0 Mitt Romney, Lyme Disease, And The Media

Well, I guess I had to come out of the woodwork to comment on this recent turn of events... If life wasn't so hectic lately, I could have blogged sooner, and written about David Suzuki's observations on how changes in the environment have led to increased incidence of Lyme disease, or Senator Blumenthal's request for personal stories of patients who have been affected by Lyme disease, or the discovery of a new, serious  tickborne phlebovirus in Missouri.

But no, that didn't happen...

The first opportunity I really have to sit down and write here, the news that is crossing my desk and getting a lot of airtime is about Presidential candidate Mitt Romney and the media's commentary on how his support for greater awareness of chronic Lyme disease has been used to ignite interest in Virginia voters who have been struggling with the disease.

And the media has not stopped there, with its opinion pieces focused on how any candidate for office can and will try to influence the vote of certain subgroups of people affected by issue x or issue y... No, after initial criticism was volleyed at Romney, a number of journalists posted articles on chronic Lyme disease and how it is not a real medical condition.

Well, here we go again. It is the same story told by some newspapers and writers, over and over again, about how chronic Lyme disease doesn't exist and how doctors who treat it are taking unfair advantage of patients who are suffering and how patients are naive dupes for a disease based on pseudoscience.

I honestly think at this point that many of you who are writing these pieces for publication have a template for about five boilerplate articles on chronic Lyme disease that you have slight variations on, and publish each article just far apart from each other that the busy, overworked, and exhausted public won't notice that you essentially wrote the same damn thing again - but perhaps with a little twist.

When I first began this blog, it was because of an article written in the Chicago Tribune which was supposed to be about how chronic Lyme disease is a dubious diagnosis - when the content of the article itself had no relationship to the title, and did not examine the issue of whether or not Borrelia burgdorferi - the bacteria which causes Lyme disease - could potentially cause a persistent infection in some people.

What the article in the Chicago Tribune did was look at two doctors who were said to have treated chronic Lyme disease who were reported for disciplinary action to their medical boards for various reasons unrelated to Lyme disease and one charlatan who - like many who promise to offer a cure for cancer - has no cure and no credentials whatsoever.

What a brave and insightful piece of literature it was, to move beyond the carefully crafted soundbites of a puffed-up opinion piece, by closely examining all the issues behind why some doctors, researchers, and patients may think that Lyme disease could persist - and why and why that isn't supported by existing evidence.

Not.

The article did not in any way, shape, or form discuss the scientific complexity involved in Borrelia infections, and the difficulty that doctors can have in properly diagnosing it as its symptoms mimic other conditions. It did not look at the state of the science on Borrelia burgdorferi sensu latu, and how a broad range of strains have different effects and disseminate at different rates.

Anyone reading it would have walked away not with the message that Lyme disease and other tickborne infections can produce a complex symptom presentation. Anyone reading it would not have learned how to prevent such illnesses or to even learn if there are differential diagnoses which one should look at which may be confused with chronic Lyme disease. It wasn't a helpful article that way. What they would have walked away with is the message that there are some doctors out there who have been disciplined for various reasons who happen to treat people with persisting symptoms related to Lyme disease, and some misinformation online about what Lyme disease is and is not.

The recent spate of articles which spend time criticizing Mitt Romney's move to spread awareness of Lyme disease as part of his future goals if elected have also had pretty much the same kind of content, and as opinion pieces are intended to persuade the audience and win them over to the writer's view. However, it should be noted that in no way should these opinion pieces be taken as the final word or even current word in science on what Lyme disease is all about - because as opinion pieces, they are neglecting mention of the scientific evidence needed to support their assertions.

The New Yorker's  recent article, "Mitt Romney Versus Lyme Disease And Science", states that:

"...If left untreated, Lyme disease can be crippling, yet it is a difficult illness to contract: a tick needs to attach itself to your body for at least twenty-four hours. Even then, two weeks worth of commonly prescribed antibiotics will kill the bacterium."

Yes, indeed, if left untreated Lyme disease can be crippling. This much is true: late stage, untreated Lyme disease can lead to cardiac, neurological, and arthritic complications. However, there is more to the rest of the story when it comes to the remainder of this passage: If a tick is on your body for fewer than twenty-four hours, there are circumstances under which transmission of Lyme disease (as well as other tickborne infections) may occur - including if the tick is improperly removed. Also, even the most conservative reading of the IDSA's 2006 guidelines for the treatment of Lyme disease would state that given certain objective and clinical signs, some patients may need retreatment or more than two weeks' worth of antibiotics - particularly if there are certain cardiac, neurological, and arthritic symptoms present.

The New Yorker article simplifies the nature of Lyme disease and makes sweeping statements here. What it could have said - and still be true to mainstream infectious disease canon - could have been this:

"...If left untreated, Lyme disease can be crippling. In American scientific research to date, it has been shown that in most cases, an Ixodes scapularis or pacificus tick needs to attach itself to your body for at least twenty-four hours before Lyme disease can be contracted. Improper tick removal and other factors may, however, contribute to earlier contraction of disease. One might note that there is some evidence that in Europe, Ixodes ricinus ticks have a shorter transmission time for passing on Lyme disease bacteria than American ticks. But even then, in acute cases, the immediate treatment of two weeks' worth of commonly prescribed antibiotics will kill the bacterium in most cases. If symptoms continue, further evaluation for more severe infection and tickborne coinfections is needed."

I think some more qualifiers are needed there. And I know - this is, perhaps, a less targeted passage in that it steps outside of American research and points at what's happening in Europe. But the point is, Lyme disease is a global issue and a global problem, due to global warming and climate change. It's not just Virginia's. Or even the eastern seaboard's problem.

People travel. People get sick overseas. Lyme disease is overseas. And perhaps it helps to raise the question of how much scientific research on Borrelia may be applicable in different locations the more that is learned about the bacteria as a whole... More research here is really the key to better understanding this bug.

I will, however, give The New Yorker's Michael Specter credit for this mention:

"In fact, there is a clear scientific issue that can only make Lyme disease worse—but it is a problem that Romney and the Republicans have ignored. The Intergovernmental Panel on Climate Change has noted that increasing temperature helps keep ticks alive. More ticks means more Lyme disease. This is a connection, as Mother Jones first noted, that Romney has failed to consider. Instead, he has said that spending huge sums trying to reduce CO2 emissions is “not the right course for us."

Climate change is a huge player in the tickborne illness game, and I don't need Al Gore or the IPCC or even David Suzuki to point this out for me. Look outside every year, and tell me what I don't see with my own eyes: The ticks are out there earlier, and out there for longer periods of time than they've been in the past. Ask the epidemiologists and entomologists, too, if you need confirmation... Sure populations will wax and wane to a degree - but what's the trend over time?

The Business Insider's article, "Why Romney's Statements About Chronic Lyme Disease Are Dangerous", does tend to give the topic a somewhat more balanced approach by acknowledging that there is a debate within the medical and scientific community by stating, "Many doctors and researchers don't believe in this syndrome, which lasts much longer than your run-of-the-mill Lyme disease infection. The CDC, NIAID, and leading medical professionals agree that the syndrome doesn't exist. There are others within the scientific community, and especially outside of it, that debate these experts."

This, at least, is an opening gambit which sets the tone for the rest of the article by acknowledging there is a debate - with the primary focus being that politicians such as Mitt Romney should steer clear of medical debates and leave such debates to science, where they belong. Politicians are not qualified to participate in such debates.

One notable passage for me was this one:

"The symptoms of chronic Lyme disease could also be caused by an auto-immune reaction to the infection, or lasting damage from the bacterial invasion. Either way, these symptoms aren't helped by additional long-term antibiotic treatment, which has side effects and dangers of its own."

This is perhaps the first and only statement in the entire article which focuses on what some potential causes are of chronic Lyme disease, giving it some acknowledgement that yes, in fact, this condition does exist - even if its cause has been greatly debated. But there are no citations and there is no supporting evidence given to back this passage - nor a good percentage of other statements made in the article. There is no mention, either, of Dr. Monica Embers' "Persistence of Borrelia burgdorferi in Rhesus Macaques" study or other research which present the possibility that Borrelia burgdorferi might persist after antibiotic treatment.

In Slate magazine, Laura Helmuth reports this personal story:

"A friend of one of my brothers had been suffering for years from headaches, fatigue, a sense of despair, a belief that she wasn’t worthy of her job or her boyfriend. She was diagnosed with chronic Lyme disease and was treated with antibiotics, which were ineffective. What she wasn’t treated for, and could have been, was severe depression. She killed herself."

