ME/CFS: An Infectious Disease by Dr. Rosemary Underhill

Gemini

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Excellent review article.

Dr. Underhill summarizes research into the role of infections in ME/CFS going back decades covering outbreaks worldwide.

She presents evidence supporting the hypothesis that ME/CFS is an infectious disease; discusses the immune system & host factors; & offers suggestions for further research--

www.medical-hypotheses.com/article/S0306-9877(15)00382-5/fulltext

Dr. Underhill trained as a physician, surgeon & obstetrician in London & has significant knowledge of the Royal Free outbreak.

She was on the writing committees for the "ME/CFS Primer for Clinical Practitioners" & "A Consensus Manual for the Primary Care and Management of CFS" & has presented CFSAC Testimony on this topic.

Article is very timely. Should be required reading for new ME/CFS researchers entering the field, at NIH for example.
www.medical-hypotheses.com/article/S0306-9877(15)00382-5/fulltext
 
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Yes, very refreshing to know that there are actually real scientists involved in the effort. I just found it very discouraging that so few autopsies have been performed on deceased ME/CFS victims. How else can researchers analyze the presence of a virus in the nervous tissue?
 

Gemini

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This paper is a fantastic read...
Yes, fantastic indeed!

@M Paine Thank you for correcting me on the title of the Primer & providing the link.

Just last month Science (print version) published Carl Nathan's "From Transient Infection to Chronic Disease" describing recent discoveries related to the infectious disease "hit and run" theory long thought to apply to a subset of ME/CFS patients & covered in Dr.Underhill's article:
(may be behind a paywall)
www.sciencemag.org/content/350/6257/161.full.pdf

Especially like Nathan's terminology describing how a resolved infection can "injure" and "scar" the immune system leading to long-lasting immune dysfunction & a wide range of chronic conditions like RA & other inflammatory & autoimmune diseases.

To Drs. Lipkin/Horning re:the microbiome study, wonder if the "context dependent pathogenicity" Nathan describes (friendly microbes like lactobacilli turning pathogenic due to immune dysfunction or other changes) will be explored?

Anyway, it's great to see the "hit and run" theory alive & well in mainstream research. Add this paper to the NIH reading list!
 

Research 1st

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It's hard to prove infections in ME, if you don't make antibodies to pathogens. Thus it's easy to get dumped with the 'autoimmune' label, in effect because no one can find out why you are sick and it's presumed the body is attacking it's own tissue for no reason, rather than the tissue being infected.

A paradox then appears in ME and Lyme that the less sick you are, the more evidence you have of being sick, and the more sick you are, the less evidence you have being sick! Case in point, we then discover that PWME, with no known history of tick bites, and no rash, often harbour intracellular infections that have very low antigenic activity.

For example, in bacterial Lyme co infections in patients with this class of infection that only produces a low antibody effect, or in patients with this immune defect, you need to resort to using an cellular activity assay like an LTT Cytokine test to demonstrate intracellular bacterial infections, if your body doesn't launch antibodies to protect you. (Other 'superior' methods are PCR and culture, but culture is usually not possible to obtain, and PCR often has poor sensitivity meaning you may need multiple blood tests over time to strike lucky with a positive test, or you may never test positive because the infection is in your tissue, not your blood).

We learn that people with severe infections in neuro Lyme (told they have ME or CFS) have to resort to having high dose antibiotics, to even have a chance of producing antibodies (antibiotics have poor penetration into the CNS), so then in effect, you have to be treated, to test positive. Think how crazy that is, and how tragic it is for the patients crippled for maybe decades or for life, by a misdiagnosis, or a null diagnosis for Borrelia. Often out comes the psych theory ideas, the patients must all have some 'idea' they have a hidden infection. Now granted, some may do, but many may genuinely be infected but cannot prove it.

What this means in the doctor's office and wider society is you can have antibody tests (serology), but they come out false negative, for a whole host of Borrelia or Borrelia Co infections with regards to Lyme related bacterial infection. So few PWME CFS are aware you actually are chronically infected, with potentially, multiple pathogens too.

It's a big issue, especially if in ME sufferers there are important novel pathogens (causing immune suppression) that haven't even been discovered yet, or have been, but no reliable commercial assay exists in which patients can obtain to test themselves.

