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Parvovirus B19 in an Icosahedral Nutshell

Joel (snowathlete) reviews the research on ME/CFS and Parvovirus B19.

Parvovirus B19. Image curtesy of Dr Jean-Yves Sgro, Virusworld

Parvovirus B19. Image courtesy of Dr Jean-Yves Sgro, Virusworld [*]

Parvovirus B19 (B19) is a small virus with an icosahedral shell (a polyhedron having 20 faces) [1] and has been linked with the onset of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). B19 was discovered fortuitously in 1975. There are several other parvoviruses, but most don’t infect humans.

You may have heard of the parvovirus which infects dogs and often causes fatality, but B19 is not the same virus, or even in the same genus, so B19 is not a zoonotic. In humans, B19 is often caught in infancy and causes “slapped cheek”, also referred to as “fifth disease”, and is considered to be mild and self-limiting. B19 is highly contagious and is transmitted via respiratory droplets, in the same sort of way as influenza is transmitted. If you don’t catch it in childhood then you can catch it in adulthood and it may be a mild illness, sub-clinical, or it can be more severe causing symptoms such as fatigue, arthritis and heart problems.

Even in adulthood, B19 infection is generally considered to be short lived, with most adults getting over it in weeks or sometimes months. Nonetheless, there are a neglected minority of people out there, predominately women, with chronic B19 who get little attention and who have this very debilitating infection on an ongoing basis.

A little more detail
The inner genetic material that makes up the viral part is comprised of single-stranded DNA. The primary target of B19 infection are the erythroblast cells, which are found in the bone marrow and mature to become erythrocytes (red blood cells).

The virus encodes three major proteins; Viral Protein 1 (VP1), Viral Protein 2 (VP2), and a non-structural protein (NS1).

About half of all adults have been exposed to the virus and developed immunity to it. B19 can be a problem for some disease groups, including AIDS sufferers, who often develop anemia as a result of the infection. B19 when caught for the first time and while in pregnancy can also be serious.

Intravenous Immunoglobulin is the primary treatment for Parvo B19

Intravenous Immunoglobulin is the primary treatment for Parvo B19

Treatment
Surprisingly, perhaps, there aren’t many treatments available for B19. The frontline treatment is intravenous immunoglobulin (IVIG) which is where antibodies from at least a thousand healthy blood donors are pooled and then shot into your veins (sounds tempting doesn’t it?)…

This new immunoglobulin in your veins tackles pathogens in your body, and modulates the immune system. It is an FDA approved treatment for many immune deficiencies, and for various autoimmune diseases. It is an off-label treatment for B19 and many other diseases.

Not all IG products are the same, with brands processed differently and containing different additives. People often respond better to certain brands than others, and adverse reactions are more common in some brands too. There are studies on this, and you should investigate for yourself if you are considering IG treatment.

You have the risk of this product coming from multiple sources. So as to be sterile, the FDA guidelines state that the product should be screened and treated for viruses and should not come from patients who have HIV or hepatitis. Adverse effects are not uncommon and range from headaches, or dyshidrotic eczema, to anaphylactic shock, renal failure or transmission of diseases such as HIV via contamination.

The good news is that there have been several studies on IVIG in ME/CFS and although most of the findings conflicted with each other, all the studies of IVIG in parvovirus-induced ME/CFS were positive. If you tested positive for a current B19 infection then it might be worth thinking about, but if you have complicated co-infections as well, then it may be a harder decision due to the lack of available data. More on this later…

But say you don’t want to, or cannot access IVIG (it is quite expensive) – what are the alternatives?

Equilibrant is supposed to work on it, some say, so that may be a treatment that people want to try first as it’s perhaps less risky and is not prohibitively expensive, but to my knowledge it hasn’t been through any formal trials on B19. On a positive note Dr Chia was involved in one of the B19 studies on ME/CFS, so perhaps he has a view on Equilibrant and its efficacy against B19?

B19 and ME/CFS
Parvovirus B19 has been linked with ME/CFS for some time, there are several papers on it, though not much has been written about it outside of the medical journals. ME/CFS patients, when tested for it, often have higher than normal levels of IgG antibodies for B19, suggesting that some may have a persistent B19 infection. Additionally, there is some evidence that people with chronic B19 infection have a defective IgG antibody immune response [2].

Not all people with ME/CFS test positive for B19, so perhaps it isn’t the cause of ME/CFS for all, but it may be for some, and in others it could be an opportunistic infection, and others may not have it at all…Then again, as you will read below, blood tests don’t necessarily tell a reliable story.

