Friday, 24 September 2010
Dear Lyme Community:
As you know, some Lyme advocates have chosen to pull out of the IOM Lyme Disease workshop
They are legitimately concerned that the agenda is heavily biased against the patients’ interest. We respect their concerns and their decision to pull out of the workshop. However, upon careful consideration, we have decided to participate in the IOM workshop to represent the Lyme patient’s perspective and show support for our presenters. While we have our own reservations, we are working hard to improve the agenda.
Here are some facts and thoughts to consider in making your own decision:
1) The IOM Lyme workshop is not a forum to debate whose science is right or wrong. It is, rather, an assessment of the state of the science as presented from all points of view, for the purpose of determining the science and research still needed. This workshop is not designed to draw conclusions, but to determine where future research needs to go.
2) If Lyme patients and Lyme doctors fail to participate, the only perspective presented will be that of the IDSA. If our Lyme doctors and advocates don’t participate, the committee can’t include them in the record and it will appear in the report as if we don’t exist or care.
3) The IOM committee will accept comments for the record up to 3 or 4 days after the workshop. If you don’t know what was said at the workshop, you cannot draw intelligent comments.
4) Clinicians will have a microphone reserved solely for their use, with extra time allocated to their questions or comments which will be included in the final report. Lyme doctor participation is critical or the IDSA clinicians will be the only ones at the microphone and on record.
5) A Congressman worked hard for the appropriation to fund this project. Abandoning this workshop is abandoning him, and will compromise his future ability to argue successfully for Lyme patients in Congress. This Representative needs Lyme community support at this workshop. We cannot “burn our Congressional bridges” with the very people who are critical to our cause.
6) When you withdraw from the Washington process, you won’t be asked back again. Each time this happens, we lose our ability to be taken seriously. History shows that progress is made when we work within the system, not when we abandon it. Admittedly, it is by nature, a long and arduous process.
Bottom line: the workshop will proceed with or without our community; without representation we concede to the IDSA. We can’t let that happen! If the situation warrants it, there will be time to write a minority report.
Please attend this workshop and explain your views on the gaps in science and the research you think is needed. For example, the gaps in diagnosis that caused your disease to go unrecognized; the lack of uniformity in approaches of the states; the problem of underreporting; the unreliability of testing and the other issues you believe should be addressed by the science.
Monte L. Skall
Executive Director, the National Capital Lyme & Tick-Borne Disease Association
President, Michigan Lyme Disease Association
President, National Tick-Borne Disease Advocates
President, Lyme Disease United Coalition
Lyme Disease Association of Iowa
Minnesota Lymefighter’s Advocacy
South Dakota LDUC
Kansas Lymefighters, Inc.
Washington (State) LDUC
North Dakota LDUC
In the Lyme Light, MN LDUC
Wright County Minnesota LDUC
Annondale MN LDUC
Chairman, Minnesota Lyme Fighter’s Advocacy
Vice President, Lyme Disease United Coalition
Tina J. Garcia
Founder, Lyme Education Awareness Program
Thursday, 23 September 2010
Lyme Patient Groups Compelled to Withdraw from Scientific Meeting
Posted on Lyme Disease Association here
September 20, 2010 - In a move designed to protest the Institute of Medicine’s upcoming Lyme disease workshop, three of the nation’s largest and most influential Lyme groups have pulled out of the process. After much deliberation, speaker Diane Blanchard, co-president of the Time for Lyme (TFL- CT) has withdrawn from the panel. The national Lyme Disease Association (LDA- NJ) and the California Lyme Disease Association (CALDA), along with TFL, will not participate in the workshop and their IOM commissioned scientific paper will not be submitted.
The scientific workshop was promoted by the Institute of Medicine (IOM) to be a conference about the state of the science regarding Lyme and tick-borne diseases. Despite the groups request for transparency and a balance of scientific viewpoints, as delineated in Congressional Appropriations language, neither the hearing panel nor the speakers selected by the IOM satisfy the Congressional intent or objectives.
The IOM’s mission was to provide “independent, objective and non-partisan” advice to policy makers, yet the majority of the participants sitting on its Lyme disease panel belong to the Infectious Diseases Society of America (IDSA), a medical society with a known bias. Many key speaker roles were given to physicians who are IDSA members and supporters, a number of whom were involved with the IDSA’s controversial guidelines for Lyme. IDSA’s Lyme guideline development process was investigated by the Connecticut Attorney General which resulted in exposing the guideline panel as being riddled with undisclosed conflicts of interest.
In spite of the recommendations to NIH by Congress, the conference opens with perhaps the most polarizing figure in the chronic Lyme debate-- Dr. Gary Wormser of Westchester Medical Center -- who chaired the IDSA Lyme guideline panel and whose highly controversial biased views are well known. There are no scheduled speakers with opposing viewpoints of similar scientific weight to balance his presentation about the research gaps in Lyme disease. Many state-of-the-art scientific researchers and experienced clinicians have been relegated by the IOM and NIH to simply spectator positions.
The patient-oriented Lyme groups believe that this amount of bias undermines the integrity of the scientific workshop and that its final report will reflect this lack of objectivity. “We believe the entire process has the potential to cause additional harm to patients. After much deliberation our only recourse is to withdraw our support for this seriously flawed process. From the inception, TFL, LDA and CALDA have communicated our concerns, which were ignored. We remain hopeful that NIH/IOM will revamp the program to comply with the Congressional language which was responsible for initiating the workshop,” the groups said in a joint statement.
Time for Lyme, www.timeforlyme.org, the national Lyme Disease Association, www.LymeDiseaseAssocation.org, and California Lyme Disease Association, www.lymedisease.org, are non-profit organizations that were founded by individuals who had personal experience with Lyme disease, in order to address the lack of research, education and support services available for this emerging infection.
Contacts for Media:
Time for Lyme, Diane Blanchard, Co-President, 203-461-3417
The California Lyme Disease Association, Lorraine Johnson, Chief Executive Officer, 310-365-3233
Lyme Disease Association, Pat Smith, President, (732) 938-4834
Now go to here to sign the petition to Congress this affects us all around the World .
To read more about this and the background go to CALDA blog here
Read Dr Kenneth Leigner's response to IOM here
Monday, 20 September 2010
It is encouraging that Pennsylvania is considering Lyme and related tick-borne disease education, prevention and treatment legislation.
As a psychiatrist, I work with late-stage Lyme patients and have treated thousands of well-documented cases of Lyme and tick-borne diseases that could have been avoided by earlier and more effective intervention.
Unfortunately, this epidemic is exacerbated by a highly restrictive approach and misinformation propagated by a small but highly influential group of individuals who appear to lack vision or have competing interests and deny the full breadth and depth of this epidemic.
There are many forward thinking, highly motivated and compassionate physicians who recognize the seriousness of this epidemic.
Their freedom to help their patients with their best clinical judgment and a fair and balanced review of the medical literature should not be hampered.
see more here
ROBERT C. BRANSFIELD MD
and Associated Diseases Society
Friday, 17 September 2010
In 2009 there were a further c1000 articles published and several every week are currently being published, many of which support the case for Chronic Lyme disease and ILADS treatment on long term antibiotics.
There is to be a conference shortly at the Institute of Medicine in Washington
'A Workshop on the Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-borne Diseases: the Short-Term and Long-Term Outcomes'
'At the request of the NIH, National Institute of Allergy and Infectious Diseases, the IOM will convene a committee to plan and conduct a scientific workshop to assess the state of the science of Lyme and other tick-borne diseases. The workshop will represent the broad spectrum of scientific views on Lyme disease and should provide a forum for public participation and input from individuals with Lyme disease as requested in congressional appropriations report language in House Committee Report 111-120 and Senate Committee Report 111-66. The product to be delivered will be a committee authored meeting summary that highlights workshop presentations and discussions.'
Our UK 'expert' Dr Sue O'Connell from the Lyme Reference Unit at Southampton will be presenting.
It is clear to those of us with Chronic Lyme that this will be the same old whitewash.
If you only present one side of an argument and refuse to include those with opposing views that does not prove you are right, it just leaves sick people sick and costing the Economy money.
The president of ILADS has written to the IOM details here http://www.ilads.org/news/lyme_press_releases/iompanel_lyme.html
The letter also quotes Dr. Willy Burgdorfer, formerly of the National Institutes of Health and discoverer of the Lyme spirochete:
“The controversy in Lyme disease research is a shameful affair. And I say that because the whole thing is politically tainted. Money goes to people that have for the past 30 years produced the same thing— nothing.”
But what I would really appreciate you reading is the letter below sent by Dr Kenneth Liegner I highlight the most pertinent points.
September 14, 2010
Dear Lonnie King, Christine Coussens, Trevonne Walford and Panel Members:
I spoke with Trevonne a few days back to inquire whether or not there would be opportunity for attendees of the up-coming meeting to make comments and/or statements in the context of the meeting and learned that the meeting was structured only to allow focused questions in response to a preceding presentation or discussion.
I mentioned in passing that I was pleased to see that there was representation of a diversity of views in terms of choice of speakers which included Carl Brenner, John Aucott, Brian Fallon, Sam Donta and Pam Weintraub.
It has since been pointed out to me that many of these individuals have very limited time in which to articulate a position concerning the issue of chronic Lyme disease since the physicians are ensconced within discussion panels and do not have the opportunity to speak at length.
The process of planning the meeting has been, as far as I can tell, quite opaque and it is notable that clinicians who actually treat persons with chronic Lyme disease have been nowhere to be found on either the planning committee or the panel. Neither is any clinician afforded adequate time to present, in a formal way, an opposing position to what must be viewed as the “keynote” speech by Dr. Wormser. Dr. Wormser’s extreme view on the existence of the entity of chronic Lyme disease needs no repeating but does need rebuttal.
Physicians who have cared for persons with chronic Lyme disease have faced harassment at a minimum and for some, their careers have been ruined. Researchers who have seriously dedicated themselves to the scientific study of chronic Lyme disease in humans and/or animals have often found themselves attacked or marginalized. To persist in their researches would have resulted in virtual career suicide and some have been forced, by exigencies of survival, to leave the field.
Laboratories that test extensively for Lyme disease, including use of direct detection methods such as PCR, have found themselves subjected to concerted smear campaigns and harassed. Whereas PCR is a well-accepted method in virtually all other infectious diseases, its clinical use for Lyme disease has also been marginalized. Direct detection methods developed more than a decade ago by some of this country’s finest physician-researchers and biomedical research scientists (Dorward DW, Schwan TG, Garon CF. Immmune Capture and Detection of Borrelia burgdorferi Antigens in Urine, Blood, or Tissues from Infected Ticks, Mice, Dogs, and Humans. J Clin Microbiol 1991;29:1162-1170 & Coyle PK, Deng Z, Schutzer SE, Belman AL, Benach J, Krupp L, Luft B. Detection of Borrelia burgdorferi antigens in cerebrospinal fluid. Neurology 1993;43:1093-1097 & Coyle PK, Schutzer SE, Deng Z, Krupp LB, Belman AL, Benach JL, Luft BJ. Detection of Borrelia burgdorferi-specific antigen in antibody-negative cerebrospinal fluid in neurologic Lyme disease. Neurology 1995;45:2010-5) have been moth-balled, I believe, for political and medical socioeconomic reasons.
Seronegativity, a well-recognized feature of spirochetal disease (e.g. in syphilis) is held to not need consideration despite early recognition of this phenomenon in Lyme disease, ironically, by a signer of the 2000 and 2006 IDSA Lyme disease guidelines (Dattwyler RJ, Volkman DJ, Luft BJ, Halperin JJ, Thomas J, Golightly MG. Seronegative Lyme Disease. Dissociation of T- and B-Lymphocyte Responses to Borrelia burgdorferi. N Engl. J Med 1988;319:1441-6).
That there is no active support by the Federal government for training programs for pathologists or support for pathologic laboratories for in-depth pathologic study of tissues from humans with chronic Lyme disease using all available methods (and which, hopefully, might develop new and superior methods) indicates a choice to remain in ignorance. There could and there should be one or more such laboratories of highest scientific calibre where such methods could be made available to clinicians and researchers and their patients, comparable to the Armed Forces Institute of Pathology, which has been known for excellence in the study of syphilis.A key formative influence in the creation of the National Institutes of Health was Metropolitan Life Insurance Company (Harden VA. Inventing the NIH. Federal Biomedical Research Policy 1887-1937.Johns Hopkins University Press. 1986. pp.57-59,114 & 122).
It would be naïve not to consider the possibility of ongoing behind the scenes influence of the insurance industry on N.I.H. policy.
Honest review of the worldwide peer-reviewed scientific literature reveals an abundance of evidence for the existence of chronic Lyme disease in humans and animals.
Much of this evidence was presented to the Lyme Disease Review Panel of the Infectious Diseases Society of America on July 30, 2009. Regrettably, the panel chose to sustain the 2006 IDSA Lyme Disease Guidelines. IDSA leaders were defiant from the outset asserting the Connecticut Attorney General could make them review the guidelines but that he couldn’t make them change them. In retrospect it was a serious strategic error to leave the review process within the hands and ultimately under the control of the IDSA itself.
The standard of care set by the IDSA 2006 Lyme disease guidelines is one of medical neglect of persons suffering from chronic Lyme disease.
However, such guidelines are indeed useful. They serve to shield from liability physicians who neglect persons with chronic Lyme disease. By misusing CDC case surveillance criteria as the sole basis for a clinical diagnosis of Lyme disease, these guidelines serve the insurance industry very well indeed because such cases represent but the tip of the iceberg of actual cases of Lyme disease, whether acute or chronic.
Denial of the possibility of seronegative Lyme disease, likewise serves the insurance industry well and also such simplistic constructs for Lyme disease also serve those physicians who cannot wrap their minds around the true complexity of this illness.
The medical profession and the United States Public Health Service, predecessor to the CDC, have a long history of medical neglect of persons suffering from spirochetal infection. The profession and the USPHS were completely unable to reform themselves from within in this regard. It required moral and political intervention from without to bring the Tuskegee Experiment to an end with Senator Edward Kennedy’s hearings in February and March, 1973 before Committee of Labor and Public Welfare’s Sub-Committee on Health (Jones JH. Bad Blood: the Tuskegee Syphilis Experiment – a tragedy of race and medicine. The Free Press. New York. 1981 pp. 213).