Hence the roll out of CBT GET and the advise not to test patients. I've found out to my cost, as have many others, that a diagnosis of ME CFS, is actually potentially dangerous to your health, as you are told ''all tests are normal'' and you believe this to be true. However if you go after intracellular bacterial infections, for some patients, this turns out to be the exact opposite.

So its good to see doctor's discussing ME CFS as an infectious disease, as it is for some and even a multiple infection based disease.
 
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M Paine

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Just last month Science (print version) published Carl Nathan's "From Transient Infection to Chronic Disease" describing recent discoveries related to the infectious disease "hit and run" theory long thought to apply to a subset of ME/CFS patients & covered in Dr.Underhill's article:
(may be behind a paywall)
www.sciencemag.org/content/350/6257/161.full.pdf
Yes, this is behind a paywall. One day I'd love to have a Nature/Science subscription... one day.
 

M Paine

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Yes, very refreshing to know that there are actually real scientists involved in the effort. I just found it very discouraging that so few autopsies have been performed on deceased ME/CFS victims. How else can researchers analyze the presence of a virus in the nervous tissue?
Lumbar puncture could be one way? Cerebrospinal fluid from the CNS of living patients?

I wonder if renewed efforts could look more closely at B-lymphocytes as a potential site for latency or retroviral infection, I.E. a Virus with tropism for B Cells
 
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Gemini

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Yes, this is behind a paywall..
I was afraid of that. Thanks for letting me know.

Here's three excerpts relevant to ME/CFS, Nathan paper (Science, 9 Oct 2015):

"An infection is considered to be resolved when the causative microbe has been cleared and host structure and function return to normal--except perhaps for a scar in the affected tissue. In a recent study, da Fonseca et al argue that some resolved infections leave scars of another sort--long-lasting immune dysfunction. The authors propose that "immunologic scarring" by resolved infections may account for a wide range of chronic diseases."

"...it is now recognized that some bacterial species that are usually nonpathogenic may cause disease when the host becomes immune-deficient or when the bacteria occupy a new location in the host, acquire virulence factors through infection by a plasmid, and/or face sudden lack of competition from their usual microbial neighbors."

"...the observations of da Fonseca et al are likely to breathe new life into the search for infectious provocateurs of chronic immune and inflammatory disorders, whether the trigger is an transient infection by a known pathogen or a cryptic, chronic infection by a microbe that is usually nonpathogenic."

Hopefully Drs. Lipkin/Horning's ME/CFS work will benefit from this new life!
 

halcyon

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Lumbar puncture could be one way? Cerebrospinal fluid from the CNS of living patients?
Testing this way is not sensitive enough, especially for the pathogens most suspected of triggering ME such as enteroviruses. False negatives are fairly common using PCR testing of CSF, even in acute cases.
 

M Paine

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Testing this way is not sensitive enough, especially for the pathogens most suspected of triggering ME such as enteroviruses. False negatives are fairly common using PCR testing of CSF, even in acute cases.
Yea, limit of detection in PCR is a problem. Also that PCR relies on primers directed to highly conserved sequences of the genomes being looked for.

You may be interested in VirCapSeq-VERT. Unfortunately it suffers from similar LOD, but it casts a bigger net

http://mbio.asm.org/content/6/5/e01491-15


ABSTRACT 
Insensitivity and technical complexity have impeded the implementation of high-throughput nucleic acid sequencing in differential diagnosis of viral infections in clinical laboratories. Here, we describe the development of a virome capture sequencing platform for vertebrate viruses (VirCapSeq-VERT) that increases the sensitivity of sequence-based virus detection and characterization. The system uses ~2 million probes that cover the genomes of members of the 207 viral taxa known to infect vertebrates, including humans. A biotinylated oligonucleotide library was synthesized on the NimbleGen cleavable array platform and used for solution-based capture of viral nucleic acids present in complex samples containing variable proportions of viral and host nucleic acids. The use of VirCapSeq-VERT resulted in a 100- to 10,000-fold increase in viral reads from blood and tissue homogenates compared to conventional Illumina sequencing using established virus enrichment procedures, including filtration, nuclease treatments, and RiboZero rRNA subtraction. VirCapSeq-VERT had a limit of detection comparable to that of agent-specific real-time PCR in serum, blood, and tissue extracts. Furthermore, the method identified novel viruses whose genomes were approximately 40% different from the known virus genomes used for designing the probe library. The VirCapSeq-VERT platform is ideally suited for analyses of virome composition and dynamics.
 

