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The Post Infectious Syndromes Pt I

They came down with infection and never got over it. They’re experiencing fatigue, dizziness, abdominal pain, muscle and joint aches, headaches, sleep problems, weight loss and vision problems.  They’re not ME/CFS or fibromyalgia patients – they’re Ebolavirus survivors – but the resemblance is uncanny.

The Ebolavirus outbreaks are prompting examinations of the virus after- effects in survivors. Given the high incidence of infectious onset in both chronic fatigue syndrome (ME/CFS) and fibromyalgia any examination of a post-infectious illness is interesting.

This blog  the first of two – focuses on three of these: post-infection Ebolavirus syndrome, post-infectious mononucleosis and Giardia syndrome.  It asks if the symptoms, course and possible causes of  these post-infectious disorders are similar or different?

Does one central post-infectious illness exist or are there many separate ones?

Post Ebolavirus Disease Syndrome (PEDS)

A recent study published in Lancet  found that two years after a 2007 outbreak survivors commonly experienced blurred vision, headaches, neurological symptoms, fatigue, sleep problems, joint pain, low mood and memory loss.

The most common persisting symptoms appear to be fatigue, joint, muscle and chest pain, and headache.  Approximately 50% of Ebolavirus survivors, most of whom are or were engaged in occupations requiring manual labor, experienced severe fatigue – and difficulty working. At least four studies over time have examined Ebolavirus survivors and they have all had similar results.

Ebolavirus

Post Ebolavirus Disease Syndrome – Is it similar to ME/CFS?

The Ebolavirus survivors all look like they have one form of ME/CFS/FM – a form that is characterized, in particular, by high rates of joint pain. Some symptoms – not found in all survivors – such as hearing loss – are not commonly found in ME/CFS or FM.  Problems with concentration and attention span – found in about a quarter of survivors – may also be less common than in ME/CFS and FM.  Anorexia may be another symptom that is more commonly in post-EBV syndrome.

Still the general symptomology with a focus on fatigue, joint and muscle pain and headache is similar. Early studies of myalgic encepthalomyelitis found that symptoms might begin differently but they tended to devolve over time into the same symptoms: mainly fatigue, exertion problems, muscle and joint pain, etc.

What’s causing all this illness? The first disease the Ebolavirus study cites as an example of post-viral syndrome, encouragingly, is chronic fatigue syndrome. As in ME/CFS, the severity of the initial immune response may play a role in who comes down with PEBV; one study found that the Ebolavirus survivors with higher antibody titers were more likely to experience joint pain.

The author proposed several ways Ebolavirus could be causing long term problems, most of which have to do with persisting infection in the central nervous system or other areas.

  • Fatigue – persisting infection produces encephalomyelitis (inflammation of the brain/spinal cord)
  • Joint pain – Ebola virus replication in the joints or the deposition of immune complexes or intravascular coagulation.
  • Eye problems –  persisting infection

 Infectious Mononucleosis (Epstein-Barr Virus)

Infectious mononucleosis. Henry H Balfour Jr1,, Samantha K Dunmire1 and Kristin A Hogquist. Clinical & Translational Immunology (2015) , e33; doi:10.1038/cti.2015.1; published online 27 February 2015

Infectious mononucleosis (IM) is usually associated with later onset Epstein-Barr virus (EBV) infection.

EBV ME/CFS

EBV can trigger ME/CFS, MS and lymphoma but there’s no consensus how.

IM typically presents itself in one of two ways; a sudden onset of sore throat and swollen neck due to lymph node enlargement or the slow development of malaise, muscle pain and fatigue; i.e. there is such a thing as gradual onset IM. Many of the symptoms of IM and ME/CFS are identical.

Considerable research indicates IM is a risk factor for ME/CFS. After two years approximately 5% of people with IM experience an ME/CFS-like illness.