The Tuskegee Experiment involved about 400 subjects. Lacking the taint of racism, nonetheless the “mainstream” handling of chronic Lyme disease affects far more people; it would be a fair estimate to say, Tuskegee X 10,000 in the United States alone.
Furthermore, the standards held out by the CDC and the IDSA have worldwide influence. Canadians are unable to get care for chronic Lyme disease. We are seeing significant numbers of persons with chronic Lyme disease forced to leave Canada for care.
State legislators have begun taking matters into their own hands and the states of Rhode Island, Connecticut, California, New York, Massachusetts and Minnesota have passed laws or promulgated policies protecting physicians who treat persons with chronic Lyme disease. Are these legislators stupid? Are they dupes of Lyme activists? Or can they see what is so obvious to the patients and to any good clinician, that Lyme disease can be a chronic infection that often requires a long-term treatment approach?
Furthermore, as the disease spreads and more and more individuals are affected, legislator’s staffers, their wives, their children and they themselves are experiencing the effects of chronic Lyme disease.
In the fullness of time, the mainstream handling of chronic Lyme disease will be viewed as one of the most shameful episodes in the history of medicine because elements of academic medicine, elements of government and virtually the entire insurance industry have colluded to deny a disease.
This has resulted in needless suffering of many individuals who deteriorate and sometimes die for lack of timely application of treatment or denial of treatment beyond some arbitrary duration.
I am forwarding by mail copies of two of my abstracts and several published articles concerning such individuals for each panel member as I do not have these in PDF format (Liegner KB, Rosenkilde CE, Campbell GL, Quan TJ, Dennis DT. Culture-confirmed treatment failure of cefotaxime and minocycline in a case of Lyme meningoencephalomyelitis in the United States [abstract]. Programs and abstracts of the Fifth International Conference on Lyme Borreliosis, Arlington, VA, May 30-June 2, 1992. Bethesda,MD: Federation of American Societies for Experimental Biology; 1992:A11. & Liegner KB, Duray P, Agricola M, Rosenkilde C, Yannuzzi L, Ziska M, Tilton R, Hulinska D, Hubbard J, Fallon B. Lyme Disease and the Clinical Spectrum of Antibiotic-Responsive Chronic Meningoencephalomyelitides. J Spirochetal and Tick-borne Dis 1997;4:61-73 & Liegner KB. Lyme Disease: The Sensible Pursuit of Answers. (Guest Commentary). J Clin Microbiol 1993;31:1961-1963 & Liegner KB & Jones CR. Fatal progressive encephalitis following an untreated deer tick attachment in a 7 year-old Fairfield County, Connecticut child. [Abstract] VIII International Conference on Lyme Disease and other Emerging Tick-borne Diseases, Munich, Germany, June 1999 & Liegner KB, Shapiro JR, Ramsay D, Halperin AJ, Hogrefe W, Kong L. Recurrent Erythema Migrans Despite Extended Antibiotic Treatment with Minocycline in a Patient with Persisting B. burgdorferi Infection. J Amer Acad Derm 1993;28:312-4.). I urge the panel members to be scrupulous in considering all of the available evidence concerning the issue of chronic Lyme disease, to issue a report which will not be regarded as a whitewash for the IDSA 2006 Lyme Disease Guidelines, that it may acquit itself well in the eyes of history.
Very truly yours, Kenneth B. Liegner, M.D.
Member, Treatment Panel, N.I.H. State-of-the-Art Conference on Lyme Disease, March 1991, Bethesda, MD. Co-Chair, Treatment Poster Discussion Section, Fifth International Conference on Lyme Borreliosis, May/June 1992, Arlington, VA.Participant, N.I.A.I.D. Consultations on Chronic Lyme Disease, February & October, 1994, Rockville, MD. Member, Program Committee, 7th International Conference on Lyme Borreliosis, San Francisco, CA., Spring 1996. Presenter to Infectious Diseases Society of America Lyme Disease Review Panel, July 30, 2009, Washington, D.C.
There is more about this on CALDA blog Lyme policy wonk https://www.lymedisease.org/554/
Thursday, 16 September 2010
- The retroviruses
Will you please comment on the newly discovered MLV-related retroviruses in CFS patients, and what relationship they might have to the other infectious pathogens you have found in CFS.
Thanks.Rich Van Konynenburg
The newly evolving field of human gamma retroviruses (HGV), also called XMRV , and chronic illnesses like CFS/FMS is fascinating. This type of virus has now been found at high incidence in some but not all studies on CFS patients. There may be technical reasons why some groups have not found these infections, but the field is new and in constant flux.
My guess is that similar to other related retroviruses the HGV may cause changes in our immune systems rather than directly causing the most obvious signs and symptoms associated with CFS. Their effect may thus be indirect, just like the HIV-1 retrovirus causing immune suppression in AIDS rather than directly causing the symptoms of AIDS.
Thus HGV may set up patients for other opportunistic infections, such as Mycoplasma, Chlamydia, Borrelia, CMV, HHV6 and other bacteria and viruses that actually cause most CFS symptoms.
This is why patients who have these other infections, such as bacterial infections, benefit from their specific treatment in the absence of anti-viral treatment. This would not occur if the symptoms were entirely caused by a retrovirus.
Thus I predict that anti-retrovirus treatment will not eliminate most symptoms in CFS patients, because they are more likely caused by other infections.
However, modulating immune responses by suppressing viruses that could affect immune systems could have some positive effects. Eventually this will all be worked out, and we will find out what role retroviruses, along with other bacteria and viruses, play in chronic illnesses like CFS and FMS.
From Prohealth here
All questions and answers can be found here
Wednesday, 15 September 2010
A Workshop on the Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-borne Diseases: the Short-Term and Long-Term Outcomes
On first reading this, most Lyme Disease patients would think, good at last all will be put out in the public domain and discussed openly.
Not a bit of it, even to the uninitiated it is not difficult to see that none of the ILADS doctors are presenting.
Yes those doctors around the World who are involved with treating Thousands of patients for Lyme disease most of which improve on their treatments, are not included. ILADS doctors do not just treat Lyme Disease but the many co infections that IDSA members conveniently ignore.
Many patients who fail the short courses of treatment doled out by IDSA doctors just move along and find a good Lyme literate doctor who is prepared to consider that for some ILADS treatment guidelines are needed.
How will the IDSA doctors ever learn if they close their ears and minds to alternative views?
Has science stopped evolving when it comes to Lyme Disease?
When you have been in so much pain and disability, from in my case Arthritis and muscle weakness and after months of antibiotics clawed your way back to nearly 100% health is it any wonder the patients advocate for a more open process.
Below is a letter to the IOM from the President of ILADS.
IOM panel and selected speakers for Lyme Disease and Other Tickborne Diseases: The State of the Science
Dear Dr. Coussens: I am writing on behalf of the International Lyme and Associated Diseases Society (ILADS) to express our disappointment with the lack of balance in the selection of the IOM panel and speakers for the “State of the Science” review of Lyme disease.
The science in Lyme disease has been a topic of great debate and polemic viewpoints. The two viewpoints are reflected in Lyme guidelines from the Infectious Diseases Society of America (IDSA) on the one hand and the Lyme guidelines from ILADS on the other, both evidence-based.
It is of great concern that four of the six panel members selected by the IOM are IDSA members because IDSA is known to have a strong institutional bias in its interpretation of the science in Lyme disease. In addition, IDSA has been investigated by the Connecticut Attorney General, who found extensive conflicts of interest and suppression of scientific evidence in the guideline development process. The fact that IDSA ultimately vindicated its own guidelines through a self-selected review panel that excluded treating physicians and was comprised almost exclusively of IDSA members should be no surprise given the bias of the review panel.
There is a significant disconnect between IDSA and the community of physicians who treat Lyme disease. There is also an urgent need for transparency in recognizing the limitations of the existing Lyme research. The bulk of the research on Lyme treatment has been controlled by IDSA researchers. Their research is based on sample populations that do not reflect those seen in clinical practice. These researchers then apply their interpretation of their own research (in which they have a vested interest in terms of personal reputation, academic careers, and commercial interests related to diagnostic tests, vaccines, and expert witness fees) to clinical care through guidelines, resulting in enormous harm to patients.
Dr. Willy Burgdorfer of the National Institutes of Health and discoverer of the Lyme spirochete, puts the research into perspective: “The controversy in Lyme disease research is a shameful affair. And I say that because the whole thing is politically tainted. Money goes to people that have for the past 30 years produced the same thing— nothing.”
In particular, we have grave concerns that:
· The speakers do not include any physicians from ILADS, many of whom have published in peer-reviewed journals, conducted clinical research, and are extensively familiar with the science related to Lyme disease;
· Dr. Wormser, who authored the IDSA guidelines and ran the guidelines panel that suppressed non-conforming evidence, is the only person addressing the state of the science and gaps, and as the first speaker he will frame the issues for the conference without opposing viewpoints being presented;
· Dr. Aguero-Rosenfeld, who, until recently, worked for Dr. Wormser until recently, is the key speaker on laboratory testing, and opposing viewpoints on this topic will not be presented;
· Seven of the speakers were either members of the IDSA guidelines panel or were included on copycat guidelines generated with members of the IDSA guidelines panel;
· Over 70% of the physicians awarded the key 25 minute speaking slots are either members of IDSA or sat on the IDSA guidelines panel or were included on copycat guidelines generated with members of the IDSA guidelines panel;
· Researchers and physicians who are more open-minded in terms of understanding the treatment implications of research for chronic Lyme disease were either excluded from speaking, relegated to topics that are not their specialty, or placed on panels where their time to speak will be severely limited.
We do not believe that the selection of the “State of the Science” panel or the speakers reflects the diversity of scientific viewpoints in this highly controversial area. This lack of balance and diversity will necessarily erode the integrity of the process and the results. We encourage you to revamp the process to address these issues.
Dr. Robert Bransfield, MD, DLFAPA
see details on CALDA blog also here here and here
Tuesday, 14 September 2010
This interesting video is of a mother and daughter diagnosed with Chronic Lyme Disease and sick housebound for the last four years. Recently they were found to have XMRV retrovirus and following controversial treatment with anti retrovirals they are both improving significantly.
Thanks to the Whittemore Peterson Institute for the work they are doing at their private clinic not only seeking the causes of ME/CFS but also many other Neuro immune Diseases.
Below is another video of a child with Autism who is benefiting by treatment through the Whittemore Peterson Institute.
For more information on the Whittemore Petterson Institute visit their Facebook page at here
Saturday, 11 September 2010
On the question of clarity of the diverse study results
Dr Mikovits: We saw at this meeting several posters and we heard from 4 physicians, Dr Cheney, Dr Bell, Dr Peterson, Dr Komaroff on the Lo study.
These are experts at the diagnosis of, and they are diagnosing the same patients generally and we saw the same percentage of positive patients in those.
Those are patients geographically located from as you heard Dr Cheney say, from around the world… from the NE US in the case of the Hanson-Bell study, I know that Nancy Klimas gets a lot of patients form Florida.
So we can begin to address that because there are clinicians that have been identifying similar positivity rates so we can pull positive samples from each of those and really begin to put together literally hundreds to do that very thing.
Joe – clinician – I also want to support the comments from the person from Pittsburgh.
I have a question because the golden standard that is normally presented during these presentations is the CDC or the Fukuda criteria, but are there data on the performance and the variability with doctors using these criteria?
In other words is it conceivable that one doctor would rank a person “in” and another doctor “out” (of these criteria)?
Dr. Mikovits: Yes, the criteria are highly variable and probably some of the physicians in the - they’re really, really subjective,
and unless if you look for various immunological defects rather than just subjective defects, that you get a lot closer to seeing what we see in our patients,
the patients that we identified in UK in the London area, and what Drs Bell and Komaroff are (seeing)…
Dr (indecipherable): If that’s the case, if you’re going to compose clinical cohorts I think it’s important that you have different clinicians selecting and that you also create some data of other doctors looking at the same patient and confirming whether a patient is in or out.
Dr Mikovits: Well they’ve been looking for that for decades, biomarkers and things that could help better define this disease because it is so heterogeneous in how it’s defined.
Dr. Joe Barrascano, Clinician. Over the past day and a half I’ve been struck by the consistent inconsistencies of the results. In other words the groups that find the virus find it in 2/3 or ¾ of patients, and maybe 5% who are not.
And then there are groups who find it in absolutely nobody. It’s very important to work out methodology and so forth. But I think what could explain this tremendous difference that is consistent.
And I think it might go one step before. Maybe it’s the collection and storage of the blood prior to processing that’s really causing the problem here… because if it were a methodological problem you’d see variation from 1,2,10,20,40,50% rather than zero or 80%.
Dr. Mikovits: Actually that is true Joe, and … we have learned literally in past 2 wks in the BWG that processing may be a key
and we may have found an opportunity to have a processing protocol where everyone would at least find viral RNA in plasma and blood products without culture.
Dr. David Wilford, GSK – My question is to Judy but other people are looking at detection of XMRV. Before the XMRV studies, specifically the Virochip showed I believe that there were multiple viruses present in some of these CFS samples.
I’m just wondering with these XMRV positive samples if we’ve being looking specifically at serology or PCR for other types of viruses being more reactivated than controls or if anybody else there is doing these XMRV studies looking for other viruses, or just specifically for XMRV.
Dr. Mikovits – Yes, we set up this program as a study to look at all the viruses, because CFS patients have a lot of activated things like CMV and HHV-6a herpes viruses, mycoplasma, Lyme.
So the idea in the beginning is, as with HIV-AIDS that the retrovirus creates an underlying immune deficiency as-yet-unknown, allowing the immune system not to be able to control pathogens the rest of us can control, because we don’t have that underlying immune deficiency.
So that what we see is the sickest of the sick, the tip of the iceberg, as in the earliest days of HIV-AIDS, where we saw Kaposi’s Sarcoma, pneumocystomonia and the other 25 AIDS-defining illnesses.
So that is the hypothesis we’re following.
And we’ve developed chips to look at all the Herpes viruses and pathogens in correlation with expressed virus in our patient population. . bec we don’t have that underlying immune deficiency, we’re seeing sickedst of the sick.