While I am very saddened to hear of this woman's death, there isn't enough information here to know exactly what happened. She may have had severe depression, she may have had Lyme disease, and/or she may have had a completely different medical issue. I simply don't know - there's no way to verify this story - it is also possible the woman in question had both Lyme disease and depression, because it happens to a number of people. It happened to me, too... I was in so much pain in the past, I was begging for God to take me.

If you are depressed, I hope you will seek treatment for it, and see a qualified licensed therapist for help. But it has been said by many in the medical profession to seek alternative causes for depression and fatigue, as hypothyroidism and other conditions may give rise to these symptoms. There can be underlying medical reasons for one's depression, and it may be that antidepressants are not the primary tool for healing.

In any piece of writing, it is important to consider the following questions:

• What is the expertise and education of the person writing?
• What is the agenda of the writer? Are they trying to promote an idea, sell a product, evoke a strong emotional response to gain readership, present different sides of a contested issue, or educate the public on an important matter?
• What is the outcome that can be achieved by publishing this specific piece in this particular publication?
• What references and citations has the writer given to support their assertions and statements?
• Does a thorough survey of the information provided and research completed from different sources provide evidence which support the writer's position? 
• Is there information and research which supports an alternative position? What is the strength of the evidence supporting these positions?

I encourage anyone reading these articles about Mitt Romney and chronic Lyme disease to ask themselves the same questions above, and to do your own research on whether or not Lyme disease can lead to persisting symptoms after initial (especially delayed) treatment with antibiotics.

The entire Internet is out there at your disposal to use, and scientific journals, books, PubMed, and other reliable sources from which to get your information on Lyme disease - all free of spin.

Of course, you yourself will end up walking away from all the research required to even begin to understand Borrelia burgdorferi with your own personal spin - but at least you will know more than you can learn from reading a random article which gets published in an online newspaper or magazine.

And write to researchers if you want to better understand their research. It's the honest way to understand what their position is on their own work, rather than assume their position based on others' interpretations of their work. They will likely be touched that you made the effort to ask questions than assume someone else's interpretation (which may or may not be correct), and be pleased that you took the attitude that no question is a stupid question.

As for your vote: vote with your conscience. I can't tell anyone how to vote and it's not my job to tell you how to vote. I can only tell you that after seeing George W. Bush in office and how little attention and assistance he gave the Lyme disease patient community after his own battle with the disease that I have little faith in any politician delivering the much needed funds for translational medicine and treatment research that will help me and my fellow patients.

I feel pretty much the same about anyone else running for office, and anyone trying to stay in office: Show me you can make my life better, either directly or indirectly through concrete and substantial action - or hire someone working for you who will.

I don't want someone to discuss synergy (some vague assertion with no concrete plan), creating another task force or Lyme disease committee, or official state day in observance of Lyme disease. No. What I want to see is money going directly towards treatment and testing research - towards something tangible that has clear actionable goals and benchmarks to be met. What I want to see is concerted effort towards directly supporting those who are ill, with access to a wider range of treatment options, home health care aides, transportation, and supportive services (therapy to help patients physically and emotionally) during the darkest times of our lives.

I also am not a "single issue voter", either. If you are running for office and you make campaign promises that are about promoting awareness of Lyme disease - but slash support for medicare and disability, and make it harder for those of us who are ill and dysfunctional to get the help we need on a broad scale - I can't in my good conscience vote for you. I have to vote for someone who supports all of us who are dealing with disabilities - my fellow humans who are suffering - and those who are currently well who, unfortunately, may one day join our ranks.

In closing, I leave you with one passage from The Business Insider:

"Romney should pledge to funnel money into research organizations that could find the actual cause of this disease, and he could help stop its spread by addressing the causes of global climate change, the main reason the disease has reached so far and wide and continues to spread."

I wouldn't stop there. EVERYONE should pledge to funnel money into research organizations that could find the actual cause of this disease - and more importantly, effective treatment and testing for it.


Image Credit: Former Governor Mitt Romney giving an interview at a supporters rally in Paradise Valley, Arizona. December 6, 2011. Source: http://www.flickr.com/photos/gageskidmore/6468744615/. Taken by Gage Skidmore. This image is licensed under the Creative Commons Attribution-Share Alike 2.0 Generic license.

This work by Camp Other is licensed under a Creative Commons
Attribution-NonCommercial-ShareAlike 3.0 Unported License.

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3 NOTES: House Subcommittee Hearing On Lyme Disease

Here are some very rough notes from today's hearing on Lyme disease in Washington, DC. Please be aware that notes on about 5 minutes of testimony are missing towards the end of the day's hearing. If the webcast is archived, viewers may wish to refer to it to make their own notes.

House Committee on Foreign Affairs, Subcommittee on Africa, Global Health, & Human Rights hearing

2PM EDT
Tuesday, July 17, 2012
2172 Rayburn HOB
Washington, DC, USA

"Global Challenges in Diagnosing and Managing Lyme Disease - Closing Knowledge Gaps"

OPENING REMARKS

CHRIS SMITH - CHAIR - NJ Rep

We have a missed decade on Lyme disease research
Chris mentions chronic Lyme disease controversy
Mentions bill to establish tickborne disease committee and take fresh look at all the scientific approaches to Lyme disease
Mentions some history about Lyme disease including Borreliosis in Europe and discovery in Lyme, CT
2010 - 20,000 cases reported, but actual number of maybe 300,000 cases in US in 2010
North America Borrelia burgdorferi s.s.
Different species = different manifestations of disease
Clinical manifestations come in three stages
Mentions two distinct views of Lyme and research conflicting
Hard to catch, easy to cure vs. easy to catch, hard to cure
IDSA states short course of abx ok - anything else is risky
ILADS says the science is unsettled
One or more cause of chronic Lyme disease symptoms is possible, including persistent infection
Persistent symptoms could be due to a combination of persistent infection and immune problems

Three areas we need to took at:
1) diagnostics
2) post treatment symptoms
3) available treatments in light of science

CDC: 2 tier serological testing, but should be used for surveillance not diagnosis -unfortunately it is used for diagnosis by some doctors instead of clinical diagnosis
Europe: 8 immunoblots were shown to have a wide range of sensitivity and specificity
Bolen/NIAID: Lyme multistage disease is difficult to diagnose at any stage
Dr. Eshoo: Has exciting info on new diagnostic tools

Persistence: IDSA says Lyme disease cannot be persistent
Chris Smith says there is plenty of evidence that it can persist past antibiotic treatment
Mentions Barthold's studies and persistence in animal model studies
Mentions possible mechanisms of persistence studies: morphological changes (cell wall deficient, biofilms, etc)

Counterargument by IDSA: there are no convincing arguments that post treatment persistent Lyme disease infection is possible.
Chronic Lyme disease is a misnomer according to IDSA.
IDSA treatment guidelines should be based on best science - Smith argues they don't take into consideration possibility of persistent infection and deny patients needed treatment.

Chris Smith reports that the IDSA, NIH, and CDC were invited to the hearing today. The IDSA representative had scheduling conflict, and they were requested to testify at a very near future date before the subcommittee.

MS. BASS

Mentions the serious concern of missing early diagnosis
States few cases of LD in CA - MS. Bass says she thinks Lyme disease is under reported in CA especially in Central Valley
"Deer ticks" aptly named, as deer can carry 1000 ticks on their back on average.
But white footed mice are now known to be major carriers of the disease.
Other animals are now suspected including birds.
Need new solutions and explorations.
Changes in temperature, weather, and precipitation and their role in spread of Lyme disease should be examined.
Improved detection of early disease is contributing to higher reported numbers to some degree.
Local health departments are increasing awareness in spring and summer.
How can we improve awareness with limited budgets and resources?
Work with WHO to prioritize the disease esp in emerging areas such as Asia.

Rep. GIBSON

This is constituent driven. Major issue in upstate NY. (After he retired from army, so many people are suffering from LD and are confused and medical community is divided over its treatment. A Lyme disease task force would resolve this. Need more awareness about disease and diagnosis. Need to make sure money goes to right place. Money has gone into similar place before and the results were the same.

Most encouraging is research to be published in next year about role of confections in persistent symptoms.