What do the published studies tell us?
1995

The first published study on B19 in ME/CFS was by Komaroff [3] and was small. It looked in blood and bone marrow and found no link between B19 and ME/CFS. The patients also had other conditions that potentially may actually have skewed the results, including mild leukopenia (low white blood cells), thrombocytopenia (low platelets), or anemia. Still, there is a first step in everything, and this was the first B19 study in CFS.

1996

The next year came a report from Jacobson et al. that a single patient with an illness indistinguishable from CFS was found to have a persistent B19 infection and treatment with Intravenous immunoglobulin (IVIG) resolved the illness [4].

1997

Then, Jonathan Kerr came onto the scene in 1997 with another small study looking for B19 in the skeletal muscle of six CFS patients [5]. He found it in one patient and in one control who suffered from mild arthralgia and at the time he concluded that B19 was not likely involved in the etiology of CFS.

2002

Five years later in 2002, Jonathan Kerr [6] published another paper looking at patients with arthralgia (joint pain) and fatigue as a result of B19 infection. Only 13 out of 51 patients studied had fatigue and only five of these met the CDC (Fukuda) criteria. So still we didn’t have a large sample to draw conclusions from, however it reaffirmed what we already knew – that not everyone who gets B19 gets CFS, but some do. The most notable finding, perhaps, was that arthralgia could be caused by parvovirus.

An interesting study from the University of Washington [7] came later in the same year, and looked for differences in 22 pairs of identical twins where one of the twins was diagnosed with CFS. Part of this study looked at B19 but only looked for it by PCR (looked for the viral DNA in the blood) and only for IgM antibodies, not IgG. This limits the study’s usefulness. They found no difference between healthy and CFS twins.

2003

Given Kerr’s prior conclusion in 1997 that B19 was not involved in the etiology of CFS, it may have been a surprise that he published a paper the next year reporting the “Successful intravenous immunoglobulin therapy in 3 cases of parvovirus B19-associated chronic fatigue syndrome” [8]. Though based on the report from Jacobson, he may well have felt that persistent B19 infection in CFS may represent a subset of patients and warranted further study. And indeed, his new study was three times the size of Jacobson’s’…it looked at three CFS patients…nonetheless his results matches Jacobson’s: “IVIG therapy led to clearance of parvovirus B19 viremia, resolution of symptoms, and improvement in physical and functional ability in all patients, as well as resolution of cytokine dysregulation.”

Non-parvovirus specific treatment of CFS with IVIG has been studied a few times with mixed results [9, 10, 11, 12]

2005

More work followed by Kerr and colleagues in 2005 [15], adding to another paper in 2001 [13] and 2003 [14], exploring some of B19’s mechanisms of persistence, including raised levels of cytokines and host gene expression variability in CFS.

Another paper from McGhee et al. reported the successful IVIG treatment of a single patient with B19-associated CFS [16].

2008

In 2008 researchers from Japan – Seishima et al. – got in on the act and examined 210 patients following acute B19 infection [17]. They looked at antibody production, the presence of B19 DNA and complement protein levels (complement proteins are part of the innate immune system). They found no persistence of DNA or antibodies in CFS patients compared to controls (which didn’t agree with earlier findings by Kerr et al.), but did find a “persistent decrease in a greater proportion of patients with persistent symptoms”, suggesting that these persistent symptoms may be the result of something other than B19 DNA presence in the blood.

The Japanese study suggested that there were other factors involved, and the same year Kerr published more research showing an association between psychological stress and acute and chronic fatigue and arthritis following B19 infection [18]. The study data is not without its limitations, but suggested that stress may predispose people to infection with B19 and affect disease progression.

2009

In 2009 two different groups, one from Japan [19], the other from Egypt [20], reported very similar findings: no increased prevalence of B19 IgG or IgM antibodies in CFS patients compared to controls. Both sets of authors concluded that B19 bears no relationship to CFS. Nonetheless, both groups did also report an increased IgG titer in the CFS group compared to controls, which was significant.

A study by Pironi et al. [21] reported that B19 infection may be localized in the intestinal mucosa and may be associated with inflammatory bowel disease. The same year, De Meirleir reported B19 in the intestinal mucosa of 40% of ME/CFS patients versus 15% of controls [22] and recently (in 2013) reported with Lombardi the discovery of HERV expression within the duodenum of patients [23]. Could there be some association between these two findings?

Of additional interest was the finding that 11 out of 32 patients were positive for B19 in the intestinal tract, but were found to be negative when tested in the blood. This further supports the view that B19 infection may be tissue localized, and may explain the persistence of symptoms reported by Seishima et al. [17], despite the disappearance of B19 DNA from the blood.