We’re seeing tip of iceberg – so that is hypothesis we’re following – we’ve developed chips to look at all the herpes viruses and pathogens in correlation with expressed virus in our patient populations.
Dr. Wilford – What I’m worried about, is XMRV the cause of this immunosuppression or is it just another of these viruses that is being expressed.
Dr Mikovits – Retroviruses are not ubiquitous and they’re not generally benign – so the kind of biology that we’ve looked at with HTLV1 with the HTLV1-associated myelopathy and the acquired immunodeficiency virus, HIV.
That’s a reasonable hypothesis. So it has not been a passenger in the other human retroviral-associated diseases so there is no reason to expect that it would behave other than another human retrovirus.
But of course this is the first human gammaretrovirus. So Sandy (Ruscetti) knows in that family of viruses the envelope is both an oncoprotein and a neurotoxin.
We heard yesterday about HIV creating a dementia distinct from the immune deficiency based on the viral envelope protein, so these are all hypotheses that we’re following.
then -- an earlier question by
Mindy Kitei, Journalist – My question is about treatment because that’s what people who go to my blog want to know. When are we going to start drug trials, what drugs are going to be used? Monotherapy, triple cocktail. Where, when, why.
I will skip many of the replies and jump to one of Judy Mikovits final comments.
Dr. Holmberg:-------------------So I think it’s really a step-wise approach:
- Define the prevalence of the pathogen
- Focus on those with it
- Determine whether it’s quantifiable
- Do initial phase 1-2 experiments to see whether you can alter the level of the pathogen short-term and then longer term treatment to see if there’s a clinical benefit.
Dr Mikovits: So I’ll just comment on that.
So I think that what the group back there and what we were saying is,
we have identified hundreds of certified XMRV +ve people,
from whom we have isolated the virus, who are very sick.
And I think that the commentary that accompanied the paper last week, the Lo paper by andy mason
– in those pts who have been bedbound, have not left their house, have not had a life for 25 yrs,
the benefit far outweigh the risks of multiple therapies that we have used for now more than 25, 20 yrs in HIV-infected individuals.
Dr. Mellors: I think you’re on the right track. But I think that what’s really important in this field Judy is for your findings to be validated independently so that there are a couple of sources that agree upon your findings so that there’s not the underlying skepticism generated by 0% prevalence in people who are bedbound.
And we’ve heard several examples of that. And so yes, you’re right. But it needs to be extended beyond WPI to different groups.
Dr. Mikovits: We have independant confirmation from 3 groups doing those studies you heard of today in several posters that were not from the WPI.
But the patients exist with XMRV, with disease.
And if we could put something together with them in advance of the larger prevalence studies.
They’re infected, they’re ill, they have what you’d expect from a gammaretroviral infected associated disease – and we could begin to do clinical trials, where we crossed over infected people, and switched the drugs and looked for benefits and followed markers, followed infectious virus by assays like the Dersey assay,
we’re getting more sensitive assays, serology assays, learning about the immune response, learning about the inflammatory cytokine and chemokine profiles that we have associated with these infections.
There are significant numbers of very sick people with this virus in whom these things could be started.
Those of us following developments with ME/CFS and Lyme Disease have to wonder if only CDC, Infectious Diseases Society of America and our Health Authorities around the World had listened over the last 30 years, instead of as is the case of Lyme Disease relying on just a handfull of people denying the existence of Chronic Lyme and with ME/CFS listening to the Psychobabble, whether science would have moved forward at a much quicker pace.
Instead it has been private funding pushing science forward and patients suffering the consequences of years of denial by our Health Authorities.
Friday, 10 September 2010
Posted on the ME/CFS Forums here
and thanks to Lannie in the Lymelight for posting here
I attended and was a poster presenter at the recently completed XMRV conference at the NIH. It was fascinating and I took perhaps 30 pages of notes.
The bio-political undertones were also intense but I have to say that the presentations of XMRV association with CFS (4 presentations) were much stronger than the presentations of negative XMRV associations with CFS (4 presentations).
They were stronger specifically because of the multiple methods they employed and not just PCR.
Very interesting in this regard were comments by the head of the blood working group at the NIH who is trying to determine the cause of the discrepancy. He hinted strongly that it is the way blood is collected and processed for nucleic acids and not the detection methods for XMRV itself that divides the two groups.
In an NIH blood group sponsored study, a group comparison study with both camps represented detect successfully, in a blinded fashion, XMRV spiked buffer in varying concentrations but they nevertheless divide into two camps when clinical blood samples are taken and processed for XMRV nucleic acids.
Using only PCR, one camp sees ~80% positive in CFS and one camp sees 0% positive in CFS There is no one in between and no middle ground between the two groups which was striking and noted by Joe B. (BURRASCANO ) who was also in attendance.
There is no evidence by mouse mitochondrial DNA probes, that any of the positive associations were contaminated. However, one of the negative association speakers found non-human mouse virus MLV contamination perhaps localized to heparin tubes used for blood collection. Heparin is often produced in China where mice are common as pets. When the contamination was cleared, she found no association of XMRV with CFS.
I also wanted to share some other highlights of the conference Among them, a very interesting presentation was made by a group connected to Abbott Labs that infected male and female Macaques (monkeys closely related to man) with human XMRV to see what happens and where the virus ends up or concentrates itself.
Within a few weeks, the virus was largely cleared from blood where it was initially injected in high concentration. Even antibody response was lost over time (months) as the infection was largely removed from the blood and virus did not appear to persist in the blood.
Apparently, there was not enough viral antigen to keep antibody levels high or persistent. However, the virus was found more or less in every organ, at least initially, and thought to be carried around the body in T-cells and B-cells during the active phase of infection. This is consistent with the ubiquitous nature of the Xpr1 receptor used by the virus to gain access to almost all cells of the body.
Organs where the virus was initially most concentrated appeared to be lymphoid organs such as the spleen, liver and mesenteric nodes of the GI track and in sex organs and in particular the epithelium of the prostate gland where it was highly concentrated at first and then the infected cells later apoptosed and infection disappeared from the epithelium and then the virus was more likely to be seen in the interstitial cells in the stroma or matrix of the prostate, especially the fibroblasts which may be one reservoir in all the various organs that are initially infected.
The virus was also found in the epithelium of the cervix in the female macaque. Over time, the infections of various organs tended to be cleared by either immune mechanisms but especially by restriction enzyme systems present in almost all human cells that hypermutate the virus so it cannot persist as a competent infectious agent.
Indeed, mutated viral strains are almost always found in CFS cases by both Judy Mikovits at WPI and Frank Ruscetti at NCI. Sometimes this makes the virus incompetent as an infectious agent and sometimes has no effect on infectiousness.
Very interesting is that another cell that appears to be a reservoir of XMRV other then fibroblasts within tissue stroma are tissue macrophages The pulmonary alveolar macrophages were absolutely loaded with XMRV virus and other tissue macrophages could also be a potential reservoir in other tissues as well, especially in the GI tract, sex organs and sinuses.
Tissue macrophage reservoirs would be analogous with HIV as well. It would seem that bronchial secretions, nasal secretions and sex organ secretions as well as feces and urine are well positioned to help the virus to spread itself to other macaques, especially if activated.
As for activation of more or less low level or quiescent but persistent infectious virus, there seem to be several mechanisms.
The virus has both a glucocorticoid response element (GRE) and an androgen response element (ARE) in its promotor region. It also has binding regions for NK Kappa B proteins in its response elements.
In any organ with high levels of local androgenic stimulation such as the prostate and perhaps during puberty, the virus could activate. No mention was made of the effect of the predominant female sex hormones but estrogen is the equivalent androgen-like hormone in females.
As for the GRE in the promotor region, severe stress will activate the virus or the use of glucocortocoid hormones and perhaps any precursor steroid hormone such as pregnenolone.
As for the NF Kappa B sites, any strong immune response with an associated cytokine storm would also be a strong stimulant and such stimulation certainly occurs in the bronchial tree which is frequently stimulated with antigen, especially during allergy season.
Perhaps most interesting of all was what happened with the injection of a bolus of foreign peptides into macaques that had apparently completely cleared the virus from blood.
There was a huge reactivation of infectious virus in the blood proving that latent but persistent virus is just below the surface and that XMRV infection cannot be completely cleared from all reservoir sites.
The peptide injection mimics an acute infection (? borrelia or the flu), an immunization or even acute mold exposure.
The effect of XMRV infection over time was not studied in the macaque but a similar gammaretrovirus called Feline Leukemia virus (FeLV) has been well studied in cats for decades. I will in another post describe a most interesting talk at this conference by a veterinarian on the life history of infection by a gammaretrovirus in cats.
Paul Cheney, M.D.
Tuesday, 7 September 2010
About 150,000 people in the UK have ME/CFS, 15,000 of whom are children.
The condition is characterised by physical and mental exhaustion following normal activities. Symptoms can include muscle pain, sore throat, tender lymph nodes, multi-joint pain and headaches.
In the study, funded by ME Research UK and The Young ME Sufferers (Tymes) Trust, 25 children aged between seven and 14 with ME/CFS were assessed, along with 23 children of a similar age in a control group.
The report, published in the Archives of Paediatrics and Adolescent Medicine, said abnormalities were found in the blood of all the children with ME/CFS.
The results were similar to those previously identified in adults with the condition.
Samples taken from youngsters with ME/CFS contained higher than normal levels of free radicals - molecules that can damage cells, tissues and organs.
The above was reported in the BBC News see here
Below is from the original study see here
Conclusions Biomedical anomalies seen in adults with CFS/ME—increased oxidative stress and increased white blood cell apoptosis—can also be observed in children with clinically diagnosed CFS/ME compared with matched controls. Unlike in their adult counterparts, however, arterial stiffness remained within the reference range in these pediatric patients.
Discussions on the BBC Breakfast news this morning revolve around this indicating a virus - I could be wrong but the study does not differentiate as to the cause of infection so assumption that is viral rather than bacterial would appear premature.
How many of these children were tested thoroughly for such as Lyme Disease and the many known co infections that are being found to go hand in hand with Tick Borne illness.
Nevertheless it is excellent to see this research that takes us one step closer to finding the cause of ME/CFS in some patients what a pity the media didn't pay as much attention to the research findings of XMRV and MLV's .
Monday, 6 September 2010
Michael D. Parent
There is an abundance of evidence demonstrating that Borrelia Burgdorferi, the causative agent of Lyme Disease, and related pathogenic species, can persist within specific body tissues and cells of various mammals despite adequate antibiotic therapy: ponies [93.5, 111.5], non-human primates [50, 86], dogs [65.5, 70, 80, 81, 82, 84], mice [44, 62, 88, 100, 107, 108, 110, 114], and humans [all others].
There is also abundant evidence that Borrelia Burgdorferi has evolved in a manner similar to other bacteria that evade the immune system via pleomorphic modification, in other words, the bacteria can change its shape beyond the conventional spirochetal form [45, 55, 61, 64, 90, 105, 109, 113].
L-forms, and cystic Borrelia have been identified in a number of studies [45, 68, 77, 87, 105, 109, 112, 113].
When these "forms" are exposed to the typical antibiotics, such as Penicillin family antibiotics or Doxycycline, they are unaffected. When the antibiotic is removed from the environment, the bacterium will alter its form once more, morphing back into a spiral form, allowing ongoing mobility [45, 68, 87, 90, 105, 109].
I have taken the time to "bold" the conclusions and various other aspects that clearly indicate a deviation from the point of view given by a number of physicians and researchers who deny the possibility of ongoing chronic infection within the human host.
The current guidelines issued by the Infectious Disease Society Of America (IDSA) are consistently used to dismiss further discussion regarding the subject of persistence. The guidelines are titled: “The Clinical Assessment, Treatment, and Prevention of Lyme Disease, Human Granulocytic Anaplasmosis, and Babesiosis” Clinical Infectious Diseases 2006; 43:1089–134.
Patients who receive a diagnosis of Lyme Disease, either based on clinical observation and/or objective indicators often improve with antibiotic therapy [1, 4, 18, 19, 26, 33, 66].
However, if they have been undiagnosed and untreated for Lyme Disease for a long period of time, it often takes longer courses of antibiotics beyond those currently recommended to see progress in symptom reduction [15, 66, 73, 93, 105].
The U.S. National Institute Of Health funded a number of randomized double-blind placebo-controlled trials (RCT) regarding the long term treatment of Lyme Disease.
However, these RCT's were 3 months in duration or less.
Patients with documented medical records indicating Chronic Lyme Disease or a Lyme-Like Illness who have been untreated often do not see meaningful improvement until after 4-6 months of treatment, and even still, the improvements are modest initially in many patients and may require an ongoing open ended treatment regimen with antibiotics [66, 93].
It is well understood and agreed upon universally that the more time Borrelia Burdorferi has had to disseminate into various ligaments, bones, collagen, muscles, and other tissues, then the higher the probability of ongoing complications or symptoms post-antibiotic therapy.
Presently, studies indicate that antibiotics can not access many of the areas that Borrelia Burgdorferi disseminates to unless the bacterium itself leaves the safe haven of a Fibroblast skin cell [11, 22, 23, 24, 25, 29, 35, 52, 64, 70, 72, 80, 81, 84, 94], or synovial tissue cells and fluid [1, 7, 9, 31, 34, 37, 42, 60, 61, 69, 70, 71, 102].
Therefore, we have studies demonstrating abundant persistence.
We have National Institute Of Health funded studies that do not treat patients long enough to confirm whether the treatment really is effective or not.
The short term studies we do have contradict other studies as well as those based on clinical reports from health care providers treating these patients with antibiotics beyond the currently accepted time frame.
It is unwise for the IDSA to claim that long-term antibiotic therapy doesn't work when you've only performed a study for 3 months, when the vast majority of the patients in the study have had the infection for many years and require at least 3-6 months of oral antibiotic before clinical improvements are seen.
IV antibiotics may demonstrate minor to moderate symptomatic improvement after 1- 3 months, but if that treatment is only given for 3 months and then discontinued, then it will be equally ineffective and the symptoms will return to pre-treatment levels. Coincidentally, that's exactly what happened in Dr. Brian Fallon's study. Some symptoms improved, but then returned upon discontinuing therapy.