WITNESS TESTIMONY

DR. STEPHEN BARTHOLD, UC DAVIS

Borrelia persists normally in immune competent host
i.e. mice rats hamsters gerbils guinea pigs dogs nonhuman primates
antibiotics are likely to fail under some circumstances if not many circumstances
finds self in contentious field - is somewhat of a pariah
we know in pre-immune stage animals can be cured
in immune stage, animals are not easily cured by antibiotics
Only a few places are really studying post antibiotic treatment Lyme - my group, Finland, NY, Louisiana... [?]
Ceftriaxone, Tigecycline, Amoxicllin, Zithromax: spirochetes are shown to survive these antibiotics in animal models
clonal population of Lyme disease spirochetes -> given antibiotic treatment -> results in non cultivable but living spirochetes
Transcribing RNA = metabolically alive spirochetes
exoplant -> carries infection from Bb infected animal to naive animal

Completed study, hope to publish it soon: 12 month post treatment resurgence of spirochetes found in mice.
what is significance of these spirochetes?
viruses can re-ignite and cause disease - question is: can spirochetes?
The answer is not known yet; something unique is going on with Bb and needs further study

DR. RAPHAEL STRICKER
San Francisco, CA - LLMD

speciality in internal medicine, ILADS Vice President
has 2,000 LD patients
number of patients has grown exponentially in past 15 yrs
patients all over the world Canada Brunei Costa Rica UK even NJ
reflects an increasing rate of LD around the world
Lyme disease is the most common TBD

patients develop muscle, joint, neurological, and cardiac symptoms
despite common disease, doctors are ignorant of how to diagnose and treat:
a bulls eye rash may be absent (50% not seen)
patient may be unaware of tick bite (some bitten by poppy seed size tick)
patients have a wide range of symptoms - doctors are often unaware of this wide range

testing remains problematic (not standardized and insensitive)
treatment has evolved in haphazard fashion (IDSA guidelines only address acute infection; standard guidelines ignore more chronic and severe form)
LD has become international medical disaster
thousands of patients suffer from undiagnosed and untreated Lyme disease
and even though it is all over media
the IDSA sits by and does nothing

State of California is grateful to state health board for forming a state Lyme disease advisory board
for requiring mandatory laboratory reporting of Lyme disease to Department of Health just like system for reporting STIs
California has a physician protection law which allows doctors to treat Lyme disease patients as they deem appropriate
Stricker thinks a model for a Lyme disease national advisory board could stem from CA state model

We need CDC and NIH to abandon failed Lyme disease research programs
need them to have targeted research for better tests just as they did for AIDS
need to have more research on treatment of chronic Lyme disease
need to get them to look at evidence and discard dogma about what chronic Lyme disease is
we need for them to listen to patients and how they are affected

Almost 2 decades ago Dr. Joe Burrascano testified before the Senate. He said, "The very existence of 100s of LD support groups, etc underscores many problems which exist in real world of LD." Two decades later and it's the same story.

DR. MARK ESHOO
IBIS Biosciences, Abbott Labs

Need to develop better diagnostic tests
number cases steadily increasing
Lyme disease is severely under reported
Babesiosis is also important
Babesiosis can be mistaken for malaria (Babesia looks similar to malaria under the microscope, too)
Other TBDs are also present

Lyme spread by ticks to mice, and then ticks infect more mice
mice become chronically infected with Lyme disease
bacteria evolved to evade immune system, especially immune privileged sites (e.g. skin, joints)
humans can have long lasting or chronic infection
those infected develop neurological and joint problems
best time to treat is early in infection
most typical early symptoms are bulls eye rash, flu-like, fatigue, aches

CDC 2 tier test - involves indirect detection of antibodies; has 3 problems:
1) can take Lyme patient more than 3 wks for immune system to detect infection
2) interpretation of 2 tier tests can be subjective and change outcome
3) even after treatment, patient can remain positive… controversy over how long to treat patient (weeks? months? years?)

Abbott Labs is looking directly at presence of DNA of pathogens
Sensitive direct assay of organism is historically very difficult because spirochetes are present in small numbers
Abbott made an assay with 8 independent tests to detect the presence of bacteria in blood
they use large volume of blood
and find way to amplify the presence of small numbers of bacteria (bacterial DNA) in blood

Eshoo et al did a study which could find organism very early in infection in doctor's office (refer to abstract) in 62% of patients

Another area of research Eshoo is working on:
variations of strains may determine type and severity of disease
need to study 100 different strains of Bb and what makes them different in terms of impact of disease

We need more government research and funding
- sensitive test for direct detection early in infection before dissemination (monitor responses to treatment
- find out cause of PTLDS. A direct diagnostic tool would be useful
- need to increase research into diff Borrelia strains differences and their role in human infection

PAT SMITH, LDA USA

LD called yuppie or housewife disease
patients have been referred to by some doctors as being paranoid, hysterical, hypochondriac, etc. without any evidence and without looking that something else could be wrong
many advocacy organizations in the world have been victimized in peer reviewed publications
Many patients confide they'd rather have cancer than Lyme disease due to the misunderstanding and controversy over the disease
Patients want studies which solve their dilemmas (such as doctors don't believe they're sick, answer the question "Why isn't the government doing anything?")
The outcome of small clinical trials/studies put a coffin the nail for treatment of chronic Lyme disease and for a number of reasons, these studies were inadequate.
The conclusion was that no treatment is effective for long term Lyme.

Lyme in the south - there are many myths. Myths that:
No lyme disease can be found in south or west
No reservoir hosts in the south
Deer ticks on lizards prevent Lyme disease in ticks all throughout the south
Deer ticks in south do not bite people (?!)
These claims are not scientifically backed.

Patients are overburdened with medical problems.
There are cutbacks in public health depts. so number of cases are unknown.
Pharmacists who won't fill prescriptions for Lyme disease patients in some places.
Munchausens by proxy charges are made toward mom's who treat kids with Lyme disease with long term antibiotics.

Guidelines that are written by researchers and not clinicians are problematic
IDSA is against any sort of treatment for CLD - either antibiotics, alternative treatment, or the use of supplements
CDC surveillance criteria for Lyme disease has formed basis of IDSA guidelines and this is problematic
patients can die of Lyme disease: study of 114 patients who had Lyme disease who died. After they died, most terminal events for which LD was known as the underlying cause have listed on their death certificate a reported cause of death which researchers stated were thought to be unrelated to Lyme disease. Only one patient was said to have died of complications of Lyme disease directly. Question that.

Has seen recorded 22 point IQ drop in kids with Lyme disease due to infection affecting brain
kids have killed themselves due to Lyme disease - due to pain and due to disbelief by peers and others of their having the disease

Pat Smith has had 2 daughters affected by Lyme disease

CDC, NIH, IDSA were absent at hearing and she thinks they are avoiding responsibility when they were invited to be part of the process to help patients.

EVAN WHITE, NYC
Patient - Had Chronic Lyme Disease

(wife just had baby, he is on SKYPE  - his life is now normal being part of point of his testimony)

20 yr advocate borne out of very tragic case of his own Lyme disease due to being given limited antibiotic treatment
at end he is now well because of conscientious doctors
today is father and practicing attorney and employer.

he says his case is an illustration: if not for long term treatment, none of this would be possible

so many people do not have benefits he had
if they had access to treatment, they would be contributing members of society
his story has happy ending
he is fighting for fellow Lyme patients to have same access to treatment
he is advocating for change in limited guidelines

his case study is that short term treatment did not work
long term treatment helped him recovered
he was ill at 11 yrs old
missed school due to flu-like symptoms
doctor did diagnose Lyme disease and he was given 1-2 wks of antibiotics
after 2 weeks he did not get better
the response to not recovering after 2 wks was that PT and psych therapy was needed after those 2 weeks
daily his condition deteriorated
he was a 12 yr old who trusted his doctor
but 6 months later so bad could not do anything
could not go to school, had trouble getting out of bed
blood test showed Lyme disease and confections were very much present months later

here is devastating result of un (or under treated) Lyme disease
6 months of no treatment sent him into tailspin
he vastly deteriorated, went from active athletic child to one who couldn't care for himself
had muscle atrophy, neurological problems
60 lbs at age 13, called a vegetable, and doctors were confused by his state
doctors put him in children's rehabilitation care
did brain scan
it revealed Lyme disease's affect in its passing the BBB: hypoperfusion
he had trouble reading and talking
and was surrounded by doctors who had no idea why he was in condition he was in
2 yrs bounced from hospital to hospital
6 months in children's hospital

went home and parents arranged for appt with LLMD
the LLMD "got it" and had their own personal experience with the disease - not just treating other patients
he had long road ahead for recovery but this was his turning point
he was on long term antibiotics coupled with supplements
2 year crawl to get out of that place
even if it were 10 yr crawl that would have been ok with him
stopped using wheelchair
got out of bed
began to take care of self
began to read again
began to be able to communicate again
got him on trajectory to become person he is today and fully recovered

hoping through this testimony that patients who are affected can get treatment they need to recover from chronic Lyme disease
the net effect of current guidelines restricting treatment deprives so many if not all from having health care option to seek long care treatment that does work for many patients so that they can recover and live long healthy lives