2010

Parvovirus. Used by kind permission of Eye Of Science.  Image © eye of science

Parvovirus B19.
Image © eye of science [**]

Kerr, along with Enlander, then published a study together in 2010 [24]. This study looked at 88 genes previously linked with ME/CFS in 56 new patients and 55 patients from a previous study. The patients were tested for the presence of antibodies to B19 as well as other pathogens including EBV, enterovirus, and Coxiella burnetti. B19 was positive in 74% of patients – in line with the general population, as were the other pathogens. Nothing significant in that. The significance of this paper was in the area of gene expression and the potential to identify subtypes, and although the B19 patients had gene expression consistent with other ME/CFS patients, compared to controls, it was not possible to identify specific differences in the B19 positive patients compared to the rest of the patient sample. This is not really surprising given the high prevalence of B19 within the patient sample.

Around the same time, we got another study from Enlander and Kerr along with several other colleagues, including well-known ME/CFS researchers Komaroff and Chia [25]. 200 patients and 200 controls were recruited. The subjects were tested for antibodies against B19 VP2, B19 NS1 and viral DNA. As expected, seroprevalence (B19 VP2) was similar between the two groups.

But when they compared B19 NS1 antibodies they found clear differences between the two groups. 83 (41.5%) of the CFS patients were positive for B19 NS1 compared to just 14 (7%) of the control group. 61 of the 83 patients complained of chronic joint pain, strongly suggesting that the joint pain was as a result of dysfunctional immune control of the virus, irrespective of whether B19 was the inducer of ME/CFS or an opportunistic infection.

On that point, only 11 of the 200 patients were positive for B19 viral DNA, compared to zero controls, to which the authors state:
“this finding may suggest that the disease in these 11 patients may have been somehow induced by acute B19 infection. Such patients have previously been shown to respond very well to intravenous immunoglobulin (IVIG)…In patients with antibodies to anti-B19 NS1, but without parvovirus B19 DNAaemia, it is possible that the parvovirus infection was latent and reactivated at a low level.”

However, the findings of De Meirleir [22], which reported finding B19 DNA in the intestinal tract but not the blood, suggest that looking for B19 DNA in the blood may not be a reliable approach, and perhaps with this in mind, the authors speculate:

“Following the acute phase of infection, B19 virus DNA persists, possibly life-long in many tissues of the human body. It is possible that chronic B19 antigen stimulation may be responsible for an inflammatory state which could increase levels of these transcription factors, although this requires confirmation.”

2012

The most recent study published on parvovirus in ME/CFS (Fukuda definition) is from Latvia and looked at B19 as well as HHV-6 and HHV-7 [26]. They found B19 IgM antibodies – suggesting acute infection – in a surprisingly high proportion of patients: 60/108 patients (55%) compared with 11/90 practically healthy controls (12%), which disagrees with the findings by Koelle et al. [7].

Though not specific to B19, perhaps of note is that a variety of concurrent active infections were common in the patient sample (29/108) but were absent in the 90 controls, who made up the majority of those with latent infections or without any infection.

The researchers looked to correlate symptomology with the presence of active infections. It is surprising that of the nine symptoms measured (based on Fukuda criteria), the 11 patients with a single active B19 infection all provided the same answer, resulting in scores of either 0/11 or 11/11 patients for each symptom and suggesting strong statistical significance. This is unusual, but if this data is right then it suggests a very clear subset of patients with CFS which may be caused by B19. The more recent International Criteria [27], for example, have postexertional malaise (under the name ‘Postexertional neuroimmune exhaustion’) as a compulsory feature of ME diagnosis, which effectively would have excluded these 11 patients with single active B19 infection.

What’s next?

As you can see, there have been a fair number of studies into B19 in ME/CFS, but we probably need more research before we can really crack the icosahedral nut of B19 and fully understand what role it plays in the ME/CFS puzzle.

We have several ME/CFS doctors wh are familiar with B19, having researched it before, and we know that Dr Marshall in Australia also has some recent experience with B19, albeit in another disease (common variable immunodeficiency) [28]. Some ME/CFS physicians test for B19 and treat for it if appropriate. We don’t know for sure if anyone is researching B19 in ME/CFS right now, but it looks like the B19 story in ME/CFS has more pages yet to be written.

Joel was diagnosed with ME/CFS in 2009 but struggled with the illness for some time prior to this. He loves to write, and hopes to regain enough health to return to the career he loved and have his work published.

