All posts tagged Dubbo

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

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

infection - chronic fatigue

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

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

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

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

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

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

The Post-Infectious Illness Group

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

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

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

That’s obviously not a small number of people.

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

The Epidemiological Efforts

Giardia

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

The Biopsychosocial Efforts

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

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

chaos

The biopsychological studies have failed to provide consistent theme

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

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

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

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

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

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

Biological Efforts

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

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

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

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

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

consistency

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

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

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

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

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

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

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

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

Steps Per Day

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

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

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

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

Predictors of Chronic Fatigue

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

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

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

Predictable Results?

So how did Wyller get such pitiful results?

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

Wyller testing ME/CFS

Wyller’s testing regimen made a biological result unlikely.

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

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

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

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

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

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

Lenny Jason’s Chicago Studies

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

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

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

Conclusion

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

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

trigger - post-infectious fatigue

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

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

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

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

 

 

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

It’s one of the bigger puzzles in medicine and one that has obvious implications for chronic fatigue syndrome (ME/CFS): why some people given oral antibiotics recover from Lyme disease while others sometimes remain sick for decades. Given the infectious trigger often seen in ME/CFS, any post-viral or post-bacterial illness is of interest. For the most part, researchers don’t know why some people fail to recover fully from an infection; they’ve hardly touched the subject, but an answer in Lyme disease may be coming.

The Study

The study was not large, containing 32 patients and 18 healthy controls, but the results were exciting, providing for the first time a possible biological explanation for the puzzling problem of post-treatment Lyme disease syndrome (PTLDS).

targeted approach Lyme

The ability to target a specific part of the immune system was the key to this studies success.

It’s not taking away anything from the researchers that the study wasn’t particularly innovative. In fact, it did something rather obvious, something that’s been done and is being done in ME/CFS (by Lenny Jason). The study took people with early Lyme disease (n=32) and healthy controls (n=18) and then (after providing the standard antibiotic regimen) followed them over two years, measuring their immune status.

The difference between this successful Lyme disease study and the less successful ME/CFS studies that measured cytokines, gene expression, and autonomic functioning is that the Lyme researchers had a clear target. Mouse studies have shown that the Borrelia burgdorferi bacteria that cause Lyme disease hammer the B-cells, and that’s what the study focused on.

Results

We herein identify plasmablasts as a key B cell population that correlates with resolution of Bb infection and Lyme disease in humans. The authors

They found that B-cells called plasmablasts were elevated prior to antibiotic treatment in patients who returned to health.  Plasmablasts are activated B-cells which circulate for a time in the blood in response to an infection.  The higher level of plasmablasts in the recovered patients suggests that these patients simply mounted a stronger immune response to the infection. That was kind of a no-brainer, but the strength of the study was that they were able to specify what part of our amazingly complex immune system the problem was in.

They also determined that the patients who returned to health also exhibited significantly greater clonal expansion: their activated B-cells produced more clones designed to target and get rid of the bacteria. Again, in retrospect, not a surprising finding, but one that does open up a possible treatment option that hasn’t previously been available.

b-cell Lyme disease

A type of B-cell called a plasmablast turned out to be the key.

Along the way this group also produced a possible diagnostic test which may a) be able to identify Lyme disease infections very early on and b) have high rates of accuracy.  The current Lyme tests do neither; they’re only about 50% accurate during the early stages of infection when studies show treatments are most effective.

They also demonstrated that Lyme disease prompts the expansion of a type of memory B-cell (CD27−) associated with some infections and, more commonly, with autoimmune diseases (rheumatoid arthritis, lupus and multiple sclerosis).

Possible Therapy

Finally, the results point to an unexpected potential therapy – monoclonal antibody drugs. Monoclonal antibody drugs (the “mabs”, e.g. Rituximab) can be theoretically designed to trigger the immune system to target any cell in the body or to influence how the immune system works in other ways. In cancer, for instance, many monoclonal antibodies have been produced that target specific cancer cells. In autoimmune diseases such as rheumatoid arthritis, Crohn’s disease and ulcerative colitis, monoclonal antibodies bind to and inhibit the pro-inflammatory cytokine TNF-a.

Over 75 monoclonal antibody drugs have been approved by the FDA.  Only one, interestingly, specifically has targeted an infection (HIV).  These drugs have, however, recently been effectively used in Ebola and syncytial virus infections.