M Paine

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Another relevant excerpt from the time when the infamous Mady Hornig/Ian Lipkin Cytokine study was released...

"Drs. Hornig and Lipkin expect to report the results of a second study of cerebrospinal fluid from ME/CFS patients. In separate ongoing studies, they are looking for “molecular footprints” of the specific agents behind the disease—be they viral, bacterial, or fungal—as well as the longitudinal look at how plasma cytokine patterns change within ME/CFS patients and controls across a one-year period"

https://www.mailman.columbia.edu/pu...-evidence-chronic-fatigue-syndrome-biological

Given that Ian Lipkin is closely involved with VirCapSeq-VERT and CFS research, it stands to reason they will use this technology in the aforementioned study. Very exciting. :thumbsup:
 

Gemini

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I wonder if renewed efforts could look more closely at B-lymphocytes as a potential site for latency or retroviral infection, I.E. a Virus with tropism for B Cells
Good point especially with all the new molecular tools available.

EBV, CMV, & HHV-6 are harbored in B-cells. I believe certain enteroviruses are as well, but perhaps someone else can verify this?
 

Gemini

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CFSAC Testimony on this topic.
Dr. Underhill's CFSAC Testimony re: ME/CFS outbreaks 3 Oct 2012:

www.hhs.gov/advcomcfs/meetings/presentations/underhill_rosemary_100312.pdf

Interestingly at the 11 May 2011 CFSAC meeting Social Security Administration presenter John Federline reported historic ME/CFS disability claims data by year & geography appeared to show US cluster outbreaks. If requested he could provide it for analysis.

Perhaps CFSAC patient rep Donna Pearson or the Solve rep could follow-up & request it? Would be of value to NIH's new studies among other things.
 
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I was afraid of that. Thanks for letting me know.

Here's three excerpts relevant to ME/CFS, Nathan paper (Science, 9 Oct 2015):

"An infection is considered to be resolved when the causative microbe has been cleared and host structure and function return to normal--except perhaps for a scar in the affected tissue. In a recent study, da Fonseca et al argue that some resolved infections leave scars of another sort--long-lasting immune dysfunction. The authors propose that "immunologic scarring" by resolved infections may account for a wide range of chronic diseases."

"...it is now recognized that some bacterial species that are usually nonpathogenic may cause disease when the host becomes immune-deficient or when the bacteria occupy a new location in the host, acquire virulence factors through infection by a plasmid, and/or face sudden lack of competition from their usual microbial neighbors."

"...the observations of da Fonseca et al are likely to breathe new life into the search for infectious provocateurs of chronic immune and inflammatory disorders, whether the trigger is an transient infection by a known pathogen or a cryptic, chronic infection by a microbe that is usually nonpathogenic."

Hopefully Drs. Lipkin/Horning's ME/CFS work will benefit from this new life!
"...the observations of da Fonseca et al are likely to breathe new life into the search for infectious provocateurs of chronic immune and inflammatory disorders, whether the trigger is an transient infection by a known pathogen or a cryptic, chronic infection by a microbe that is usually nonpathogenic."


Carriage of Staphylococcus aureus may be that infectious provocateur.
http://www.antimicrobe.org/history/LID 2005 V5 - Werthiem-Saureus.pdf

This would help explain the effectiveness of the Staphylococcus vaccine in reducing symptoms of CFS.
http://www.ncbi.nlm.nih.gov/pubmed/10700309
 

Rrrr

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It's hard to prove infections in ME, if you don't make antibodies to pathogens. Thus it's easy to get dumped with the 'autoimmune' label, in effect because no one can find out why you are sick and it's presumed the body is attacking it's own tissue for no reason, rather than the tissue being infected.

A paradox then appears in ME and Lyme that the less sick you are, the more evidence you have of being sick, and the more sick you are, the less evidence you have being sick! Case in point, we then discover that PWME, with no known history of tick bites, and no rash, often harbour intracellular infections that have very low antigenic activity.