Rep. SMITH

intro Stella in UK

STELLA HUYSHE-SHIRES
Lyme Disease Action (UK)

UK doctors not taking patients seriously
Department of Health accreditation of Lyme Disease Action, Lyme Disease Action is now considered an unbiased source of information on Lyme disease in the UK
papers say Lyme Disease is overdiagnosed
public say it is underdiagnosed
what is the evidence?
we don't know incidence of Lyme disease in the UK
One GP practice finds it 20x greater than numbers which are reported
1300 cases found in one year may mean there are really more like 26,000 cases in UK

survey:
23% patients found ot have Lyme disease but the rest with similar symptoms were diagnosed with CFS
there is concern CFS patients are misdiagnosed and have Lyme disease
on the flip side maybe
100 people year in clinics in UK may be misdiagnosed with Lyme disease
But in a CFS clinic - 40% patients were misdiagnosed with CFS

Why is LD difficult to diagnose and what can be done about it?
we need unequivocal tests and clear guidelines
none exist in UK
most doctors haven't seen Lyme enough and rely on blood tests for diagnosis in UK

unreliable info on internet, certain labs, etc only part of story even if there is an element of truth in it
European challenge of more than one strain of Bb adds to complexity of test issue
Scotland uses more bands in its lab than other locations - leading to different line drawn for positive test results and access to treatment

Most treatment recommendations based on opinion not evidence
need other stakeholders to investigate Lyme disease
Lyme Disease Action (UK) is working with James Lind Alliance to engage doctors in more awareness of LD in patients and in general

The biggest challenge globally is recognition of unknowns in Lyme Disease
All across Europe there is a polarization of opinions along IDSA/ILADS poles
and there may be reluctance to climb out of one's entrenched view of Lyme disease

In Northern Europe doctors rely heavy on test results - similar issues found there.
In Central Europe, doctors have more experience: Lyme is a big problem, doctors say the tests are not good enough; doctors say they don't know how to effectively treat all patients.

Politics are a problem.
Uncertainty of the science is a problem.
Politics prevents recognition of the uncertainties.

QUESTION AND ANSWER SESSION (Rep Smith/Rep Gibson ask questions)

HUYSHE-SHIRES

A: HPA guidelines come from IDSA
Worse thing when patients are told symptoms are in their head
IDSA only recognizes visible arthritis then patient may get further tx
HPA does follow IDSA guidelines
indiv doctors sometimes make indiv clinical decision
case studies London school of hygiene (4-5 yr period) - some patients did not recover after initial course of abx, then some not after second, then some had a third. Between each treatment, patients were believed and found rising antibody levels.
Doctors will say adequate tx occurred, but it's adequate in terms of meeting guidelines but not in terms of effectively treating patient

BARTHOLD

Q: Are proposals being rejected for research at NIH?

A: Peer review is an issue. Peers are divided just are anyone else in Ld community
have direct exp in prejudicial statements in grant application reviews - peer view of applications does not get over the barrier
NIH is struggling to fund investigators
young people are not entering science, old people are leaving
in that environment combination of things - anything controversial having difficulty being funded
made NIH call for application on research on persistence after antibiotic treatment
only suggestion is his
we scientists are always looking for money. Follow the money.
NIH invests in biodefense then people gravitate towards biodefense research.

STRICKER

Q: Rep.brings up conflicts of interest and suppression of data in IDSA guidelines review.

A: IDSA hearing was organized by IDSA and no treating physicians were on the committee
Even though guidelines were flawed they were ruled acceptable.
Stricker encouraged by Dr Eshoo's research and development of advanced early testing.

["To date no antibiotic treatment treats biofilms." - attribution?]

Q: Rep comments to Barthold: issue of "mopping up" after antibiotics
host immune system must mop up remaining spirochetes... Explain.

BARTHOLD

A: using biofilm analogy: there is a population of microorganisms, some of which are dormant
dormant non-dividing bacteria are universally tolerant of antibiotics and are not dividing or active metabolically
Borrelia: we know it is dividing and disseminating and susceptible to antibiotics early on but during the immune phase in animals there is a 10 fold reduction in population (not necessarily in biofilms) and what is found are non-dividing spirochetes; they are dormant and antibiotics are not touching them
What is unique is they grow out but they cannot be cultured - they may be attenuated.


STRICKER

A: Borrelia has molecular machinery to make biofilms according to Dr. Stricker.
Stricker states cell wall deficient form evades antibiotics and it needs to be researched more.

Q: Rep. Asks Dr. Eshoo: How close are you to coming up w new test and why is Big Pharma not getting further involved?

ESHOO

A: It's a small market according to BP and takes lots of money and time to invest.
Lot of people in medical community say current test is good enough.

Eshoo thinks sensitivity needs to be improved and tests need to be improved to end the controversy.

Who wants to be infected for 3 weeks or more untreated waiting for a positive blood test? Nobody.

Rep. Q to Stricker:

Are there people outside the IDSA guidelines panel who notice there's a problem [with testing]?
Does Dr. Francis Collins (NIH director) say "What is wrong here? Why is this a persistent bone of contention?"

STRICKER

A: Blumenthal investigation found there are 14 people in the IDSA who control guidelines, testing, and diagnostic guidelines of Lyme Disease. The rest of the IDSA (8,000 people) defer to this group.

PAT SMITH, Lyme Disease Association

LDA has Scientific and professional review board
It is voluntary board
If issues need to be addressed or LDA is considering funding research, the board is asked to comment on it using their expertise
CALDA, LRA, etc also rely on this board

STRICKER

Q: Rep. [?]: you have 2,000 patients. What is your takeaway from this huge patient number and how are they when they find you?

A: Number of patients exceeds CDC reporting. That's one thing it tells me. Number of those affected may be 10 fold higher.
Many come after yrs of misdiagnosis and no treatment.
70% of patients get better. He finds this gratifying and he turns a deaf ear to the controversy because of outcome.
Uses long term antibiotic treatment.
Published study last year on neurological patients needing 6-12 months of antibiotic treatment to improve.

[5-6 minutes of testimony notes missing]


COMMENTS NEAR END

8.75 million dollar research fund Chris Smith says has been put forward. Chronic Lyme is supposed to be included in this research. How should the wording for the law be improved and how can there be better oversight to get money to the right place?

Barthold said: Follow the money.
If you enlarge the pot and spend it on research that's already been done, we get nowhere.
If we and NIH recognize persistence after treatment as an issue, then new research would be done on this issue.
A more narrowly focused call for applications would help if NIH would agree with that - research on chronic symptoms and the biology/pathology of the organism.

Dr. Eshoo said the field needs support to get off the ground and that RFAs must be specifically targeted toward solving narrowly defined problems.

PAT Smith has concern research money goes to post Lyme disease syndrome and not chronic Lyme disease - which is a different condition.
Patient perspectives on issues of the disease is important and knowing how it's affecting them is important.
Advocates, treating physicians, and patients need to be involved in the process of determining what needs to be researched.

Q: Rep. Gibson: How do you expand Lyme literacy among old and new doctors?

STRICKER

A: ILADS has preceptorship program. Can learn about diagnosis and treatment of Lyme disease. Program is funded privately. Mentor doctors who want to get involved sign up.

Stricker has trouble finding physicians willing to get involved due to controversy. This has had a chilling effect on mentorship.


Q: Rep Gibson: is that because state med board may censor them?

A: Yes. Though state has protection law, the risk censoring by board and other doctors may still go on.

Has 27 studies in table in written testimony (table 2) showing persistence in humans after IDSA guidelines-based treatment.

BARTHOLD

We need to know what is happening in humans but animals allow us to extrapolate models. Many people are using animals but looking only at acute early phase of infection. Not many people are looking at chronic persistent infection in animals. Fewer than five labs worldwide are studying this but it is the most important aspect of the disease.

HUYSHE-SHIRES

Borrelia has been isolated in patients after initial treatment - there are some cases recorded in published papers.
Some people improve after longer treatment
We need more investigation to determine how to better diagnose and treat Lyme disease

IDSA guidelines are accepted in the UK
Summary of recommendations for treatment by European Federation of Neurology Specialists (organization name needs fact checking) - make the point that in neurological Lyme there are no good trials of more than 28 days antibiotic treatment for neuroborreliosis.
They base this on opinion because there is no trial in Europe for longer term treatment of neuroborreliosis.