I have discussed merely one specific possibility for the failure of patients to thrive and improve during the currently available randomized double-blind placebo-controlled clinical trials (RCT). Dr. Daniel J. Cameron writes in the Journal Of Medical Hypothesis that a number of limitations exist within the currently structured (RCTs), that strongly support the position I've laid forth. Med Hypotheses. 2009 Jun;72(6):688-91. Epub 2009 Mar 5. Insufficient evidence to deny antibiotic treatment to chronic Lyme disease patients. First Medical Associates, Medicine, 175 Main Street, Mount Kisco, NY 10549, USA. Cameron@LymeProject.com
"Evidence for the hypothesis: There are eight limitations that support the hypothesis: (1) the power of the evidence is inadequate to draw definite conclusions, (2) the evidence is too heterogeneous to make strong recommendations, (3) the risk to an individual of facing a long-term debilitating illness has not been considered, (4) the risk to society of a growing chronically ill population has not been considered, (5) treatment delay has not been considered as a confounder, (6) co-infections have not been considered as a confounder, (7) the design of RCTs did not address the range of treatment options in an actual practice, and (8) the findings cannot be generalized to actual practice. Implications of the hypothesis: This hypothesis suggests that physicians should consider the limitations of the evidence before denying antibiotic treatment for Chronic Lyme Disease (CLD). Physicians who deny antibiotic treatment to CLD patients might inform their patients that there are some clinicians who disagree with that position, and then offer to refer them for a second opinion to a doctor who could potentially present a different point of view. The hypothesis also suggests that health care insurers should consider the limitations of the evidence before adopting policies that routinely deny antibiotic treatment for CLD patients and should expand coverage of CLD to include clinical discretion for specific clinical situations."
There is more than enough information to justify at least a neutral position in respect to whether Borrelia Burgdorferi and related infectious species persist in human beings despite the Infectious Disease Society Of America's recommendations. Due to this uncertainty, treating physicians can not conclusively deny that persistence in human beings may be more problematic than assumed.
The scientific studies available on Lyme Disease contradict each other to a significant degree. Many study authors state in no uncertain terms that the discussion of Lyme Disease is a closed case. I disagree. The evidence disagrees. The Chief Medical Officer in the United Kingdom echoed the sentiments of the IDSA in 2009 stating: "There is no biological evidence of symptomatic chronic Lyme disease amongst those who have received the recommended treatment regimen." - CMO, Autum 2009, Issue 49, pg. 4. The IDSA states: "To date, there is no convincing biologic evidence for the existence of symptomatic chronic B. burgdorferi infection among patients after receipt of recommended treatment regimens for Lyme disease." - Clin Infect Dis 2006 Nov 1;43(9):1089-134
Skepticism is the heart of science. Cynicism is the death of reason.
The following studies are organized by year, page, and study title within the Study table index.
Study Table Index:
1986 page 18
Ann Intern Med. 1986 Jun;104,6:798-800. Borrelia burgdorferi in joint fluid in chronic Lyme arthritis. Snydman DR, Schenkein DP, Berardi VP, Lastavica CC, Pariser KM.
J Am Acad Dermatol. 1986 Sep;15,3:459-63.Treating erythema chronicum migrans of Lyme disease. Berger BW.
1987 page 18
Arthritis Rheum. 1987 Apr;30,4:448-50.Failure of tetracycline therapy in early Lyme disease. Dattwyler RJ, Halperin JJ.
1987 page 19
Arthritis Rheum. 1987 Jun;30,6:705-8. Lyme meningoencephalitis: report of a severe, penicillin-re sistant case. Diringer MN, Halperin JJ, Dattwyler RJ.
1988 page 19
Pediatr Infect Dis J. 1988 Apr;7,4:286-9. Borrelia burgdorferi in a newborn despite oral penicillin for Lyme borreliosis during pregnancy. Weber K, Bratzke HJ, Neubert U, Wilske B, Duray PH.
1988 page 19
Ann N Y Acad Sci. 1988;539:346-51. Treatment of erythema chronicum migrans of Lyme disease. Berger BW. Department of Dermatology, New York University School of Medicine, New York 10016.
1988 page 20
Arthritis Rheum. 1988 Apr;31,4:487-95. Spirochetal antigens and lymphoid cell surface markers in Lyme synovitis. Comparison with rheumatoid synovium and tonsillar lymphoid tissue. Steere AC, Duray PH, Butcher EC.
1988 page 20
AMA. 1988 May 13;259,18:2737-9 Fatal adult respiratory distress syndrome in a patient with Lyme disease. Kirsch M, Ruben FL, Steere AC, Duray PH, Norden CW, Winkelstein A.
1988 page 20
J Infect Dis. 1988 Oct;158,4:905-6. Cultivation of Borrelia burgdorferi from joint fluid three months after treatment of facial palsy due to Lyme borreliosis. Schmidli J, Hunziker T, Moesli P, Schaad UB.
1988 page 21
N Engl J Med. 1988 Dec 1;319,22:1441-6. Comment in: N Engl J Med. 1989 May 11;320,19:1279-80.Seronegative Lyme disease. Dissociation of specific T- and B-lymphocyte responses to Borrelia burgdorferi. Dattwyler RJ, Volkman DJ, Luft BJ, Halperin JJ, Thomas J, Golightly MG.
1989 page 21
Am J Clin Pathol. 1989 Jan;91,1:95 7. Spirochetes in the spleen of a patient with chronic Lyme disease. Cimmino MA, Azzolini A, Tobia F, Pesce CM Istituto Scientifico di Medicina Interna, Università di Genova, Italy.
1989 page 22
Conn Med. 1989 Jun;53,6:335-7. Treatment of Lyme disease. Schoen RT.
1989 page 22
Infection. 1989 Jul-Aug;17,4:216-7. High-dose intravenous penicillin G does not prevent further progression in early neurological manifestation of Lyme borreliosis. Kohler J, Schneider H, Vogt A.
1989 page 22
Dtsch Med Wochenschr. 1989 Oct 20;114,42:1602-6. Neuro-borreliosis or intervertebral disk prolapse? [Article in German] Dieterle L, Kubina FG, Staudacher T, Büdingen HJ.
1989 page 23
Infection. 1989 Nov-Dec;17,6:355-9.Survival of Borrelia burgdorferi in antibiotically treated patients with Lyme borreliosis. Preac-Mursic V, Weber K, Pfister HW, Wilske B, Gross B, Baumann A, Prokop J. Neurologische Klinik Grosshadern, München, FR Germany.
1990 page 23
Acta Trop. 1990 Dec;48, 2:89-94.Clinical implications of delayed growth of the Lyme borreliosis spirochete, Borrelia burgdorferi. MacDonald AB, Berger BW, Schwan TG.
Department of Pathology, Southampton Hospital, New York 11968.
1991 page 24
Infect Immun. 1991 Feb;59,2:671-8. Intracellular localization of Borrelia burgdorferi within human endothelial cells. Ma Y, Sturrock A, Weis JJ.
1991: Journal of Infectious Diseases, Feb;163,2:311-8 Randomized comparison of ceftriaxone and cefotaxime in Lyme neuroborreliosis. Pfister HW, Preac-Mursic V, Wilske B, Schielke E, SÃrgel F, EinhÃ¤upl KM.
1991 page 25
Medicine, Baltimore. 1991 Mar;70,2:83-90. Lyme disease: clinical features, classification, and epidemiology in the upper midwest. Agger W, Case KL, Bryant GL, Callister SM.
1991 page 25
N Engl J Med. 1991 Apr 18;324(16):1137. Chronic neurologic manifestations of Lyme disease. Logigian EL, Kaplan RF, Steere AC. Department of Neurology, Tufts University School of Medicine, Boston, MA 02111.
1991 page 26
Arthritis Rheum. 1991 Aug;34,8:1056-60. Treatment of refractory chronic Lyme arthritis with arthroscopic synovectomy. Schoen RT, Aversa JM, Rahn DW, Steere AC.
1992 page 26
Clin Exp Rheumatol. 1992 Jul-Aug;10,4:387-90. Molecular detection of persistent Borrelia burgdorferi in a man with dermatomyositis. Fraser DD, Kong LI, Miller FW.
1992 page 27
J Infect Dis. 1992 Aug;166,2:440-4.Fibroblasts protect the Lyme disease spirochete, Borrelia burgdorferi, from ceftriaxone in vitro. Georgilis K, Peacocke M, Klempner MS. Department of Medicine, New England Medical Center, Boston, Massachusetts.
1993 page 27
J Am Acad Dermatol. 1993 Feb;28,2 Pt 2:312-4. Recurrent erythema migrans despite extended antibiotic treatment with minocycline in a patient with persisting Borrelia burgdorferi infection. Liegner KB, Shapiro JR, Ramsay D, Halperin AJ, Hogrefe W, Kong L.
1993 page 27
J Infect Dis. 1993 May;167,5:1074-81.Invasion of human skin fibroblasts by the Lyme disease spirochete, Borrelia burgdorferi. Klempner MS, Noring R, Rogers RA.
1993 page 28
Infection. 1993 Mar-Apr;21,2:83-8. Azithromycin versus doxycycli ne for treatment of erythema migrans: clinical and microbiological findings. Strle F, Preac-Mursic V, Cimperman J, Ruzic E, Maraspin V, Jereb M.
1993 page 29
J Neurol. 1993 May;240,5:278-83. Borrelia burgdorferi myositis: report of eight patients. Reimers CD, de Koning J, Neubert U, Preac-Mursic V, Koster JG, Müller-Felber W, Pongratz DE, Duray PH.
1993 page 30
Arthritis Rheum. 1993 Nov;36,11:1621 6. Persistence of Borrelia burgdorferi in ligamentous tissue from a patient with chronic Lyme borreliosis. Häupl T, Hahn G, Rittig M, Krause A, Schoerner C, Schönherr U, Kalden JR, Burmester GR.
1993 page 30
J Clin Neuroophthalmol. 1993 Sep;13,3:155-61; discussion 162. 59: First isolation of Borrelia burgdorferi from an iris biopsy. Preac-Mursic V, Pfister HW, Spiegel H, Burk R, Wilske B, Reinhardt S, Böhmer R.
1993 page 31
Cent Eur J Public Health. 1993 Dec;1,2:81-5. Electron microscopy and the polymerase chain reaction of spirochetes from the blood of patients with Lyme disease. Hulínská D, Krausová M, Janovská D, Rohácová H, Hancil J, Mailer H.
1993 page 32
Neurology. 1993 Dec;43,12:2705-7. Stroke due to Lyme disease. Reik L Jr. Department of Neurology, University of Connecticut Health Center, Farmington 06030-1845.
1994 page 32
N Engl J Med. 1994 Jan 27; 330,4:282-3.Detection of Borrelia burgdorferi DNA by polymerase chain reaction in synovial fluid from patients with Lyme arthritis. Nocton JJ, Dressler F, Rutledge BJ, Rys PN, Persing DH, Steere AC.
1994 page 33
J Clin Microbiol. 1994 Mar;32,3:715-20.Isolation of Borrelia burgdorferi from biopsy specimens taken from healthy-looking skin of patients with Lyme borreliosis. Kuiper H, van Dam AP, Spanjaard L, de Jongh BM, Widjojokusumo A, Ramselaar TC, Cairo I, Vos K, Dankert J. Department of Medical Microbiology, Academic Medical Centre, University Hospital, University of Amsterdam, The Netherlands.
1994 page 33
J Rheumatol. 1994 Mar;21,3:454-61. Lyme disease: an infectious and postinfectious syndrome.Asch ES, Bujak DI, Weiss M, Peterson MG, Weinstein A.
1994 page 34
Ann Intern Med. 1994 Mar 15;120,6:487-9. The persistence of spirochetal nucleic acids in active Lyme arthritis. Bradley JF, Johnson RC, Goodman JL.
1994 page 34
Ann Intern Med. 1994 Oct 15;121,8:560-7.The long-term clinical outcomes of Lyme disease. A population-based retrospective cohort study. Shadick NA, Phillips CB, Logigian EL, Steere AC, Kaplan RF, Berardi VP, Duray PH, Larson MG, Wright EA, Ginsburg KS, Katz JN, Liang MH.
1994 page 35
Infect. 1994 Nov;29,3:255-61.Treatment of late Lyme borreliosis. Wahlberg P, Granlund H, Nyman D, Panelius J, Seppälä I.
1994 page 36
Late complaints after erythema migrans Herta Klade, MD and Elizabeth Aberer, MD. JSTD 1994; 1:52-56.
1994 page 36
Borrelia burgdorferi - Seek and ye shall find. Expanding the envelope Kenneth Liegner, MD. JSTD 1994; 1:79-81.
1994 page 37
Psychiatric aspects of Lyme disease in children and adolescents: A community epidemiologic study in Westchester, New York Brian A. Fallon, MD, MPH; Hector Bird, MD; Christina Hoven, DrPH; Daniel Cameron, MD, MPH; Michael R. Liebowitz, MD; and David Shaffer, MD. JSTD 1994; 1:98-100.
1994 page 37
Persistence of Borrelia burgdorferi despite antibiotic treatment Michael A. Patmas, MD. JSTD 1994; 1:101.
1994 page 38
J Infect Dis. 1994 Nov;170,5:1312-6 Comment in: J Infect Dis. 1995 May;171,5:1379-80. Fate of Borrelia burgdorferi DNA in tissues of infected mice after antibiotic treatment. Malawista SE, Barthold SW, Persing DH. Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut.
1995 page 39
Antimicrob Agents Chemother. 1995 May;39,5:1127-33. Effects of penicillin, ceftriaxone, and doxycycline on morphology of Borrelia burgdorferi. Kersten A, Poitschek C, Rauch S, Aberer E.
1995 page 40
Persistent PCR positivity in a patient being treated for Lyme disease. Kornelia Keszler, MD and Richard C. Tilton, PhD. JSTD 1995; 2:57-58.
1995 page 40
Neuroborreliosis in Texas Audrey Stein Goldings, MD. JSTD 1995; 2:59-61.
1995 page 40
Vartiovaara I. 1995 Living with Lyme. Lancet, 345:842-4 A Finnish physician ’s account of his experiences that beginning with a tick bite in Vancouver in 1987.