The IM review paper missed the idea that IM is a risk factor for ME/CFS completely, but it did indicate that it is a “strong” risk factor for multiple sclerosis and non-Hodgkins lymphoma.  Either individuals with IM are believed to have a predisposition to all three illnesses or their demonstrated lack of early control of the virus –  manifested in their IM –  result in poor later control of the virus – and the later appearance of EBV triggered MS or lymphoma.

Cause

But what causes IM associated post-infectious illnesses?

Determining how IM is causing ME/CFS, has not been easy. Katz and Jason found no evidence that many of the usual suspects (peak work capacity, activity level, orthostatic intolerance, salivary cortisol,  natural killer cell number and function) believed to play a role in ME/CS, did so. They did find, however, differences in autonomic nervous system functioning, exercise efficiency (oxygen consumption, peak oxygen pulse), gender, psychological factors and cytokine networks, between those who recovered and those who did not.

The Dubbo studies found no link between viral load or cytokine levels and a post-infectious illness. Alterations in immune genes suggest an immune factor is present.

Unlike Ebola but like Giardia below, EBV infections often cause few symptoms except in individuals who are severely affected. That suggests that a genetic predisposition to coming down with IM – and perhaps lymphoma and MS – is present as well.  A huge Danish study indicated that IM does indeed tend to run in families.  A Simmaron Research Foundation study is beginning to examine hereditary factors in EBV infection in ME/CFS.

Genetic factors, plus alterations in autonomic nervous system functioning, plus possibly exercise problems, etc. may contribute to post infectious ME/CFS but how EBV is causing those problems is unclear.

Several hypotheses exist:

  • Low level EBV reactivation is present – Lerner
  • Partial EBV reactivation produces proteins that produce an immune response and possibly NK cell dysfunction – Williams (major study underway)
  • EBV reactivation in localized nervous system tissues triggers an immune response via the vagus nerve- Van Elzakker (preliminary study underway)
  • An initial infection alters central nervous system functioning in some way – Lloyd (neuroinflammation study underway, I believe, in 2016)

Preventing ME/CFS (and MS and Lymphoma?)

There is no approved treatment for infectious mononucleosis (IM).  Why? Possibly because a recent review described it as a three week illness that rarely has severe immediate complications. It is clear, however, that IM is a risk factor for MS and lymphoma.

Two studies in 2007 and 2010 studies found that valacyclovir, described as a very safe drug, reduced  EBV loads and symptoms in people with IM. Because symptom severity was strongly associated with an increased risk of coming down with ME/CFS after an infection, in the Dubbo studies, that’s a potentially very important finding. If researchers can identify individuals at risk of coming down with ME/CFS after IM, giving them a short treatment of a safe antiviral could possibly prevent decades of illness. Leonard Jason has begun a large study attempting to identify those individuals.

EBV’s association with autoimmune diseases and cancers has made it an object of considerable study.  A recent review article listed three priorities for EBV research:

  1. The development of a vaccine in order to prevent or modify the severity of infectious mononucleosis, multiple sclerosis, EBV-positive Hodgkin lymphoma, endemic Burkitt lymphoma and nasopharyngeal carcinoma and other diseases. That work is underway.
  2. Define the factors that enable EBV to trigger cancer or autoimmune disease and infectious mononucleosis.
  3. Develop specific anti-EBV drugs to treat infectious mononucleosis.

Giardia

Halliez MCM, Buret AG. Extra-intestinal and long term consequences
of Giardia duodenalis infections. World J Gastroenterol 2013; 19(47): 8974-8985

Like infectious mononucleosis, an initial giardia infection is often asymptomatic but can in some individuals cause diarrhrea, bloating, etc. The fact that Giardia often causes no problems at all confused  the medical profession for well, about three hundred years.  It took three hundred years (from 1681-1981) for the medical profession to recognize that giardia can cause illness.

giardia

The most common parastic infection in children was not believed to cause disease for hundreds of years

Giardia is now considered to be the most common parasitic infection in children.  It’s present in from 20-30% to even 100% of the population in some developing countries. (Contrast that with exposure rates in developed countries of 3-7%.) The WHO lists it as a neglected tropical disease. The infection tends to be self-limiting; i.e. the body takes care of the pathogen and moves on – but not always.