There are some trials which show good recovery, but at most 60-70% patients experience a good response. A patient does not consider 7 of 10 people responding to treatment as being a rate that is excellent.

PAT SMITH

Children are most affected by Lyme. They have more complications and are greatly impacted by their peers and teachers and what they are saying about them.

It is appalling what comments are being made about students who are ill with Lyme who cannot make it to school because they are too sick. No one wants to stay at home with their mother from school for four years.

One problem is inadequate early antibiotic treatment may lead to a poor antibody response and negative tests, which then put child at further risk for being disbelieved for having Lyme disease.

Some family services will take kids away from parents if those parents treat one child with antibiotics for chronic Lyme disease. This is serious and kids are psychologically damaged by the disease as well as the response from society and their community towards their illness.

We have the knowledge and tools in this country to stop this.

HUYSHE-SHIRES

1-3 people in UK are believed to have expertise on Lyme in UK, and those 1-3 apply IDSA guidelines and support them
NHS did not make any needed changes to their guidelines even though they should be made to suit the UK patient population

ETHAN WHITE

If sick, seek out people who will lead you to knowledgeable doctors who will offer treatment for Lyme disease.

SOME CLOSING COMMENTS

Barthold thinks people on both sides are good people, and he thinks we need to move past contentiousness and work together to help those affected by Lyme disease.

We need to work to get out of entrenched positions and get to the bottom of what's happening using science.

It's time for people to get together and show their cards and be willing to act in the best interest of patients and work past this contentiousness.

---

Comments:

Will be adding links relevant to this testimony soon.

If anyone who gave testimony at the hearing reads these notes and sees a correction that needs to be made, please request correction in comments and I will revise this post.

UPDATE - July 17:

Original testimonies are now available for download including additional materials from each of the witnesses. Scroll down this page for pdf files: http://foreignaffairs.house.gov/hearings/view/?1455

UPDATE - July 19:

Ustream has two streaming video archives of the hearing available at the following links:

http://www.ustream.tv/recorded/24058724

http://www.ustream.tv/recorded/24060689

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2 Microarray Analyses of Inflammation Response of Human Dermal Fibroblasts to Different Strains of B. burgdorferi S.S.

This interesting abstract just got posted on PubMed and is in PLoSONE:

Microarray Analyses of Inflammation Response of Human Dermal Fibroblasts to Different Strains of Borrelia burgdorferi Sensu Stricto

Schramm F, Kern A, Barthel C, Nadaud S, Meyer N, Jaulhac B, Boulanger N.

Abstract

In Lyme borreliosis, the skin is the key site of bacterial inoculation by the infected tick, and of cutaneous manifestations, erythema migrans and acrodermatitis chronica atrophicans. We explored the role of fibroblasts, the resident cells of the dermis, in the development of the disease.

Using microarray experiments, we compared the inflammation of fibroblasts induced by three strains of Borrelia burgdorferi sensu stricto isolated from different environments and stages of Lyme disease: N40 (tick), Pbre (erythema migrans) and 1408 (acrodermatitis chronica atrophicans).

The three strains exhibited a similar profile of inflammation with strong induction of chemokines (CXCL1 and IL-8) and IL-6 cytokine mainly involved in the chemoattraction of immune cells. Molecules such as TNF-alpha and NF-κB factors, metalloproteinases (MMP-1, -3 and -12) and superoxide dismutase (SOD2), also described in inflammatory and cellular events, were up-regulated.

In addition, we showed that tick salivary gland extracts induce a cytotoxic effect on fibroblasts and that OspC, essential in the transmission of Borrelia to the vertebrate host, was not responsible for the secretion of inflammatory molecules by fibroblasts.

Tick saliva components could facilitate the early transmission of the disease to the site of injury creating a feeding pit. Later in the development of the disease, Borrelia would intensively multiply in the skin and further disseminate to distant organs.

Link: http://www.ncbi.nlm.nih.gov/pubmed/22768217

Comments:

Take note of that last paragraph:

"Tick saliva components could facilitate the early transmission of the disease to the site of injury creating a feeding pit. Later in the development of the disease, Borrelia would intensively multiply in the skin and further disseminate to distant organs."

Do you think the implications of the above fit in nicely with the mathematical modeling of Borrelia burgdorferi infection cycles mentioned in an earlier entry?

Why or why not?

See:

Abstract: Population Dynamics Of Borrelia burgdorferi In Lyme Disease
http://campother.blogspot.com/2012/04/abstract-population-dynamics-of.html

The implications - for me at least - seem to fit a model where the first wave of infection dies off but then a bigger, immune-resistant subpopulation explodes onto the scene (the site of infection).

Awaiting PLoSONE to publish the full text so I can give a more thorough analysis...

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23 Let's Not Be Rash About Erythema Migrans

On May 21, Skidmore College in New York conducted the Lyme Next Forum in which various doctors, researchers, patient advocates, and Lyme disease organization leaders gave presentations on various topics related to Lyme disease and its coinfections. (All presentations in four parts can be viewed as streaming videos on Joanne's Looking at Lyme blog.)

While different presentations may have grabbed the attention of other patients, one presentation which stood out for me early on was Holly Ahern's presentation.

Holly is an associate professor at SUNY Adirondack who teaches microbiology and was recipient of a 2008-2009 Research Residency award from the American Society for Microbiology (ASM). So she knows a little something about Lyme disease from a microbiological perspective. But she also has more direct experience of what it is like because her daughter developed a chronic form of the disease.

Holly's presentation was about the potential impact of Lyme disease in New York State in terms of projected undiagnosed cases and unreported cases. But what grabbed my attention in particular was the portion of her presentation focused on research related to the well-known "bull's eye" rash - also known as erythema migrans (EM).

Prior to this, I've read different reports of how many patients who are diagnosed with Lyme disease initially present with an EM rash and how to identify one, so some of this information was not new to me.

While everyone thinks about a Lyme disease rash as being a bull's eye with central clearing (it looks like a target) a 2007 paper published in the Journal of Emergency Medicine, 'An update on the diagnosis and treatment of early Lyme disease: "focusing on the bull's eye, you may miss the mark"', states the following in its abstract:

"To confidently diagnose and treat Lyme disease, the clinician must first understand the natural history of this disease, especially its protean early manifestations. Emergency physicians, primary care physicians, and other providers need to be vigilant in terms of the timely recognition of erythema migrans (EM), the unique marker of early localized stage 1 disease. The classic EM, originally described as a slowly expanding bull's eye lesion, is now recognized to be present in only the minority of cases (9%); the dominant morphologic lesion of EM is now recognized to be the diffusely homogenous red plaque or patch, which occurs in over 50% of cases. This update will define the current morphologic features of early Lyme disease, the indication for serologic studies, and the most recent treatment guidelines, including therapeutic pitfalls."

Based on this, a more evenly colored rash is typical with Lyme disease - whereas a target-like presentation is actually in the minority.

And there are other reports of just how wide the variety of rashes and skin manifestations of EM there can be.

In his testimony to the FDA in preparation for discussion of the approval of the Lymerix vaccine, Dr. Vijay Sikand shared his experience with rashes related to Lyme disease:

"In terms of the variability of Lyme disease, it is indeed a very variable infection, if not a very complex infection. In its very simplest form, it is erythema migrans, well localized, which we can all recognize and which we can all easily treat and from which most patients can get better. However, erythema migrans is not a single beast. Certainly this is the one which we easily recognize and which I just referred to. Before I continue with further slides, let me point out that the erythema migrans lesions you are about to see are all biopsy lesions which were laboratory proven to be caused by Borrelia burgdorferi.

Sometimes erythema migrans can present as a pustular lesion as is this one in the popliteal fossa inviting the scalpel of a surgeon. Sometimes the lesions are vesicular in nature, inviting a diagnosis perhaps of herpes simplex infection. Sometimes our round lesion is actually triangular. Sometimes it doesn't even look round or red at all and invites a diagnosis of an intertriginous fungal infection in the groin of this patient who was biopsied and proven to have Lyme disease. Sometimes the lesion is more plaque-like, inviting diagnosis of nummular eczema, psoriasis, or other similar lesions. Sometimes it is in unusual locations. Sometimes it is large like this one. Sometimes it is small with satellite areas. Sometimes it is multiple, appearing almost like urticaria or erythema multiform. Sometimes, as in this individual who was a placebo recipient in the Lyme 008 SmithKline Beecham trial, it presents with other manifestations of early dissemination. This individual came in mainly because he was concerned about his face and it felt kind of funny and it was weak on one side. When I asked him whether he had had any unusual rashes, he said oh do you mean this one, and he showed me his arm with that EM. This is simply to illustrate the infranuclar 7th nerve palsy with which he presented. This patient, by the way, had no history of a tick bite or any unusual antecedent illness which he could remember."