For example, in bacterial Lyme co infections in patients with this class of infection that only produces a low antibody effect, or in patients with this immune defect, you need to resort to using an cellular activity assay like an LTT Cytokine test to demonstrate intracellular bacterial infections, if your body doesn't launch antibodies to protect you. (Other 'superior' methods are PCR and culture, but culture is usually not possible to obtain, and PCR often has poor sensitivity meaning you may need multiple blood tests over time to strike lucky with a positive test, or you may never test positive because the infection is in your tissue, not your blood).

We learn that people with severe infections in neuro Lyme (told they have ME or CFS) have to resort to having high dose antibiotics, to even have a chance of producing antibodies (antibiotics have poor penetration into the CNS), so then in effect, you have to be treated, to test positive. Think how crazy that is, and how tragic it is for the patients crippled for maybe decades or for life, by a misdiagnosis, or a null diagnosis for Borrelia. Often out comes the psych theory ideas, the patients must all have some 'idea' they have a hidden infection. Now granted, some may do, but many may genuinely be infected but cannot prove it.

What this means in the doctor's office and wider society is you can have antibody tests (serology), but they come out false negative, for a whole host of Borrelia or Borrelia Co infections with regards to Lyme related bacterial infection. So few PWME CFS are aware you actually are chronically infected, with potentially, multiple pathogens too.

It's a big issue, especially if in ME sufferers there are important novel pathogens (causing immune suppression) that haven't even been discovered yet, or have been, but no reliable commercial assay exists in which patients can obtain to test themselves.

Hence the roll out of CBT GET and the advise not to test patients. I've found out to my cost, as have many others, that a diagnosis of ME CFS, is actually potentially dangerous to your health, as you are told ''all tests are normal'' and you believe this to be true. However if you go after intracellular bacterial infections, for some patients, this turns out to be the exact opposite.

So its good to see doctor's discussing ME CFS as an infectious disease, as it is for some and even a multiple infection based disease.
@Research 1st Good post. So in the past I tested positive for lyme (via Igenex) and then later I did not. Could this be due to what you are describing above? I have been very sick for 25+ years.
 

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The authors propose that "immunologic scarring" by resolved infections may account for a wide range of chronic diseases."
"immunologic scarring" seems awfully vague to me. What tissues are damaged? There's a million patients, and a million theories. What I know about immunology wouldn't fill a flea-sized thimble, but I used to shovel a lot of shit, so I can smell it a mile away, and this kind of phraseology smells familiar.

Does the article give a reference to the da Fonseca study? There are 300 articles on PubMed with "da Fonseca" as lead author, and none of them contain the phrase "immunologic scarring". It would be interesting to look at the actual research as opposed to having someone pre-digest it for me.
 

jimells

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Thank you.

Cell. 2015 Oct 8;163(2):354-66. doi: 10.1016/j.cell.2015.08.030.
Microbiota-Dependent Sequelae of Acute Infection Compromise Tissue-Specific Immunity.
Fonseca DM1, Hand TW2, Han SJ2, Gerner MY3, Glatman Zaretsky A2, Byrd AL4, Harrison OJ2, Ortiz AM5, Quinones M6, Trinchieri G7, Brenchley JM5, Brodsky IE8, Germain RN3, Randolph GJ9, Belkaid Y10.
Author information
Abstract

Infections have been proposed as initiating factors for inflammatory disorders; however, identifying associations between defined infectious agents and the initiation of chronic disease has remained elusive.

Here, we report that a single acute infection can have dramatic and long-term consequences for tissue-specific immunity. Following clearance of Yersinia pseudotuberculosis, sustained inflammation and associated lymphatic leakage in the mesenteric adipose tissue deviates migratory dendritic cells to the adipose compartment, thereby preventing their accumulation in the mesenteric lymph node.

As a consequence, canonical mucosal immune functions, including tolerance and protective immunity, are persistently compromised. Post-resolution of infection, signals derived from the microbiota maintain inflammatory mesentery remodeling and consequently, transient ablation of the microbiota restores mucosal immunity.

Our results indicate that persistent disruption of communication between tissues and the immune system following clearance of an acute infection represents an inflection point beyond which tissue homeostasis and immunity is compromised for the long-term. VIDEO ABSTRACT.

Copyright © 2015 Elsevier Inc. All rights reserved.