REFERENCES

* Graphic image of parvovirus B19 used with permission, courtesy of Dr Jean-Yves Sgro, VirusWorld. Image rendering using VMD software and based on 3D data from www.rcsb.org PDB (ID 1S58). Primary citation: The structure of human parvovirus B19.  (2004) Kaufmann, B.,  Simpson, A.A., Rossmann, M.G. Proc.Natl.Acad.Sci.USA 101: 11628-11633

** SEM Image of parvovirus B19 used with permission, courtesy of eye of science

  1. Kaufmann, et al. 2004. The structure of human parvovirus B19.
  2. Kurtzman, et al. 1989. Immune response to B19 parvovirus and an antibody defect in persistent viral infection.
  3. Komaroff, et al. 1995. Absence of parvovirus B19 infection in chronic fatigue syndrome.
  4. Jacobson, et al. 1996. Chronic Parvovirus B19 Infection Resulting in Chronic Fatigue Syndrome: Case History and Review.
  5. Kerr, et al. 1997. Parvovirus B19 and Chronic Fatigue Syndrome.
  6. Kerr, et al. 2002. Chronic fatigue syndrome and arthralgia following parvovirus B19 infection.
  7. Koelle, et al. 2002. Markers of viral infection in monozygotic twins discordant for chronic fatigue syndrome.
  8. Kerr, et al. 2003. Successful intravenous immunoglobulin therapy in 3 cases of parvovirus B19-associated chronic fatigue syndrome.
  9. Lloyd 1990. A double-blind, placebo-controlled trial of intravenous immunoglobulin therapy in patients with chronic fatigue syndrome.
  10. Peterson, et al. 1990. A controlled trial of intravenous immunoglobulin G in chronic fatigue syndrome.
  11. Rowe. 1997. Double-blind randomized controlled trial to assess the efficacy of intravenous gammaglobulin for the management of chronic fatigue syndrome in adolescents.
  12. Vollmer-Conna, et al. 1997. Intravenous immunoglobulin is ineffective in the treatment of patients with chronic fatigue syndrome.
  13. Kerr. 2005. Pathogenesis of parvovirus B19 infection: host gene variability, and possible means and effects of virus persistence.
  14. Kerr, et al. 2001. Circulating tumour necrosis factor-alpha and interferon-gamma are detectable during acute and convalescent parvovirus B19 infection and are associated with prolonged and chronic fatigue.
  15. Kerr, et al. 2003. Cytokines in parvovirus B19 infection as an aid to understanding chronic fatigue syndrome.
  16. McGhee, et al. 2005. Persistent parvovirus-associated chronic fatigue treated with high dose intravenous immunoglobulin.
  17. Seishima, et al. 2008. Chronic fatigue syndrome after human parvovirus B19 infection without persistent viremia.
  18. Kerr, et al. 2008. Preexisting psychological stress predicts acute and chronic fatigue and arthritis following symptomatic parvovirus B19 infection.
  19. Kato, et al. 2009. No apparent difference in the prevalence of parvovirus B19 infection between chronic fatigue syndrome patients and healthy controls in Japan.
  20. Mohammed I Abdul Fattah, et al. 2009. Is Parvovirus B19 Infection Incriminated in Chronic Fatigue Syndrome?
  21. Pironi, et al. 2009. Parvovirus b19 infection localized in the intestinal mucosa and associated with severe inflammatory bowel disease.
  22. De Meirleir, et al. 2009. Detection of herpesviruses and parvovirus B19 in gastric and intestinal mucosa of chronic fatigue syndrome patients.
  23. De Meirleir, Lombardi, et al. 2013. Plasmacytoid dendritic cells in the duodenum of individuals diagnosed with myalgic encephalomyelitis are uniquely immunoreactive to antibodies to human endogenous retroviral proteins.
  24. Enlander and Kerr, et al. 2010. Microbial infections in eight genomic subtypes of chronic fatigue syndrome/myalgic encephalomyelitis.
  25. Enlander, et al. 2010. Antibody to parvovirus B19 nonstructural protein is associated with chronic arthralgia in patients with chronic fatigue syndrome/myalgic encephalomyelitis.
  26. Chapenko, et al. 2012. Association of active human herpesvirus-6, -7 and parvovirus b19 infection with clinical outcomes in patients with myalgic encephalomyelitis/chronic fatigue syndrome.
  27. Carruthers, et al. 2011. Myalgic encephalomyelitis: International Consensus Criteria.
  28. Marshal, et al. 2012. Common variable immunodeficiency presenting with persistent parvovirus B19 infection.

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