Based on Dr. Sikand's reports and laboratory testing, it would appear that a typical red rash is not the only manifestation of Lyme disease rashes and there can be much variation.

Having these kinds of reports - and that of the Journal of Emergency Medicine - leads to questions about the reliability of having a uniform description of a rash that doctors would need to look for as part of the definition of the disease. It also raises questions about the utility of using a uniformly described rash in the CDC surveillance case definition for determining where confirmed and probable cases of Lyme disease are reported.

When is a rash an EM rash and when isn't it an EM rash - if one is found at all?

It's clear that if a patient with Lyme disease has a rash which does not match the description of the bull's eye rash that they may be diagnosed with some condition other than Lyme disease.

One way to confirm the diagnosis in this situation would be to look at a patient's history of exposure to ticks, overall symptom presentation for symptoms which suggest Lyme disease, and to get a culture from an odd looking rash and test it for Borrelia burgdorferi even if it takes weeks to receive results.

But what if the patient does not present with an EM rash at all? Perhaps the rash is small and in the hairline where it is not easily seen. And taking it a step further: What if it never even happened?

Ahern pointed to a paper that I had cited on the blog before: "Prophylaxis with single-dose doxycycline for the prevention of Lyme disease after an Ixodes scapularis tick bite". (You may be more familiar with this paper in reference to a recent discussion on prophylactic treatment of tick bites on this blog.)

Ahern made two statements during her presentation which I hadn't recalled reading in this publication:

1. Only tick bites from nymphal ticks produced an EM rash in the host.
   
   
2. When an adult tick (assessed by entomologist in lab for age) had bitten the host, there was NO EM rash.

In addition to these two bits of data, the authors also mentioned that a prophylactic dose of antibiotics prevented the development of an EM rash.

While I had read about antibiotics preventing the development of an EM rash before, the other two pieces of data were new to me. 

So I immediately called up the paper for review to see what had been written about these two statements, and found this information:

"In untreated subjects, bites from nymphal ticks were significantly more likely than bites from adult ticks to be associated with erythema migrans (8 of 142 [5.6 percent] vs. 0 of 97 [0 percent], P=0.02)." 

"In the two groups combined, nymphal ticks were nearly twice as likely as adult ticks to be partially engorged (159 of 266 ticks [59.8 percent] vs. 64 of 197 ticks [32.5 percent], P < 0.001)."

"Untreated bites from nymphal ticks that had been attached to subjects for an estimated 72 hours or longer were more likely to result in erythema migrans than were untreated bites from nymphal ticks that had been feeding for less than 72 hours (3 of 12 bites [25 percent; 95 percent confidence interval, 7 to 57 percent] vs. 0 of 48, P=0.006)." 

"... In addition, our findings support those of previous epidemiologic studies that have shown a temporal association between the development of erythema migrans and exposure to nymphal rather than adult ticks.13 One possible explanation for this is that adult ticks (which are considerably larger than nymphal ticks) are detected and removed earlier in the feeding process than nymphal ticks [...]"

So it seems that at this point, it was already well established that nymphal ticks were already far more likely to cause an EM rash than adult ticks - and because of their small size, nymphal ticks would be less likely to be removed by someone due to not being noticed. They could more easily transmit infection due to the duration of their feeding and missed detection. That sounds logical.

However, what about the adult ticks?

Has there been verification beyond this publication that those who are bitten by adult ticks do not develop an EM rash? Does the lack of an EM rash - not even in the hairline - indicate one is not infected with Borrelia burgdorferi? Or can a host still be infected by an adult tick without the presence of an EM rash?


Further discussion of these questions and this phenomenon will be found in the next installment of "Let's Not Be Rash About Erythema Migrans"...

Image Credit:
"Bulls-eye" Lyme Disease rash by Mangojuice's father

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0 Female Pheromones and Infection May Affect Tick Behavior

Image: Researcher drags white
flannel to collect questing ticks. 

Recently I came across an abstract for the paper, "The correlation between tick (Ixodes persulcatus Sch.) questing behaviour and synganglion neuronal responses to odours".

I'm looking forward to reading the full text, as the abstract demonstrates two findings on tick behavior which may reveal who is more likely to be bitten by ticks.

In this experiment, the taiga tick or Ixodes persulcatus is used - a tick common in parts of Russia. It is unknown if other Ixodes ticks would respond to the same odors the same way, and I think the same experiment should be conducted in Western Europe and North America with local Ixodes ticks to see if there would be a similar outcome.

The researchers experimented with seeing which odors would attract and repel ticks, focusing on seeing how ticks respond to synthetic hormones and insecticides/acaricides. Osmopherone®, Osmopherine®, DEET®, ethanol, and water were placed in a simple maze, and changes in their synganglia - basically their entire central nervous system, as ticks do not have a brain as we think of one - were measured to reflect whether they were attracted, repelled, or neutral to the specific odor tested.

Also, researchers tested which odors were most likely to encourage the maximum height ticks could reach during questing behavior by placing ticks on glass rods which were held at a 75 degree angle.

Two notable findings came from these experiments:

1. Ticks were, as expected, repelled by DEET® and ethanol. It's good to have further confirmation that DEET® works as a repellent. But what was interesting is that ticks were totally neutral to Osmopherone® and water - and attracted to Osmopherine® .
   
   
2. Questing ticks were studied not only for their attraction to certain odors but were tested for whether or not they were infected with Borrelia burgdorferi sensu lato and tickborne encephalitis virus. It was found that not only did those ticks which were most attracted to Osmopherine® reach the highest questing height - but also those ticks which were infected with Borrelia burgdorferi sensu lato were more likely to reach the highest questing height.
   

What is the difference between Osmopherone® and Osmopherine®? Osmopherone® is a synthetic sex pheromone that is meant to mirror the scent human males give off. Osmopherine® is a synthetic sex pheromone that is meant to mirror the scent human females give off. Each of these pheromones are found in their natural form on people and are not an obvious smell people give off - they are registered on a subconscious level and may act as an attractant to the opposite sex.

In these experiments, it appears the female sex pheromone, Osmopherine®, attracts ticks, and ticks infected with Borrelia burgdorferi sensu lato are more likely to have the highest questing height in a laboratory.

What is not known is whether or not the same behavior occurs in the wild, outside a lab - and how much other factors may play into ticks' behavior when questing. Different ticks have different behavior in the wild to begin with, such as Amblyomma americanum tends to be more aggressive in searching out a blood meal and Ixodes scapularis is a more passive questing tick.

Ticks are already attracted to the source of their blood meal through detecting heat and carbon dioxide (CO₂) given off by exhalation. One thing I would hope the full text of this article would explain is how the presence of warm blooded, CO₂ exhaling researchers was shielded so they did not have any influence on these ticks. It may be that these indicators of the next potential dinner may play a bigger role than the gender of the potential host in front of them and whether or not the tick is currently infected with Borrelia burgdorferi s.l. 

Certainly more research is needed to determine what the case is in the wild, but in the meantime these findings provide one with more food for thought as to how a tick host's gender and the tick's state of infection might play a role in tick behavior.

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1 Abstract: Delays and Diversions Mark the Development of B Cell Responses to Bb Infection

Another insightful paper on the immune response to infection with Borrelia burgdorferi has been published. "Delays and Diversions Mark the Development of B Cell Responses to Borrelia burgdorferi Infection" by Hastey et al is closely related to previous research completed by Tunev et al on the immune response found in murine lymph nodes which were invaded by Borrelia burgdorferi.

A well-written blog article on Tunev et al's previous research on B cells and plasma cells and their associated (lack of) T cell response in reaction to Bb infection can be found here:

Spirochetes Unwound Blog - Does Borrelia burgdorferi cause an inadequate antibody response by altering B cell activation in the lymph node?

I recommend reading that link first before proceeding to the following abstract.

Christine J. Hastey, Rebecca A. Elsner, Stephen W. Barthold and Nicole Baumgarth. Delays and Diversions Mark the Development of B Cell Responses to Borrelia burgdorferi Infection. The Journal of Immunology. April 30, 2012

Abstract

B cell responses modulate disease during infection with Borrelia burgdorferi, the causative agent of Lyme disease, but are unable to clear the infection.

