatigue, etc., after a giardia infection but, interestingly, not more gut problems. This indicated, as has been shown before, that a lack of gut symptoms does not necessarily rule out the gut as a central factor in disease.

The Post-Infectious Cohort

Whether the pathogen involved is Ross-River virus, Q-fever, Epstein-Barr Virus, Giardia or other gut pathogens such as Campylobacter, Salmonella, Shigella, Escherichia coli and Trichinella spiralis, a year or so later, from 5-10% of those afflicted are still ill. Infections, whether cleared or not, clearly can have long-term consequences.  The link between infectious mononucleosis and multiple sclerosis is a classic example. Dozens of studies indicate that having infectious mononucleosis increases one’s risk of later coming down with multiple sclerosis.

The Simmaron Research Foundation is continuing its efforts to examine the role unusual infections may play in ME/CFS with its support of the Konnie Knox study examining the role that vector-borne (bird/insect borne) infections may play in ME/CFS.