The authors suggested that Borrelia burgdorferi (Bb)specific monoclonal antibodies could whack the bacteria hard enough to allow doxycycline to work in all patients, not just those with more robust B-cell responses.  In fact, recent developments in monoclonal antibody production suggest that an anti-Lyme drug could be used prophylactically to provide protection against the bug.  The limiting factor may be expense, but recent developments may bring the cost of these drugs down.

Prospecting in Chronic Fatigue Syndrome (ME/CFS)

This study indicates that prospective studies – studies which follow a population over time as some fall ill – can work really well if the study target is focused correctly.  Starting back with Dr. Lloyd’s Dubbo studies several have been done in ME/CFS. None have achieved the results that this Lyme study did, but they have been illuminating.

The Dubbo studies followed 253 people for 12 months after they were infected with one of three pathogens (EBV, Ross-River Virus, Coxiella burnetii). That 11% met the CDC criteria for ME/CFS after six months indicated that long standing illnesses after serious infections were surprisingly common.  Attempts to figure out why a significant number of people remained ill were largely ineffective though.

Some of the studies were quite small and are probably not conclusive but they suggested that neither increased herpes viral titers (herpes virus reactivation) nor changes in 35 cytokines nor gene expression nor psychological factors played a role.

Dubbo studies

The Dubbo studies found that the severity of the initial infection played a role in who failed to recover from an initial infection.bo

The only finding that initially stood out was the severity of the initial infection. People with more severe symptoms initially were significantly more likely to come down with ME/CFS.  In 2008, however, the group found a possible genetic underpinning for the disease; it turned out that polymorphisms (unusual formations) in genes coding for two cytokines (IFN-y, IL-10) affected how ill a person got and how long they remained ill. The findings suggested that a genetic predisposition for an increased inflammatory response might be tipping some people over into prolonged illnesses.

In 2009 Vollmer-Conna, a member of the Dubbo group, working outside ME/CFS found more evidence that one’s immune status makes a difference. She found immune status prior to surgery significantly affected one’s immune functioning, distress levels and ability to recover after surgery.

Next Jason and Katz began a large study of adolescents that came down with infectious mononucleosis (IM). They found no evidence that reductions in peak work capacity, or activity levels, or problems with orthostatic intolerance,  or reductions in salivary cortisol or natural killer cell number and function played a role in an adolescents inability to recover from IM.  The study, however, did suggest that early damage to autonomic nervous system, to the ability to consume oxygen, as well as psychological factors and differences in cytokine networks  were present in those who failed to recover from IM.

Another Jason-Katz study which did not examine biological factors other than autonomic nervous system functioning found, as did the Dubbo study, that the severity of the initial infection – and the amount of bed rest it prompted – played the most significant role in who remained ill. Psychological factors such as “perceived stress, stressful life events, family stress, difficulty functioning and attending school, family stress, and psychiatric disorders” had no impact.

In 2013 Jason, Katz and others began an even larger study which tracked college students after coming down with infectious mononucleosis. They’ve collected blood samples from and have been following over 4,000 college students over the past couple of years. About 5%  contracted infectious mononucleosis, a common trigger for ME/CFS. Grants applications are being written to further assess autonomic functioning, as well as cytokine, metabolome and saliva biological risk factors..

If Jason et. al. have picked the right target, this fascinating study could tell us more about what goes wrong when someone gets ME/CFS. If it doesn’t then their samples –  banked in liquid nitrogen at -80 degrees C –  provide a potentially invaluable resource for the future.

By capturing the blood of people with ME/CFS before they got sick, as they were getting sick and then after the illness became established, Jason’s unique biobank could allow future researchers to quickly determine if the factor they believe plays a critical role in ME/CFS does – saving much time and money.

Small Non-profit Potentially Makes Big Difference

Showing that you don’t have to be large to potentially make a major difference, this potential Lyme breakthrough came not from the NIH or the CDC but from a small Lyme non-profit – The Bay Area Lyme Foundation  – that’s been in business for just over five years.  The study was the product of an 2014 award, The Bay Area Lyme Foundation Emerging Leader Award, that went to Lisa Blum, PhD, a former Stanford postdoc. That award specifically targets veteran researchers who have not previously worked in Lyme research.

The Simmaron Research Foundation is another non-profit that is seeking to scientifically redefine how a disease is understood and treated.  It is currently funding studies that are using proteomics and metabolomics to study cerebral spinal fluid in ME/CFS, that are assessing the effectiveness of underutilized treatments such as Ampligen, IVIG and Cidofovir, and that are seeking to understand why the rate of a lymphoma is increased in ME/CFS.