Previous studies have demonstrated that B. burgdorferi infection induces predominantly T-independent B cell responses, potentially explaining some of these findings. However, others have shown effects of T cells on the isotype profile and the magnitude of the B. burgdorferi-specific Abs.

This study aimed to further investigate the humoral response to B. burgdorferi and its degree of T cell dependence, with the ultimate goal of elucidating the mechanisms underlying the failure of effective immunity to this emerging infectious disease agent.

Our study identifies distinct stages in the B cell response using a mouse model, all marked by the generation of unusually strong and persistent T-dependent and T-independent IgM Abs.

The initial phase is dominated by a strong T-independent accumulation of B cells in lymph nodes and the induction of specific Abs in the absence of germinal centers.

A second phase begins around week 2.5 to 3, in which relatively short-lived germinal centers develop in lymph nodes, despite a lymph node architecture that lacks clearly demarcated T and B cell zones.

This response failed, however, to generate appreciable numbers of long-lived bone marrow plasma cells.

Finally, there is a slow accumulation of long-lived Ab-secreting plasma cells in bone marrow, reflected by a strong but ultimately ineffective serum Ab response.

Overall, the study indicates that B. burgdorferi might evade B cell immunity by interfering with its response kinetics and quality.

This work was supported in part by National Institutes of Health/National Institute of Allergy and Infectious Diseases Grant AI073911 (to N.B. and S.W.B.) and T32 Training Grant AI060555 (to C.J.H. and R.A.E.).

Full text is available behind pay wall here: http://www.jimmunol.org/content/early/2012/04/30/jimmunol.1103735.full.pdf+html

Comments:

This is an interesting development in the ongoing process of trying to understand how Borrelia burgdorferi evades the immune system. What we know is what starts out looking like the host mounting a strong immune response to infection ends up looking like a poorly differentiated immune response where plasma cells are inadequate and not engaging in the right immune class switching to fight infection - and where T cells are not fully participating in B cell activation.

This study indicated that not only is the immune response inadequate and ill-directed in its early phase in lymph nodes (which Tunev et al studied) but that in later stages antibody response is inadequate as well.

These studies indicate that the host immune response fails to clear Borrelia burgdorferi and somehow the bacteria is able to evade it. More details on specifically how is likely available in the pay-for-view full text of the paper (until the six month NIH/NIAID publication embargo is over).

Questions remain as to how this research applies to human hosts. Does the same immune response occur in humans that occurs in mice? How does the introduction of antibiotics affect this response? Knowing how both the host immune system and antibiotics work together in combatting this infection would be useful.

One thing I would like to see Tunev, Hastey, Barthold, and others doing this work is to somehow detect which outer surface proteins are upregulated during the time they are invading the lymph nodes and generating a lot of inflammation. In particular, I am wondering if OspA is being expressed in the lymph nodes as much as it has been proposed as being expressed in the CNS in neuroborreliosis.

I leave those reading to consider this paper which was published in Nature, and the following excerpt from it:

OspA-CD40 dyad: ligand-receptor interaction in the translocation of neuroinvasive Borrelia across the blood-brain barrier

"Some authors have suggested downregulation of OspA in early phase of the infection 21, 22, while others have reported expression of OspA in the unique environment of the brain and CSF, but not in the serum 23, 24. Therefore, it was essential to determine whether OspA is expressed in borreliae that are present in the brain vasculature in vivo in infected laboratory animals. PCR analysis of the brain and brain microvasculature of Wistar rats infected with SKT-7.1, revealed not only the presence but also the augmented expression of OspA (Fig. 3). This finding is crucial to support a role of OspA as an adhesive molecule in the transient tethering of Borrelia."

"OspA is undoubtedly a multifunctional protein that is absolutely necessary in the various stages of borrelial lifecycle and pathogenesis. OspA is abundantly expressed in tick gut as an important adhesive molecule 29. To avoid an inflammatory response, expression of OspA is downregulated in the early stages of Lyme disease. However, OspA expression in vivo can be significantly induced if the spirochetes are kept in an inflammatory environment 46. OspA plays an important role in binding to neuronal cells. These data indicate that OspA must be upregulated during the CNS invasion and acts as an important adhesion factor, which is essential in the pathogenesis of Lyme neuroborreliosis 23. It is also well known that Borrelia can bind plasminogen via OspA on their surface 47. OspA also upregulates membrane urokinase-type plasminogen activator receptor (uPAR) 48. Plasminogen can be activated to plasmin 47, 48 leading to degradation of the extracellular matrix. The mammalian plasminogen-plasmin proteolytic system plays a crucial role in extracellular matrix degradation (intercellular junctions) and cell migration 49. Binding of host-derived proteinases (like plasminogen and MMPs) via OspA supports the theory that Borrelia exploits these proteinases to degrade the intercellular tight junctions. Owing to the hypervariability of OspA among several Borrelia strains, it is important to note that only expression of OspA is not sufficient, but its ability to interact with host's receptors is crucial in the invasion processes."

After reading a passage like this - plus these studies on B cell activation during Bb infection - I have to ask if OspA plays a role in in vivo infection not only inside the CNS in neuroborreliosis - but also in dissemination to other parts of the body. Would this account for the widespread pain patients experience from inflammation, since OspA is highly immunogenic? What is OspA's degradability?
See: http://en.wikipedia.org/wiki/Immunogenicity

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1 Three Notable NIAID 2012 Research Projects On Lyme Disease

The National Institute of Allergy and Infectious Disease (NIAID) is conducting some Lyme disease related research which I think readers should know about. There are a number of projects to be found on the Project Reporter web site which may be fascinating, but I took the time to select and highlight a few projects which would be of greater interest to patients suffering with Lyme disease and/or its coinfections.

Project: AN INTRACELLULAR NICHE FOR BORRELIA BURGDORFERI
Institution: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
PI: Skare, Jonathan

Description (by applicant):

Lyme disease, caused by the spirochetal bacterium Borrelia burgdorferi, is the leading arthropodborne infection in the United States and causes significant morbidity in endemic areas. If untreated B. burgdorferi can persistently infect individuals even though the host mounts a potent adaptive immune response such that antibodies obtained from infected patients or experimentally infected animals effectively kills in vitro cultivated B. burgdorferi. In addition, a robust cell-mediated proinflammatory response is observed that induces IL-6, IL-12 and IFN- and inhibits IL-10. Furthermore, the spirochete can resist complement killing demonstrating that this important component of the innate immune response is not sufficient to eliminate B. burgdorferi infection.

The observation that B. burgdorferi persists in such a hostile environment indicates that the spirochete is adept at evading the host immune response via mechanisms that have not been completely elucidated. One possibility is that B. burgdorferi invades host cells and survives at low levels. Recently we have determined that B. burgdorferi invade both immortalized and, more importantly, primary cells (both fibroblasts and endothelial cells) and persist as viable cells in o-culture. In addition we have preliminary data suggesting that the ability to invade host cells involves both integrin binding and Src kinase activity.

In this application we propose to further characterize the internalization of B. burgdorferi and track the fate of B. burgdorferi within thes infected cells to determine how they affect the localized host response following infection. To accomplish this we will use both in vitro correlates of invasion and intracellular survival as well as in vivo imaging of experimentally infected mice as readouts for our studies.

Specifically, we propose to:

(1) Characterize the invasion of Borrelia burgdorferi into primary fibroblasts. The working hypothesis here is that B. burgdorferi exploits invasion as an additional mechanism to avoid host clearance. Our preliminary studies demonstrate that B. burgdorferi invasion is not dependent on host fibronectin, but does involve B1 integrins other than a5B1. In this Aim we will identify the subunit that pairs with B1 to promote invasion and will also evaluate how B. burgdorferi traffics within these cells; and

(2) Determine if invasion is required for B. burgdorferi persistence in vivo. Our working hypothesis is that invasion contributes to persistence by providing an immunoprotected niche for B. burgdorferi. Since Src kinases are required for borrelial internalization in vitro, we will determine whether Src kinase inhibitors alter the infectivity potential of B. burgdorferi in vivo. In addition to standard cultivation and molecuar approaches, novel in vivo imaging will be employed to assess how the inhibitor affects colonization.

The overall goal of these studies is to determine the extent in which an intracellular locale contributes to borrelial persistence.