1995 page 40
J Neuropsychiatry Clin Neurosci. 1995 Summer;7,3:345-7. Rapidly progressive frontal-type dementia associated with Lyme disease. Waniek C, Prohovnik I, Kaufman MA, Dwork AJ.
1995 page 41
Ann Neurol. 1995 Oct;38,4:667-9. Comment in: Ann Neurol. 1995 Oct;38,4:560-2.Neuroborreliosis in the nonhuman primate: Borrelia burgdorferi persists in the central nervous system. Pachner AR, Delaney E, O'Neill T.
Eur Neurol. 1995;35,2:113-7. Comment in: Eur Neurol. 1996;36,6:394-5. Seronegative chronic relapsing neuroborreliosis.Lawrence C, Lipton RB, Lowy FD, Coyle PK.
Infection. 1996 Jan-Feb;24,1:64-8. Azithromycin and doxycycline for treatment of Borrelia culture-positive erythema migrans. Strle F, Maraspin V, Lotric-Furlan S, Ruzić-Sabljić E, Cimperman J.
Infection. 1996 Jan-Feb;24,1:9-16. Erratum in: Infection 1996 Mar-Apr;24,2:169.Kill kinetics of Borrelia burgdorferi and bacterial findings in relation to the treatment of Lyme borreliosis. Preac Mursic V, Marget W, Busch U, Pleterski Rigler D, Hagl S. Max v. Pettenkofer Institut, Ludwig-Maximilians-Universität München, Germany.
Infection. 1996 Jan-Feb;24,1:73-5. Treatment failure in erythema migrans--a review. Weber K. Dermatologische Privatpraxis, München, Germany.
Infection. 1996 May-Jun;24,3:218-26. Erratum in: Infection 1996 Jul-Aug;24,4:335. Formation and cultivation of Borrelia burgdorferi spheroplast-L-form variants. Mursic VP, Wanner G, Reinhardt S, Wilske B, Busch U, Marget W.
JAMA. 1996 Jun 5; 275,21, :1657-60. Concurrent Lyme disease and babesiosis. Evidence for increased severity and duration of illness. K rause PJ, Telford SR 3rd, Spielman A, Sikand V, Ryan R, Christianson D, Burke G, Brassard P, Pollack R, Peck J, Persing DH.
Antimicrob Agents Chemother. 1996 Jun;40,6:1552-4. Eucaryotic cells protect Borrelia burgdorferi from the action of penicillin and ceftriaxone but not from the action of doxycycline and erythromycin. Brouqui P, Badiaga S, Raoult D. Unité des Rickettsies, Faculté de Médecine, Centre National de la Recherche Scientifique, Marseille, France.
Infection. 1996 Sep-Oct;24,5:347-53.Borrelia burgdorferi DNA in the urine of treated patients with chronic Lyme disease symptoms. A PCR study of 97 cases. Bayer ME, Zhang L, Bayer MH. Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Hum Pathol. 1996 Oct;27,10:1025-34.Ultrastructural demonstration of spirochetal antigens in synovial fluid and synovial membrane in chronic Lyme disease: possible factors contributing to persistence of organisms. Nanagara R, Duray PH, Schumacher HR Jr. Allergy-Immunology-Rheumatology Division, Department of Medicine, Faculty of Medicine, KhonKaen University, Thailand.
Rheumatol Int. 1996;16,3:125-32.Intracellular persistence of Borrelia burgdorferi in human synovial cells. Girschick HJ, Huppertz HI, Rüssmann H, Krenn V, Karch H.
Antimicrob Agents Chemother. 1996 Nov;40 11 :2632-6.In vivo activities of ceftriaxone and vancomycin against Borrelia spp in the mouse brain and other sites. Kazragis RJ, Dever LL, Jorgensen JH, Barbour AG.
Brain. 1996 Dec;119, Pt 6:2143-54. Inflammatory brain changes in Lyme borreliosis. A report on three patients and review of literature. Oksi J, Kalimo H, Marttila RJ, Marjamäki M, Sonninen P, Nikoskelainen J, Viljanen MK.
Am J Dermatopathol. 1996 Dec;18,6:571-9. Heterogeneity of Borrelia burgdorferi in the skin. Aberer E, Kersten A, Klade H, Poitschek C, Jurecka W.
328: Semin Neurol. 1997 Mar;17,1:25-30.Peripheral nervous system Lyme borreliosis. Logigian EL.
J Clin Microbiol. 1997 January; 35(1): 111–116. Persistence of Borrelia burgdorferi in experimentally infected dogs after antibiotic treatment. R K Straubinger, B A Summers, Y F Chang, and M J Appel Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853, USA. firstname.lastname@example.org
Clin Infect Dis. 1997 Jul;25 Suppl 1:S52-6. Tetracycline therapy for chronic Lyme disease. Donta ST.
Clin Infect Dis. 1997 Jul;25 Suppl 1:S64-70.Why is chronic Lyme borreliosis chronic? Aberer E, Koszik F, Silberer M.
American College of Rheumatology, Vol 40,9, Branigan P; Rao J; 1997 PCR evidence for Borrelia burgdorferi DNA in synovium in absence of positive serology. Suppl, Rao J; Gerard H; Sept, p.S270 Hudson A; Williams W; Arayssi T; Pando J; Bayer M; Rothfuss S; .PCR evidence for Borrelia has been identified in synovial biopsies of patients with clinical pictures that had not initially suggested Lyme disease. Clayburne G; Sieck M; Schumacher HR.
Journal of Spirochetal & Tick-borne Diseases, Vol. 4, No. 1/2 Two lessons from the canine model of Lyme Disease: migration of Borrelia burgdorferi in tissues and persistence after antibiotic treatment. Straubinger RK; 1997 Straubinger AF; Jacobson RH; Chang Y; Summer BA;
Ann Rheum Dis. 1998 Feb;57,2:118-21.Detection of Borrelia burgdorferi by polymerase chain reaction in synovial membrane, but not in synovial fluid from patients with persisting Lyme arthritis after antibiotic therapy. Priem S, Burmester GR, Kamradt T, Wolbart K, Rittig MG, Krause A.
Med J Aust. 1998 May 18;168,10:500-2. Comment in: Med J Aust. 1998 May 18;168,10:479-80. Culture-positive Lyme borreliosis. Hudson BJ, Stewart M, Lennox VA, Fukunaga M, Yabuki M, Macorison H, Kitchener-Smith J.
Acta Clin Belg. 1998 Jun;53,3:178-83.Lyme borreliosis--a review of the late stages and treatment of four cases. Petrovic M, Vogelaers D, Van Renterghem L, Carton D, De Reuck J, Afs chrift M. Department of Internal Medicine, University Hospital Ghent, Belgium.
Eur J Clin Microbiol Infect Dis. 1998 Oct;17,10:715-9.Comparison of oral cefixime and intravenous ceftriaxone followed by oral amoxicillin in disseminated Lyme borreliosis. Oksi J, Nikoskelainen J, Viljanen MK. Department of Medicine, Turku University Central Hospital, Finland.
Neurology. 1998 Nov;51,5:1489-91. Comment in: Neurology. 1999 Sep 11;53,4:895-6. Clinical and serologic follow-up in patients with neuroborreliosis. Treib J, Fernandez A, Haass A, Grauer MT, Holzer G, Woessner R.
Infection. 1998 Nov-Dec; 26,6:364-7.A proposal for the reliable culture of Borrelia burgdorferi from patients with chronic Lyme disease, even from those previously aggressively treated. Phillips SE, Mattman LH, Hulínská D, Moayad H. Greenwich Hospital, CT 06830, USA.
Klin Monatsbl Augenheilkd. 1998 Dec;213,6:351-4. Pars plana vitrectomy in Borrelia burgdorferi endophthalmitis [Article in German] Meier P, Blatz R, Gau M, Spencker FB, Wiedemann P.
Ann Med. 1999 Jun; 3,3:225-32. Borrelia burgdorferi detected by culture and PCR in clinical relapse of disseminated Lyme borreliosis. Oksi J, Marjamäki M, Nikoskelainen J, Viljanen MK.
Zentralbl Bakteriol. 1999 Jul;289,3:301-18. Persistence of Borrelia garinii and Borrelia afzelii in patients with Lyme arthritis. Hulínská D, Votýpka J, Valeso vá M.
J Infect Dis. 2000 Mar;181,3:1069-81. Status of Borrelia burgdorferi infection after antibiotic treatment and the effects of corticosteroids: An experimental study. Straubinger RK, Straubinger AF, Summers BA, Jacobson RH.
J Clin Microbiol. 2000 Jun; 38,6, :2191-9. PCR-Based quantification of Borrelia burgdorferi organisms in canine tissues over a 500-Day postinfection period. Straubinger RK. James A. Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853, USA. email@example.com
Br J Dermatol. 2001 Feb;144,2:387-92. Is olation and polymerase chain reaction typing of Borrelia afzelii from a skin lesion in a seronegative patient with generalized ulcerating bullous lichen sclerosus et atrophicus. Breier F, Khanakah G, Stanek G, Kunz G, Aberer E, Schmidt B, Tappeiner G.
Epidemiol Mikrobiol Imunol. 2001 Feb;50,1:10-6.Persistence of Borrelia burgdorferi sensu lato in patients with Lyme borreliosis [Article in Czech] Honegr K, Hulínská D, Dostál V, Gebouský P, Hanková E, Horácek J, Vyslouzil L, Havlasová J. Infekcní klinika, Fakultní nemocnice, Hradec Králové.
Ann Neurol. 2001 Sep;50,3, :330-8.Central and peripheral nervous system infection, immunity, and inflammation in the NHP model of Lyme borreliosis. Pachner AR, Cadavid D, Shu G, Dail D, Pachner S, Hodzic E, Barthold SW. Department of Neurosciences, UMDNJ-New Jersey Medical School, Newark 07103, USA. firstname.lastname@example.org
Wien Klin Wochenschr. 2002 Jul 31;114,13-14:574-9. Cystic forms of Borrelia burgdorferi sensu lato: induction, development, and the role of RpoS. Murgia R, Piazzetta C, Cinco M.
Acta Neurol Scand. 2002 Oct;106(4):205-8. Chronic symptoms are common in patients with neuroborreliosis -- a questionnaire follow-up study. Vrethem M, Hellblom L, Widlund M, Ahl M, Danielsson O, Ernerudh J, Forsberg P.
J Infect Dis. 2002 Nov 15;186,10:1430-7. Epub 2002 Oct 23. Detection of attenuated, noninfectious spirochetes in Borrelia burgdorferi-infected mice after antibiotic treatment. Bockenstedt LK, Mao J, Hodzic E, Barthold SW, Fish D.
Antimicrob Agents Chemother. 2002 Nov;46,11:3637-40. Erythromycin resistance in Borrelia burgdorferi. Terekhova D, Sartakova ML, Wormser GP, Schwartz I, Cabello FC.
Przegl Epidemiol. 2002;56 Suppl 1:57-67.New aspects of the pathogenesis of lyme disease [Article in Polish] Zajkowska JM, Hermanowska-Szpakowicz T. Klinika Chorób Zakaźnych i Neuroinfekcji AM w Bia ymstoku.
Neurology. 2003 Jun 24;60,12:1923-30. Comment in: Neurology. 2003 Jun 24;60,12:1888-9.Study and treatment of post Lyme di sease, STOP-LD: a randomized double masked clinical trial. Krupp LB, Hyman LG, Grimson R, Coyle PK, Melville P, Ahnn S, Dattwyler R, Chandler B.
Med Sci Monit. 2003 Nov;9,11:PI136-42. Macrolide therapy of chronic Lyme Disease. Donta ST.
Vet Microbiol. 2005 May 20;107(3-4):285-94 Antibiotic treatment of experimentally Borrelia burgdorferi-infected ponies. Chang YF, Ku YW, Chang CF, Chang CD, McDonough SP, Divers T, Pough M, Torres A. College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA. email@example.com
Int J Antimicrob Agents. 2005 Jun;25,6:474-8. Susceptibility of Borrelia afzelii strains to antimicrobial agents. Ruzić-Sabljić E, Podreka T, Maraspin V, Strle F.
Int J Med Microbiol. 2006 May;296 Suppl 40:233-41. Epub 2006 Mar 10.Risk of culture-confirmed borrelial persistence in patients treated for erythema migrans and possible mechanisms of resistance. Hunfeld KP, Ruzić-Sabljić E, Norris DE, Kraiczy P, Strle F. Institute of Medical Microbiology, University Hospital of Frankfurt, Paul-Ehrlich Str. 40, D-60596 Frankfurt/Main, Germany. K.Hunfeld@em.uni-frankfurt.de
Eur J Pediatr. 2006 Jun;165,6:420-1. Epub 2006 Mar 4. Persistent synovitis in two children with Lyme arthritis linked with HLA-DRB1*1104. Hendrickx G, Demanet C, Vandenplas Y. Department of Paediatrics, Paediatric Orthopaedic and Rheumatology Unit, Academisch Ziekenhuis -Vrije Universiteit Brussel, Laarbeeklaan 101, 1090 Brussels, Belgium. firstname.lastname@example.org
Int J Immunopathol Pharmacol. 2006 Jul-Sep;19,3:545-9. In vitro susceptibility of isolates of Borrelia burgdorferi s.l. to antimicrobial agents. Santino I, Scazzocchio F, Ciceroni L, Ciarrocchi S, Sessa R, Del Piano M. Department of Public Health Sciences, La Sapienza University, Rome, Italy. email@example.com
Microbes Infect. 2006 Nov-Dec; 8,14-15:2832-40. Epub 2006 Sep 22.Invasion of human neuronal and glial cells by an infectious strain of Borrelia burgdorferi. Livengood JA, Gilmore RD Jr.