How giardia produces its most immediate effects – the diarrhea, bloating, etc. – are becoming known.  The long term symptoms giardia  can produce – particularly those not associated with the gut — are mostly a mystery.

Indeed, it’s only recently that these symptoms have been assessed at all. A recent study suggested, however, that Giardia infections will cause long term ‘extra-gastrointestinal symptoms” from a third to forty percent of those infected – a much higher rate than found in the Dubbo studies.

The long term results of a giardia infection can include eye problems, arthritis, allergies including milk allergies (possibly due to gut damage), muscle weakness, failure to thrive in children, malnutrition, irritable bowel syndrome, cognitive problems, extreme fatigue (ME/CFS), and long term gut problems.

Some may derive from a failure to fully eliminate the parasite but others clearly do not. The Norwegian Bergen studies, for instance, indicated that high rates of post-infectious illness can persist even after the parasite has been eliminated.

Several hypotheses have been advanced to explain the post–infectious symptoms giardia can produce

Possible Causes of Symptoms Associated with Post-infectious Giardia Syndrome

  • Eye problems – toxic metabolites produced by the parasite
  • Arthritis – bacterial antigens uploaded into the synovial fluid during times of increased gut permeability
  • Allergies – dysfunctional intestinal barrier; i.e. increased gut permeability
  • Failure to thrive – reduced nutrient absorption, malabsorption
  • Chronic fatigue syndrome – altered natural killer-cell levels, lower ratio CD4:CD8
  • Post-infectious irritable bowel syndrome – microscopic inflammation, gut flora alterations

An IBS Aside

Meta analyses indicate that the risk of developing IBS rises six-fold following a gastrointestinal infection and stays elevated for several years. From 7-31% of individuals with a gastrointestinal infection may develop IBS afterwards. Salmonella sp., Shigella sp., Campylobacter jejuni and Giardia duodenalis have all been shown,that  can trigger irritable bowel syndrome (IBS) – even in those patients with apparently resolved infections.

As with ME/CFS more severe and longer lasting infections and being female appears to increase the risk of coming down with IBS.

Numerous mechanisms have been proposed to be at work in IBS including  problems with gut motility, permeability, altered gut flora,  inflammation, molecular mimicry and smooth muscle hyperactivity. All of these could be initiated by an infection.

Conclusions

The Dubbo studies indicated that a post-infectious fatigue state lasting a year or more can be expected to occur in about 10 percent of people coming down with a serious infection.  That finding suggests that a considerable number of people around the world are affected by post-viral illnesses.

Post-infectious illnesses are therefore probably common but under-recognized and poorly treated. This short survey suggests that we are nowhere near close to answering whether they present common end states or distinct illnesses, or have components of both. Only the Dubbo studies, so far as I can tell, have attempted to compare post-infectious illness states caused by different infections.

How a pathogen triggers ANY post-infectious state is pretty much unclear...

How a pathogen triggers ANY post-infectious state is pretty much unclear…

Most hypotheses regarding these states revolve around the idea that either the pathogen still persists in difficult to find locations or that a continuing immune response is present. The Dubbo studies also suggested some sort of central nervous system reset occurred early in the illness.

Because Ebolavirus and EBV can affect many parts of the body, the post–infectious issues with either, could  reflect localized difficult to detect infections or the remnants of the original infection in the form of antigens, or immune complexes persisting in the body.

Because giardia does not travel outside of the gut the many symptoms attributed to post-giardia infection must come about another way.   Given the strong gut-brain  connection, gut alterations caused by Giardia could affect central nervous system functioning.

(Williams, interestingly, is examining EBV’s possible effects on gut cells and Mady Hornig is uncovering evidence of gut induced central nervous system problems in ME/CFS.)

Since ME/CFS and FM can be triggered by many different pathogens, they could consist of distinct post-infectious states or they could, as the Dubbo studies suggested, devolve into the same general illness. The more research including comparative studies of different post-infectious illnesses is clearly needed.

 

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