PUBLIC HEALTH RELEVANCE: Borrelia burgdorferi, the etiologic agent of Lyme disease, is the most common arthropod-borne infectious agent in the United States, and, as such, represents an important Public Health issue. The studies described in this application are designed to address how B. burgdorferi is able to persist effectively in infected mammals despite effective innate immune killing mechanisms and a potent adaptive immune response directed against this pathogen. The hypothesis being tested herein is that B. burgdorferi is capable of low-level intracellular survival in non-immune cells as an additional strategy to prevent borrelial host clearance.

Link: http://projectreporter.nih.gov/project_info_description.cfm?aid=8300386&icde=12284856

Comment: This really begins fulfilling my wishlist, and I look forward to the imaging study videos that I hope will be made and posted online. If there is some sort of confirmation of intracellular Bb in vivo this may explain why some patients need additional antibiotics and why existing treatments may be inadequate as a matter of timing.

This next project is bound to generate discussion, as it involves the potential role of toxins in Borrelia burgdorferi. In this case, the researcher is looking for gene clusters in Borrelia burgdorferi which may create cytolysins similar to the toxins which are found in Staphylococcus aureus, Listeria monocytogenes, and Clostridium botulinum.

Project: A COMMON DENOMINATOR OF PATHOGENESIS; A RARE OPPORTUNITY FOR NOVEL THERAPEUTIC DE(VELOPMENT)
Institution: UNIVERSITY OF ILLINOIS URBANA-CHAMPAIGN
PI: Mitchell, Douglas

Description (by applicant):

Abstract: The 20th century witnessed several major advances in medicine. Perhaps most important were the discovery of antibiotics for bacterial infections and effective vaccines for several major viruses. Unfortunately, the creation of effective vaccines for bacteria has lagged behind analogous anti-viral strategies. Compounded with the rise in antibiotic resistance and a lack of interest from the pharmaceutical industry in pursuing novel antibiotics, we risk losing the fight against bacterial pathogens.

Described herein is an unconventional strategy to exploit bacterial toxins as both novel targets for antibacterial agents and antigens for vaccine development. To intelligently address the increasing threat posed by bacterial pathogens, more effort is needed to uncover the molecular underpinnings of virulence. Our group specializes in the use of bioinformatics, in vitro reconstitution, and genetic manipulation to identify and characterize gene clusters that are responsible for the biosynthesis of virulence-promoting cytolysins. The best-known toxin in this family is the highly modified peptide, streptolysin S (SLS, produced by Streptococcus pyogenes).

SLS production is required for the infective process, but not essential life processes. Our work has uncovered SLS-like toxins are synthesized by at least three other notorious human pathogens, including Staphylococcus aureus, Listeria monocytogenes, and Clostridium botulinum. We aim to study the potential role of the SLS-like toxin in an additional organism, Borrelia burgdorferi (Bb), which causes Lyme disease.

Although widely known, the Bb molecular mechanism of pathogenesis is inadequately defined. If the SLS-like toxin was indeed employed during Bb infections, this would represent the first demonstration of toxin utilization in this family of organisms and would prompt a major revision of borrelioses.

Because bacteria typically employ disparate pathogenic mechanisms, the conserved, SLS-like pathway provides a rare opportunity to develop more broadly applicable, yet targeted countermeasures. From our perspective, new antimicrobial strategies should directly target the pathogenic mechanism, rather than DNA replication, protein synthesis, or the cell wall. This approach holds enormous potential, as these drugs will theoretically be resistant to resistance.

This project will identify inhibitors of SLS toxin biosynthesis for the specific purpose of developing novel antibacterials. Moreover, SLS is non-immunogenic, rendering it an unfeasible candidate for vaccine development.

We have succeeded in generating attenuated variants with the anticipation that these can be used for raising toxin-neutralizing antibodies. The notion of immunizing against a bacterial toxin represents a potentially general strategy for future vaccine development.

With this proposal, we aim to not only fundamentally shift the accepted view of Bb pathogenesis, but also to challenge the paradigm that antibiotics must kill bacteria and non-immunogenic toxins are intractable vaccine candidates. These seemingly unrelated goals are actually quite intertwined. Our approach rests on the philosophy that a more complete understanding of toxin biosynthetic pathways and chemical structure can be rationally exploited to design novel therapeutics.

Public Health Relevance: Bacterial pathogens employ numerous mechanisms to evade the human immune system. We have discovered a novel strategy within the organism that causes Lyme Disease, who's pathogenesis remains largely enigmatic. A greater understanding of these processes will lay the foundation for developing the next generation of antimicrobial drugs.

Link: http://projectreporter.nih.gov/project_info_description.cfm?aid=8145943&icde=12284856

Comment:

Wait... I thought Radolf & co. said Borrelia burgdorferi does not produce a toxin? I know Donta patented some genes in Bb he saw as being analogous to a toxin.

Is there now evidence of newly researched genes which create a toxin in Bb? Or is this an old hypothesis which is being revisited?

Project: ASSESSMENT OF PATIENTS WITH BORRELIA INFECTION
Institution: NIAID
PI: Marques, Adriana

Description (by applicant):

Lyme disease is a multisystem illness caused by infection with the spirochete Borrelia burgdorferi and it is the leading vector-borne disease in the United States. Our current work addresses the following areas in Lyme disease: development of new tests and biomarkers for infection, investigation of persistence of infection with B. burgdorferi in humans, search for the cause of Southern Tick-associated Rash Illness (STARI), and investigation of the role of immune response in Lyme disease and PLDS.

One of the main problems in Lyme diagnosis has been the lack of highly specific and sensitive assays for B. burgdorferi and the lack of a test that could be used to assess response to therapy. Such assays should greatly facilitate the accurate diagnosis of Lyme disease and assessment of response to therapy in individual patients. Currently, no such test is available.

We have developed a new test using the luciferase immunoprecipitation systems (LIPSs) for profiling of the antibody responses to a panel of B. burgdorferi proteins for the diagnosis of Lyme disease. A synthetic protein consisting of a repeated antigenic peptide sequence, named VOVO, had the best diagnostic performance, similar to the C6 test (a diagnostic test using a peptide ELISA that we have helped develop and is highly sensitive and specific). The VOVO LIPS test displays a wide dynamic range of antibody detection spanning over 10,000-fold without the need for serum dilution; and offers an efficient quantitative approach for evaluation of the antibody responses in patients with Lyme disease.

Recent studies have shown that B. burgdorferi may persist in animals after antibiotic therapy and can be detected by using the natural tick vector (Ixodes scapularis) to acquire the organism through feeding. Whether this occurs in humans is unknown.

We have implemented a new clinical protocol to investigate the utility of this approach for identifying persistence of B. burgdorferi in treated human Lyme disease.

STARI is a rash similar to the rash of Lyme disease that occurs in persons residing in southeastern and south-central states and is associated with the bite of the lone star tick, Amblyomma americanum. The cause of the rash is unknown, as it is the natural course of the disease.

We have a clinical protocol to investigate the cause of STARI, and we are applying new genomic tools that identify bacteria based on species-specific sequences in the 16S rRNA ribosomal genes to the skin biopsies from patients with STARI.

Inflammatory innate immune responses are critical in the control of early disseminated infection, while adaptive immune responses are vitally important, particularly the humoral immune response, in controlling spirochete levels in tissues and resolution of Lyme arthritis in animal models. We are examining the antibody response to immunogenically dominant antigens of B. burgdorferi in PLDS patients and controls.

Further investigation of the anti-borrelia immune response may help in elucidating the pathogenic mechanism of PLDS and yield important information for future approaches to diagnosis and treatment. We have a clinical protocol in which we use DNA microarrays to characterize gene expression patterns in skin biopsies from individuals with EM, with the aim of capturing the human host response to pathogen exposure.

We are also investigating the differences in immunological response between predominantly lymphocytic meningitis and predominantly neutrophilic meningitis. Results from these studies will serve as a window into the fundamental biology of the infection.

Link: http://projectreporter.nih.gov/project_info_description.cfm?aid=8336099&icde=12284856

Comment:

The existence of the VOVO LIPS test is nothing new - reports on the development of this test have been around since 2010. Also, there is already information about a chronic Lyme disease xenodiagnosis study out there.

It seems like this project has a large scope - or consists of more than one project under the same umbrella. So far, no project end date has been posted for this entry.

What would be of most interest to me would be finding differences in immunological response between patients with acute Lyme disease and those with assumed PLDS - something Alaedini has already been studying.

(Side note: I thought that it was already determined that Borrelia lonestari, a relapsing fever spirochete, was the cause of STARI or Masters disease - did I miss something?)

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