Acta Radiologica, Volume 48, Issue 7 2007 , pages 755 - 762 Brain Magnetic Resonance Imaging Does Not Contribute to the Diagnosis of Chronic Neuroborreliosis. Aalto A, Sjöwall J, Davidsson L, Forsberg P, Smedby O. Division of Radiology, Department of Medicine and Care, Faculty of Health Sciences, Linköping University, Linköping, Sweden. firstname.lastname@example.org
Pol Merkur Lekarski. 2007 Apr;22,130:275-9. Related Articles, Concentrations of pro-inflammatory cytokines IFN-gamma, IL-6, IL-12 and IL-15 in serum and cerebrospinal fluid in patients with neuroborreliosis undergoing antibiotic treatment. Article in Polish. Pancewicz SA, Kondrusik M, Zajkowska J, Grygorczuk S. Akademia Medyczna w Bialymstoku, Klinika ChorÃ³b Zakaznych i Neuroinfekcji.email@example.com
J Infect Dis. 2007 May 15;195,10:1489-96. Epub 2007 Apr 6.Anti-tumor necrosis factor-alpha treatment activates Borrelia burgdorferi spirochetes 4 weeks after ceftriaxone treatment in C3H/He mice. Yrjänäinen H, Hytönen J, Song XY, Oksi J, Hartiala K, Viljanen MK. Department of Medical Microbiology, University of Turku, Turku, 20520, Finland. firstname.lastname@example.org
Adv Med Sci. 2007;52:174-8. Concentration of TGF-beta1 in the supernatant of peripheral blood mononuclear cells cultures from patients with early disseminated and chronic lyme borreliosis. Grygorczuk S, Chmielewski T, Zajkowska J, Swierzbińska R, Pancewicz S, Kondrusik M, Tylewska-Wierzbanowska S, Hermanowska-Szpakowicz T. Department of Infectious Diseases and Neuroinfections, Medical University of Białystok, ul. Zurawia 14, 15-540 Białystok, Poland. email@example.com
Rheumatol Int. 2007 Sep;27,11:1091-3. Epub 2007 Apr 4. Seronegative Lyme arthritis. Holl-Wieden A, Suerbaum S, Girschick HJ. Children's hospital, Section of Pediatric Rheumatology, Immunology and Infectious diseases, University of Wuerzburg, Josef-Schneider-Str. 2, 97090 Wuerzburg, Germany.
Pol Merkur Lekarski. 2007 Sep;23,135:174-8. Concentration of soluble forms of selectins in serum and in cerebrospinal fluid in group of patients with neuroborreliosis--a preliminary study Moniuszko AM, Pancewicz SA, Ko ndrusik M, Zajkowska J, Grygorczuk S, Swierzbińska R. Akademia Medyczna w Białymstoku, Klinika Chorób Zakaźnych i Neuroinfekcji.
Volume 358:428-431 January 24, 2008 Number An Appraisal of "Chronic Lyme Disease" To the Editor: Feder et al., Oct. 4 issue,
Persistence of Borrelia burgdorferi Following Antibiotic Treatment in Mice Antimicrobial Agents and Chemotherapy, published online ahead of print on 3 March 2008 Emir Hodzic, Sunlian Feng, Kevin Holden, Kimberly J. Freet, and Stephen W. Barthold
Antimicrobial Agents and Chemotherapy, May 2008, p. 1728-1736, Vol. 52, No. 50066-4804 Persistence of Borrelia burgdorferi following Antibiotic Treatment in Mice Emir Hodzic, Sunlian Feng, Kevin Holden, Kimberly J. Freet, and Stephen W. Barthold*
Pol Arch Med Wewn. 2008 May;118 5:314-7. : Neuroborreliosis with extrapyramidal symptoms: a case report. Biesiada G, Czapiel J, Sobczyk-Krupiarz I, Garlicki A, Mach T. Department of Infectious Diseases, Division of Gastroenterology, Hepatology, and Infectious Diseases, Jagiellonian University School of Medicine, Kraków, Poland. firstname.lastname@example.org
J Neuroinflammation. 2008 Sep 25;5:40. Persisting atypical and cystic forms of Borrelia burgdorferi and local inflammation in Lyme neuroborreliosis. Miklossy J, Kasas S, Zurn AD, McCall S, Yu S, McGeer PL.
Microb Pathog. 2008 Sep 20. Borrelia burgdorferi expression of the bba64, bba65, bba66, and bba73 genes in tissues during persistent infection in mice. Gilmore RD Jr, Howison RR, Schmit VL, Carroll JA.
Med Hypotheses. 2008;70,5:967-74. Epub 2007 Nov 5. The association between tick-borne infections, Lyme borreliosis and autism spectrum disorders. Bransfield RC, Wulfman JS, Harvey WT, Usman AI.
Journal of Veterinary Diagnostic Investigation Vol. 20 Issue 3, 321-324 Copyright © 2008 by the American Association of Veterinary Laboratory Diagnosticians: Validation of an in-clinic enzyme-linked immunosorbent assay kit for diagnosis of Borrelia burgdorferi infection in horses. Amy L. Johnson1, Thomas J. Divers and Yung-Fu Chang
J Antimicrob Chemother. 2009 Jun;63 6:1163-72. Epub 2009 Apr 17. Assessment of methylthioadenosine/S-adenosylhomocysteine nucleosidases of Borrelia burgdorferi as targets for novel antimicrobials using a novel high-throughput method. Cornell KA, Primus S, Martinez JA, Parveen N.
Proc Natl Acad Sci U S A. 2009 Nov 3;106(44):18656-61. Epub 2009 Oct 20. Destruction of spirochete Borrelia burgdorferi round-body propagules (RBs) by the antibiotic tigecycline. Brorson Ø, Brorson SH, Scythes J, MacAllister J, Wier A, Margulis L.
Persistence of borrelial DNA in the joints of Borrelia burgdorferi-infected mice after ceftriaxone treatment HETA YRJÄNÄInen 1 , JUKKA HYTÖNen 1 , PAULIINA HARTIALA 1 , JARMO OKSI 2 and MATTI K. VILJANEN Departments of 1Medical Microbiology and Immunology and 2 Medicine, University of Turku, Turku, Finland
Evidential support for the case of Chronic Infection:
1: Ann Intern Med. 1986 Jun;104,6:798-800. Borrelia burgdorferi in joint fluid in chronic Lyme arthritis. Snydman DR, Schenkein DP, Berardi VP, Lastavica CC, Pariser KM.
Although indirect evidence suggests that chronic Lyme arthritis is caused by persistent infection with Borrelia burgdorferi, direct visualization has been lacking. We report the demonstration of B. burgdorferi from synovial fluid aspirated from the right knee of a 31-year-old man with Lyme arthritis for more than 1 year. After 6 days, culture medium inoculated with synovial fluid showed one motile and several nonmotile spirochetes. Direct immunofluorescence staining showed reactivity with anti-B. burgdorferi serum. Spirochetes were not seen in subcultured material. The patient's arthritis improved with high-dose intravenous penicillin. Identification of B. burgdorferi from the joint fluid of a patient with long-standing arthritis supports the concept that the arthritis is due to persistent infection.
2: J Am Acad Dermatol. 1986 Sep;15,3:459-63.Treating erythema chronicum migrans of Lyme disease. Berger BW.
The efficacy of antibiotic treatment of 117 patients with erythema chronicum migrans of Lyme disease was evaluated in terms of the necessity for retreatment and the prevention of the late manifestations of Lyme disease. Fifty-six patients with a minor form of the illness did not require retreatment and did not develop late manifestations following antibiotic treatment. Three pregnant patients were included in this group.Fourteen of sixty-one patients with a major form of the illness required retreatment, and five developed posttreatment late manifestations of Lyme disease consisting of Bell's palsy and persistent joint pain. Although the preferred antibiotic for treating erythema chronicum migrans of Lyme disease has not been conclusively established, tetracycline and penicillin proved effective. The use of probenecid plus penicillin may be of benefit to patients with the major form of the illness.
3: 1: Arthritis Rheum. 1987 Apr;30,4:448-50.Failure of tetracycline therapy in early Lyme disease. Dattwyler RJ, Halperin JJ.
We describe the clinical courses of 5 patients with Lyme disease who developed significant late complications, despite receiving tetracycline early in the course of their illness. All 5 patients had been treated for erythema chronicum migra ns with a course of tetracycline that met or exceeded current recommendations. The late manifestations of Lyme disease included arthritis, cranial nerve palsy, peripheral neuropathy, chronic fatigue, and changes in mental function. Our findings suggest that the use of tetracycline at a dosage of 250 mg, 4 times a day for 10 days, as a treatment for early Lyme disease should be reconsidered. To determine optimal therapy for early Lyme disease, a study that compares an increased dosage of tetracycline with alternative treatments is indicated.
4: Arthritis Rheum. 1987 Jun;30,6:705-8. Lyme meningoencephalitis: report of a severe, penicillin-re sistant case. Diringer MN, Halperin JJ, Dattwyler RJ.
Although Lyme disease frequently attacks the central nervous system, this involvement is rarely severe, and high-dose intravenous penicillin usually is adequate treatment. The patient we describe developed severe Lyme meningoencephalitis despite receiving a full course of penicillin, and his condition continued to deteriorate after reinstitution of this treatment. Intravenous chloramphenicol was used successfully and resulted in a substantial improvement.
5: Pediatr Infect Dis J. 1988 Apr;7,4:286-9. Borrelia burgdorferi in a newborn despite oral penicillin for Lyme borreliosis during pregnancy. Weber K, Bratzke HJ, Neubert U, Wilske B, Duray PH.
Department of Medicolegal Medicine, Dermatology and Microbiology, University of Munich, Federal Republic of Germany. "We now demonstrate B. burgdorferi in the brain and liver of a newborn whose mother had been treated with oral penicillin for LB [Lyme borreliosis] during the first trimester of pregnancy. ..The death of the newborn was probably due to a respiratory failure as a consequence of perinatal brain damage.”
6: Ann N Y Acad Sci. 1988;539:346-51. Treatment of erythema chronicum migrans of Lyme disease. Berger BW. Department of Dermatology, New York University School of Medicine, New York 10016.
Between June 1981 and July 1987 the efficacy of antibiotic treatment of 215 patients with erythema chronicum migrans of Lyme disease was evaluated in terms of the necessity for retreatment and the prevention of the late manifestations of Lyme disease. The principal antibiotics utilized to treat 161 patients through 1986 were varying doses of tetracycline, or penicillin alone or in combination with probenecid. Two of 8 0 patients with a minor form of the illness and 17 of 81 patients with a major form of the illness required retreatment. There were four patients who did not respond to retreatment with their original medication. A 15- to 30-day course of amoxicillin, 500 mg q.i.d., and probenecid, 500 mg q.i.d., or doxycycline, 100 mg t.i.d., and on three occasions ceftriaxone, 2-4 g/day i.v., were used to treat 54 patients in 1987. Although it is too early to judge the efficacy of treatment in these patients, increases in the incidence of Herxheimer reactions and drug eruptions were observed. Strict compliance with treatment protocols and the possibility of reactions to medications should be thoroughly discussed with patients.
7: 1: Arthritis Rheum. 1988 Apr;31,4:487-95. Spirochetal antigens and lymphoid cell surface markers in Lyme synovitis. Comparison with rheumatoid synovium and tonsillar lymphoid tissue. Steere AC, Duray PH, Butcher EC.
Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut.
Using monoclonal antibodies to spirochetal antigenes and lymphoid cell surface markers, we examined the synovial lesions of 12 patients with Lyme disease, and compared them with rheumatoid synovium and tonsillar lymphoid tissue. The synovial lesions of Lyme disease patients and rheumatoid arthritis patients were similar and often consisted of the elements found in normal organized lymphoid tissue. In both diseases, T cells, predominantly of the helper/inducer s ubset, were distributed diffusely in subsynovial lining areas, often with nodular aggregates of tightly intermixed T and B cells. IgD-bearing B cells were scattered within the aggregates, and a few follicular dendritic cells and activated germinal center B cells were sometimes present. Outside the aggregates, many plasma cells, high endothelial venules, scattered macrophages, and a few dendritic macrophages were found. HLA-DR and DQ expression was intense throughout the lesions. In 6 of the 12 patients with Lyme arthritis, but in none of those with rheumatoid arthritis, a few spirochetes and globular antigen deposits were seen in and around blood vessels in areas of lymphocytic infiltration. Thus, in Lyme arthritis, a small number of spirochetes are probably the antigenic stimulus for chronic synovial inflammation.
8: AMA. 1988 May 13;259,18:2737-9 Fatal adult respiratory distress syndrome in a patient with Lyme disease. Kirsch M, Ruben FL, Steere AC, Duray PH, Norden CW, Winkelstein A.
Department of Medicine, Montefiore Hospital, University of Pittsburgh School of Medicine, PA 15213.
A dry cough, fever, generalized maculopapular rash, and myositis developed in a 67-year-old woman; she also had markedly abnormal liver function test results. Serologic tests proved that she had an infection of recent onset with Borrelia burgdorferi, the agent that causes Lyme disease. During a two-month course of illness, her condition remained refractory to treatment with antibiotics, salicylates, and steroids. Ultimately, fatal adult respiratory distress syndrome developed; this was believed to be secondary to Lyme disease.
9: J Infect Dis. 1988 Oct;158,4:905-6. Cultivation of Borrelia burgdorferi from joint fluid three months after treatment of facial palsy due to Lyme borreliosis. Schmidli J, Hunziker T, Moesli P, Schaad UB.
Attacks typically are intermittent and last from 3 days to 12 months. The knees are affected most often, but migratory arthritis is common and other large and small joints may be involved. Only very few Borrelia strains have been cultured from joint specimens worldwide However, a high percentage of patients with Lyme arthritis, 85%, have evidence of B burgdorferi DNA, detected by PCR, in the synovial fluid The local persistence of B burgdorferi in the joint over a long period of time might be related to the exacerbations of symptoms after chondrocyte cell transplantation. B burgdorferi is difficult to detect in synovial fluid, and cultures are positive only rarely
10: 1: N Engl J Med. 1988 Dec 1;319,22:1441-6. Comment in: N Engl J Med. 1989 May 11;320,19:1279-80.Seronegative Lyme disease. Dissociation of specific T- and B-lymphocyte responses to Borrelia burgdorferi. Dattwyler RJ, Volkman DJ, Luft BJ, Halperin JJ, Thomas J, Golightly MG.
Department of Medicine, State University of New York, School of Medicine, Stony Brook 11794-8161.
The diagnosis of Lyme disease often depends on the measurement of serum antibodies to Borrelia burgdorferi, the spirochete that causes this disorder.Although prompt treatment with antibiotics may abrogate the antibody response to the infection, symptoms persist in some patients. We studied 17 patients who had presented with acute Lyme disease and received prompt treatment with oral antibiotics, but in whom chronic Lyme disease subsequently developed. Although these patients had clinically active disease, none had diagnostic levels of antibodies to B. burgdorferi on either a standard enzyme-linked immunosorbent assay or immunofluorescence assay. On Western blot analysis, the level of immunoglobulin reactivity against B. burgdorferi in serum from these patients was no greater than that in serum from normal controls. The patients had a vigorous T-cell proliferative response to whole B. burgdorferi, with a mean, +/- SEM, stimulation index of 17.8 +/- 3.3, similar to that, 15.8 +/- 3.2, in 18 patients with chronic Lyme disease who had detectable antibodies. The T-cell response of both groups was greater than that of a control group of healthy subjects, 3.1 +/- 0.5; P less than 0.001.We conclude that the presence of chronic Lyme disease cannot be excluded by the absence of antibodies against B. burgdorferi and that a specific T-cell blastogenic response to B. burgdorferi is evidence of infection in seronegative patients with clinical indications of chronic Lyme disease.
11: 1: Am J Clin Pathol. 1989 Jan;91,1:95 7. Spirochetes in the spleen of a patient with chronic Lyme disease. Cimmino MA, Azzolini A, Tobia F, Pesce CM Istituto Scientifico di Medicina Interna, Università di Genova, Italy.
A 54-year-old man had intermittent evening fever, arthralgia, transient erythematous macular eruption on the skin, and splenomegaly of two year's duration. Immunofluorescence tests for Borrelia burgdorferi serum antibodies had positive results, but G-penicillin treatment was ineffective. Splenectomy with lymph node biopsy was performed to rule out lymphoproliferative disorders. Borrelia-like spirochetes were identified histologically in the spleen; this finding was consistent with persistence of B. burgdorferi organisms in inner organs in chronic Lyme disease.
12: 1: Conn Med. 1989 Jun;53,6:335-7. Treatment of Lyme disease. Schoen RT.
Lyme disease, a tick-transmitted spirochetal infection, can be divided into three stages that can overlap or occur alone. The goals of antibiotic therapy in stage one are to shorten the duration of early disease and to prevent the development of later stages20of the illness. This can usually be accomplished with oral antibiotic therapy. Later stages of the illness are frequently more difficult to treat, requiring prolonged oral or intravenous antibiotic therapy.
13: Infection. 1989 Jul-Aug;17,4:216-7. High-dose intravenous penicillin G does not prevent further progression in early neurological manifestation of Lyme borreliosis. Kohler J, Schneider H, Vogt A.
Neurologische Universitätsklinik und Poliklinik, Freiburg.
We report two cases of Lyme borreliosis, LB, with erythema migrans, EM, and simultaneous meningopolyneuritis with radicular pain and lymphocytic pleocytosis in the cerebrospinal fluid, CSF. EM and pain disappeared completely under high-dose penicillin G therapy within few a days. Pathological findings in CSF improved. Nevertheless, during and after therapy, neurological signs of LB developed: cranial nerve palsies as well as paresis of extremity muscles with radicular distribution.
14: 1: Dtsch Med Wochenschr. 1989 Oct 20;114,42:1602-6. Neuro-borreliosis or intervertebral disk prolapse? [Article in German] Dieterle L, Kubina FG, Staudacher T, Büdingen HJ.
Abteilung für Neurologie und klinische Neurophysiologie, St.-Elisabethen-Krankenhaus Ravensburg.
Between September 1986 and November 1988, 17 patients were hospitalized and treated for neuro-borreliosis. Ten of them had been admitted with suspected lumbar or cervical root or compression syndrome. Only four patients recalled a tick bite, only three an erythema migrans. Uni- or bilateral facial paresis was a prominent feature in six patients. Three of 14 patients had no IgG antibodies against Borrelia, either in serum or cerebrospinal fluid at the initial examination, two had positive titres in serum only. Despite antibiotic treatment, usually 10 mega U penicillin three times daily, six patients had a recurrence by April, 1989, treated with penicillin again or with twice daily 100 mg doxycycline or 2 g ceftriaxon. In four of them a residual painful polyneuropathy remains.
15: 1: Infection. 1989 Nov-Dec;17,6:355-9.Survival of Borrelia burgdorferi in antibiotically treated patients with Lyme borreliosis. Preac-Mursic V, Weber K, Pfister HW, Wilske B, Gross B, Baumann A, Prokop J. Neurologische Klinik Grosshadern, München, FR Germany.
The persistence of Borrelia burgdorferi in patients treated with antibiotics is described. The diagnosis of Lyme disease is based on clinical symptoms, epidemiology and specific IgG and IgM antibody titers to B. burgdorferi in serum. Antibiotic therapy may abrogate the antibody response to the infection as shown in our patients. B. burgdorferi may persist as shown by positive culture in MKP-medium; patients may have subclinical or clinical disease without diagnostic antibody titers to B. burgdorferi.We conclude that early stage of the disease as well as chronic Lyme disease with persistence of B. burgdorferi after antibiotic therapy cannot be excluded when the serum is negative for antibodies against B. burgdorferi.
[Persistence:] However, some patients later developed symptoms of the disease despite antibiotic treatment, 9-11. Because of these observations it has become questionable if a definite eradication of B. burgdorferi with antibiotics is possible, p.357. ..The central nervous system invasion by spirochetes and a persistence of Treponema pallidum after penicillin G therapy is common in neurosyphilis, 22,23, p.358.[Treatment:] In view of the hitherto failure of treatment, low CSF concentration of penicillin G, survival of B. burgdorferi in patients treated with antibiotics, the moderate penicillin G susceptibility o f the organism and unpredictable progression of the disease, it seems appropriate to treat patients with substantially larger doses of antibiotics and/or longer than is provided in present treatment regimens. p.358.[Seronegativity:] As shown, negative antibody-titers do not provide evidence for successful therapy; antibody-titers may become negative despite persistence.
16: Acta Trop. 1990 Dec;48, 2:89-94.Clinical implications of delayed growth of the Lyme borreliosis spirochete, Borrelia burgdorferi. MacDonald AB, Berger BW, Schwan TG.
Department of Pathology, Southampton Hospital, New York 11968.
Lyme borreliosis, a spirochetal infection caused by Borrelia burgdorferi, may become clinically active after a period of latency in the host.Active cases of Lyme disease may show clinical relapse following antibiotic therapy. The latency and relapse phenomena suggest that the Lyme disease spirochete is capable of survival in the host for prolonged periods of time. We studied 63 patients with erythema migrans, the pathognomonic cutaneous lesion of Lyme borreliosis, and examined in vitro cultures of biopsies from the active edge of the erythematous patch. Sixteen biopsies yielded spirochetes after prolonged incubations of up to 10.5 months, suggesting that Borrelia burgdorferi may be very slow to divide in certain situations. Some patients with Lyme borreliosis may require more than the currently recommended two to three week course of antibiotic therapy to eradicate strains of the spirochete which grow slowly.
17: Infect Immun. 1991 Feb;59,2:671-8. Intracellular localization of Borrelia burgdorferi within human endothelial cells. Ma Y, Sturrock A, Weis JJ.
Department of Pathology, University of Utah School of Medicine, Salt Lake City 84132.
The later stages of infection by the Lyme disease pathogen, Borrelia burgdorferi, are characterized by the persistence of the organism in individuals possessing a strong anti-Borrelia immune response. This suggests that the organism is sequestered in a tissue protected from the immune system of the host or there is a reservoir of the organism residing within the cells of the host. In this report, the ability of B. burgdorferi to gain entrance into human umbilical vein endothelial cells was explored as a model for invasion. Incubation of B. burgdorferi with human umbilical vein endothelial cells at ratios ranging from 200:1 to 5,000:1 resulted in the intracellular localization of 10 to 25% of B. burgdorferi in 24 h. The intracellular location of the spirochetes was demonstrated by the incorporation of radiolabeled B. burgdorferi into a trypsin-resistant compartment and was confirmed by double-immunofluorescence staining which differentiated intracellular from extracellular organisms. Actin-containing microfilaments were required for the intracellular localization, indica ting that the host cell participates in the internalization process. Activation of endothelial cells by agents known to increase the expression of several adhesion molecules had no effect on the interaction of B. burgdorferi with the endothelial monolayer. This indicates that the endothelial receptor for B. burgdorferi is constitutively expressed and that internalization is not dependent upon adhesion molecules whose expression is induced by inflammatory mediators. The demonstration of B. burgdorferi within endothelial cells suggest that intracellular localization may be a potential mechanism by which the organism escapes from the immune response of the host and may contribute to persistence of the organism during the later stages of Lyme disease.
18: 1991: Journal of Infectious Diseases, Feb;163,2:311-8 Randomized comparison of ceftriaxone and cefotaxime in Lyme neuroborreliosis. Pfister HW, Preac-Mursic V, Wilske B, Schielke E, SÃrgel F, EinhÃ¤upl KM.
Neurological Department, Klinikum Grosshadern, University of Munich, Federal Republic of Germany.
In this prospective, randomized, open trial, 33 patients with Lyme neuroborreliosis were assigned to a 10-day treatment with either ceftriaxone, 2 g intravenously, iv, every 24 h, n = 17, or cefotaxime, 2 g iv every 8 h, n = 16. Of the 33 patients, 30 were eligible for analysis of therapeutic efficacy. Neurologic symptoms improved or even subsided in 14 patients of the cefotaxime group and in 12 patients of the ceftriaxone group during the treatment period. At follow-up examinations after a mean of 8.1 months, 17 of 2 7 patients examined were clinically asymptomatic. In one patient Borrelia burgdorferi was isolated from the cerebrospinal fluid, CSF, 7.5 months after ceftriaxone therapy. CSF antibiotic concentrations were above the MIC 90 level for B. burgdorferi in nearly all patients examined. Patients with Lyme neuroborreliosis may benefit from a 10-day treatment with ceftriaxone or cefotaxime.However, as 10 patients were symptomatic at follow-up and borreliae persisted in the CSF of one patient, a prolongation of therapy may be necessary.
19: Medicine, Baltimore. 1991 Mar;70,2:83-90. Lyme disease: clinical features, classification, and epidemiology in the upper midwest. Agger W, Case KL, Bryant GL, Callister SM.
Section of Infectious Disease, La Crosse Lutheran Hospital, Wisconsin.
Lyme disease can be classified using the terminology of syphilis. In this series of 95 cases from the upper midwest, early cases, defined as an illness of less than 2 months, were more likely to have lived in or recently visited a highly endemic area. Unlike late cases, early cases presented entirely in the nonwinter months, p less than .001. Early disease was further subdivided into primary and secondary disease. Ninety percent of primary and 43% of secondary cases had erythema migrans, while no late cases had active erythema migrans, p less than .001. Clinical manifestations of nonspecific inflammation, except for arthralgia, were more common in early than late disease, p less than .01. In secondary cases, monoarticular arthritis was slightly more common than polyarticular arthritis, with the reverse occurring in late disease, p less than .05. Indirect fluorescent antibody testing revealed a ratio of IgM to IgG antibodies to be helpful in distinguishing early from late disease. Antibacterial therapy in early, primary cases caused Jarisch-Herxheimer reaction 7% of the time. Despite longer and more frequent parenteral therapy, late Lyme disease frequently required retreatment, owing to poor clinical response, p less than .05.
19.5: N Engl J Med. 1991 Apr 18;324(16):1137. Chronic neurologic manifestations of Lyme disease. Logigian EL, Kaplan RF, Steere AC. Department of Neurology, Tufts University School of Medicine, Boston, MA 02111.
BACKGROUND AND METHODS. Lyme disease, caused by the tick-borne spirochete Borrelia burgdorferi, is associated with a wide variety of neurologic manifestations. To define further the chronic neurologic abnormalities of Lyme disease, we studied 27 patients, age range, 25 to 72 years, with previous signs of Lyme disease, current evidence of immunity to B. burgdorferi, and chronic neurologic symptoms with no other identifiable cause. Eight of the patients had been followed prospectively for 8 to 12 years after the onset of infection. RESULTS. Of the 27 patients, 24, 89 percent, had a mild encephalopathy that began 1 month to 14 years after the onset of the disease and was characterized by memory loss, mood changes, or sleep disturbance. Of the 24 patients, 14 had memory impairment on neuropsychological tests, and 18 had increased cerebrospinal fluid protein levels, evidence of intrathecal production of antibody to B. burgdorferi, or both. Nineteen of the 27 patients,70 percent, had polyneuropathy with radicular pain or distal paresthesias; all but two of these patients also had encephalopathy. In 16 patients electrophysiologic testing showed an axonal polyneuropathy. One patient had leukoencephalitis with asymmetric spastic diplegia, periventricular white-matter lesions, and intrathecal production of antibody to B. burgdorferi. Among the 27 patients, associated symptoms included fatigue, 74 percent, headache, 48 percent, arthritis, 37 percent, and hearing loss, 15 percent. At the time of examination, chronic neurologic abnormalities had been present from 3 months to 14 years, usually with little progression. Six months after a two-week course of intravenous ceftriaxone, 2 g daily, 17 patients, 63 percent, had improvement; 6, 22 percent, had improvement but then relapsed; and 4,15 percent, had no change in their condition. CONCLUSIONS. Months to years after the initial infection with B. burgdorferi, patients with Lyme disease may have chronic encephalopathy, polyneuropathy, or less commonly, leukoencephalitis. These chronic neurologic abnormalities usually improve with antibiotic therapy.
20: Arthritis Rheum. 1991 Aug;34,8:1056-60. Treatment of refractory chronic Lyme arthritis with arthroscopic synovectomy. Schoen RT, Aversa JM, Rahn DW, Steere AC.
Department of Medicine, Yale University School of Medicine, New Haven, Connecticut 06510.
Of 20 patients who underwent arthroscopic synovectomy for refractory chronic Lyme arthritis of the knee, 16, 80%, had resolution of joint inflammation during the first month after surgery or soon thereafter, and they have remained well during the 3-8-year followup period. Three of these 16 patients who were more disabled preoperatively, still had mild functional limitation at long-term followup. The remaining 4 patients, 20%, had persistent or recurrent synovitis. We conclude that arthroscopic synovectomy is effective in treating chronic Lyme arthritis in patients in whom the disease does not respond to antibiotic therapy.
21: 1: Clin Exp Rheumatol. 1992 Jul-Aug;10,4:387-90. Molecular detection of persistent Borrelia burgdorferi in a man with dermatomyositis. Fraser DD, Kong LI, Miller FW.
National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland.
A 40-year-old white man with a several year history of various immunologic disorders, including anti-Jo-1 autoantibody positive dermatomyositis, developed clinical Lyme disease after being biten by a tick. The patient was treated with oral tetracycline and his initial symptoms resolved; however, he suffered an exacerbation of his muscle disease which was difficult to control despite cytotoxic therapy. Antibiotic therapy was reinstituted after Borrelia burgdorferi was detected in the patient's peripheral blood leukocytes by the polymerase chain reaction, PCR. All serologic, T-cell stimulation, and western blot analyses, however, were negative. The patient's disease responded to oral ampicillin, p robenecid therapy and concurrent cytotoxic therapy. Subsequent leukocyte PCR testing has been negative for the causative agent of Lyme disease. This case may provide an example of the in vivo immuno-modulatory effects of spirochetes in human autoimmune disease. In addition, this case emphasizes the potential clinical utility of PCR technology in evaluating the persistent sero-negative Lyme disease which may occur in immunocompromised individuals.
22: 1:20 J Infect Dis. 1992 Aug;166,2:440-4.Fibroblasts protect the Lyme disease spirochete, Borrelia burgdorferi, from ceftriaxone in vitro. Georgilis K, Peacocke M, Klempner MS.
Department of Medicine, New England Medical Center, Boston, Massachusetts.
The Lyme disease spirochete, Borrelia burgdorferi, can be recovered long after initial infection, even from antibiotic-treated patients, indicating that it resists eradication by host defense mechanisms and antibiotics. Since B. burgdorferi first infects skin, the possible protective effect of skin fibroblasts from an antibiotic commonly used to treat Lyme disease, ceftriaxone, was examined. Human foreskin fibroblasts protected B. burgdorferi from the lethal action of a 2-day exposure to ceftriaxone at 1 microgram/mL, 10-20 x MBC. In the absence of fibroblasts, organisms did not survive. Spirochetes were not protected from ceftriaxone by glutaraldehyde-fixed fibroblasts or fibroblast lysate, suggesting that a living cell was required. The ability of the organism to survive in the presence of fibroblasts was not related to its infectivity.Fibroblasts protected B. burgdorferi for at least 14 days of exposure to ceftriaxone. Mouse keratinocytes, HEp-2 cells, and Vero cells but not Caco-2 cells showed the same protective effect. Thus, several eukaryotic cell types provide the Lyme disease spirochete with a protective environment contributing to its long-term survival.
23: J Am Acad Dermatol. 1993 Feb;28,2 Pt 2:312-4. Recurrent erythema migrans despite extended antibiotic treatment with minocycline in a patient with persisting Borrelia burgdorferi infection. Liegner KB, Shapiro JR, Ramsay D, Halperin AJ, Hogrefe W, Kong L.
Department of Medicine, Northern Westchester Hospital Center, Mount Kisco, NY.
Erythema migrans recurred in a patient 6 months after a course of treatment with minocycline for Lyme disease. Polymerase chain reaction on heparinized peripheral blood at that time demonstrated the presence of Borrelia burgdorferi-specific DNA. The patient was seronegative by Lyme enzyme-linked immunosorbent assay but showed suspicious bands on Western blot. Findings of a Warthin-Starry stain of a skin biopsy specimen of the eruption revealed a Borrelia-compatible structure. Reinfection was not believed to have occurred. Further treatment with minocycline led to resolution of the erythema migrans.
24: 1: J Infect Dis. 1993 May;167,5:1074-81.Invasion of human skin fibroblasts by the Lyme disease spirochete, Borrelia burgdorferi. Klempner MS, Noring R, Rogers RA.
Division of Geographic Medicine and Infectious Diseases, New England Medical Center, Tufts University School of Medicine, Boston, Massachusetts 02111.
The ability of Borrelia burgdorferi to attach to and invade human fibroblasts was investigated by scanning electron and confocal microscopy. By scanning electron microscopy, B. burgdorferi were tightly adherent to fibroblast monolayers after 24-48 h but were eliminated from the cell surface by treatment with ceftriaxone, 1 microgram/mL, for 5 days. Despite the absence of visible spirochetes on the cell surface after antibiotic treatment, viable B. burgdorferi were isolated from lysates of the fibroblast monolayers. B. burgdorferi were observed in the perinuclear region within human fibroblasts by laser scanning confocal microscopy.Intracellular spirochetes specifically labeled with monoclonal anti-flagellin antibody were also identified by fluorescent laser scanning confocal microscopy. These observations suggest that B. burgdorferi can adhere to, penetrate, and invade human fibroblasts in organisms that remain viable.
25: Infection. 1993 Mar-Apr;21,2:83-8. Azithromycin versus doxycycli ne for treatment of erythema migrans: clinical and microbiological findings. Strle F, Preac-Mursic V, Cimperman J, Ruzic E, Maraspin V, Jereb M.
Department of Infectious Diseases, University Medical Center, Ljubljana, Slovenia.
The effectiveness of azithromycin and doxycycline in the treatment of erythema migrans was compared in a prospective randomized trial. One hundred seven adult patients with typical erythema migrans, examined in the Lyme Borreliosis Outpatients' Clinic, University Department of Infectious Diseases in Ljubljana, were included in the study. Fifty-five patients received azithromycin, 500 mg twice daily for the first day, followed by 500 mg once daily for four days, and 52 patients received doxycycline, 100 mg twice daily for 14 days. The mean duration of skin lesions after the beginning of treatment was 7.5 +/- 5.9 days, median value 5, range 2-28 days, in the azithromycin group and 11.4 +/- 7.8 days, median value 9, range 2 days--8 weeks, in the doxycycline group, p < kappa =" 0.54"> or = 1 month, only 7, 37 percent, had positive tests, P < n =" 43," n =" 38;" p =" 0.03;" p =" 0.03;" p =" 0.04," p =" 0.04." p =" 0.02," p =" 0.01," n =" 6]," n =" 4]," n =" 3]." p =" 0.03," p =" .002," p =" .03," p =" .04," p =" .02," p =" .004," p =" .04," p =" .01," n =" 10," p =" .06." n="97," n="86," n="15," p =" 0.001."> 4 mg/L. Comparison of MBC values after 3 and 6 weeks' incubation revealed comparable results for azithromycin and ceftriaxone while for amoxicillin, cefuroxime and doxycycline, some differences were found. In one of the patients from whom there were borrelia isolated before and after treatment with cefuroxime axetil, both isolates were resistant to cefuroxime. In the other two patients, the paired isolates were susceptible to the antibiotic used for therapy.
95: Int J Med Microbiol. 2006 May;296 Suppl 40:233-41. Epub 2006 Mar 10.Risk of culture-confirmed borrelial persistence in patients treated for erythema migrans and possible mechanisms of resistance. Hunfeld KP, Ruzić-Sabljić E, Norris DE, Kraiczy P, Strle F. Institute of Medical Microbiology, University Hospital of Frankfurt, Paul-Ehrlich Str. 40, D-60596 Frankfurt/Main, Germany. K.Hunfeld@em.uni-frankfurt.de
Erythema migrans, EM, develops at the site of the tick bite in 77-90% of Lyme borreliosis, LB, patients and is therefore a common manifestation of early disease.Clinical treatment failures have been reported in early LB cases for almost every suitable antimicrobial agent. The exact risk of resistance to antibiotic treatment in patients with EM, however, is not known and there are few published cases of culture-proven treatment failure. Moreover, currently available diagnostic techniques cannot reliably discriminate between possible reinfection, true endogenous relapse and co-infection with other tick-borne pathogens. These drawbacks together with the phenomenon of r esistance to therapy in individual patients undoubtedly contribute to the inconsistencies surrounding the optimal treatment regimens for LB and are often misinterpreted and misused to support prolonged antibiotic treatment regimens. The question for the underlying mechanisms of possible antimicrobial resistance in Borrelia burgdorferi sensu lato remains unresolved but a better understanding of such genetic or phenotypic mechanisms would be helpful for the treatment of LB and other spirochetal diseases. Investigations on this issue, at best, should start with borrelial isolates cultured from patients before the start of antibiotic therapy and again after the conclusion of treatment. This task, however, remains challenging insofar, as culture is rarely successful under routine laboratory conditions after antimicrobial therapy.Here, we review recent clinical and experimental data on treatment resistance in EM patients suggesting that, although rare, borrelial persistence does occur at the site of the infectious lesion after antibiotic treatment. Borrelial persistence, however, is unlikely to result from acquired resistance against antimicrobial agents that were used for initial specific chemotherapy.
96: Eur J Pediatr. 2006 Jun;165,6:420-1. Epub 2006 Mar 4. Persistent synovitis in two children with Lyme arthritis linked with HLA-DRB1*1104. Hendrickx G, Demanet C, Vandenplas Y.
Department of Paediatrics, Paediatric Orthopaedic and Rheumatology Unit, Academisch Ziekenhuis -Vrije Universiteit Brussel, Laarbeeklaan 101, 1090 Brussels, Belgium. email@example.com
We report on two patients with a persistent Lyme arthritis. In addition both had a peculiar disease history. The first patient had oligoarticular juvenile idiopathic arthritis in remission. Five months after an infected tick bite, she developed a relapse of arthritis in the same knee. We considered Lyme borreliosis as the possible trigger for this reactivation. The disease history of the second patient was that of a classical non-responder. After extensive antibiotic treatment osteolytic lesions became visible. MRI images suggested an erosive arthropathy and arthroscopy was used to investigate possible erosive arthritis. Studies on collected material made us consider the following hypothesis. Despite demonstration of a spirochete fragment in a synovial biopsy, the patient recovered without additional antibiotic treatment. Conclusion: delay of antibiotic treatment after appearance of erythema migrans may cause systemic spread of the antigen and predispose to Lyme arthritis. If intra-articular steroids are considered when spontaneous resolution of Lyme arthritis does not occur, magnetic resonance imaging of the affected joint, prior to administration, may provide additional information. The success of synovectomy may be related to removal of undegraded antigenic material which may prolong the inflammation.
97: Int J Immunopathol Pharmacol. 2006 Jul-Sep;19,3:545-9. In vitro susceptibility of isolates of Borrelia burgdorferi s.l. to antimicrobial agents. Santino I, Scazzocchio F, Ciceroni L, Ciarrocchi S, Sessa R, Del Piano M. Department of Public Health Sciences, La Sapienza University, Rome, Italy. firstname.lastname@example.org
In the present study, we investigate the in vitro antimicrobial activity of macrolides, beta-lactams and tetracycline against Borrelia burgdorferi s.l. clinical and tick isolates. Minimal inhibitory concentrations, MICs, were determined in normal growth condition and after pre-exposure of the strains to sub-MIC of the founder of each drug family. All the classes of tested antibiotics showed good antibacterial activity against all the borreliae isolates and there were no significant susceptibility differences among clinical and tick isolates. After pre-exposure of the strains to sub-MIC of erythromycin, cefoxitin and tetracycline, we observed that some strains of B. burgdorferi s.l. showed higher MIC values to both the pre-exposed drug and drugs of the same family. The less susceptibility of borreliae, in the last growth condition in vitro, could be one of the justifications of clinical results indicating the limited efficacy of these antibiotics in treatment of B. burgdoferi infections.
98: 1: Microbes Infect. 2006 Nov-Dec; 8,14-15:2832-40. Epub 2006 Sep 22.Invasion of human neuronal and glial cells by an infectious strain of Borrelia burgdorferi. Livengood JA, Gilmore RD Jr.
Centers for Disease Control and Prevention, Divi sion of Vector-borne Infectious Diseases, 3150 Rampart Road, CSU Foothills Campus, Fort Collins, CO 80522, USA.
Human infection by Borrelia burgdorferi, the etiological agent for Lyme disease, can result in serious acute and late-term disorders including neuroborreliosis, a degenerative condition of the peripheral and central nervous systems.To examine the mechanisms involved in the cellular pathogenesis of neuroborreliosis, we investigated the ability of B. burgdorferi to attach to and/or invade a panel of human neuroglial and cortical neuronal cells. In all neural cells tested, we observed B. burgdorferi in association with the cell by confocal microscopy. Further analysis by differential immunofluorescent staining of external and internal organisms, and a gentamicin protection assay demonstrated an intracellular localization of B. burgdorferi. A non-infectious strain of B. burgdorferi was attenuated in its ability to associate with these neural cells, suggesting that a specific borrelial factor related to cellular infectivity was responsible for the association. Cytopathic effects were not observed following infection of these cell lines with B. burgdorferi, and internalized spirochetes were found to be viable. Invasion of neural cells by B. burgdorferi provides a putative mechanism for the organism to avoid the host's immune response while potentially causing functional damage to neural cells during infection of the CNS.
98.5: Acta Radiologica, Volume 48, Issue 7 2007 , pages 755 - 762 Brain Magnetic Resonance Imaging Does Not Contribute to the Diagnosis of Chronic Neuroborreliosis. Aalto A, Sjöwall J, Davidsson L, Forsberg P, Smedby O. Division of Radiology, Department of Medicine and Care, Faculty of Health Sciences, Linköping University, Linköping, Sweden. email@example.com
BACKGROUND: Borrelia infections, especially chronic neuroborreliosis, NB, may cause considerable diagnostic problems. This diagnosis is based on symptoms and findings in the cerebrospinal fluid but is not always conclusive. PURPOSE: To evaluate brain magnetic resonance imaging, MRI, in chronic NB, to compare the findings with healthy controls, and to correlate MRI findings with disease duration. MATERIAL AND METHODS: Sixteen well-characterized patients with chronic NB and 16 matched controls were examined in a 1.5T scanner with a standard head coil. T1-, with and without gadolinium, T2-, and diffusion-weighted imaging plus fluid-attenuated inversion recovery, FLAIR, imaging were used. RESULTS: White matter lesions and lesions in the basal ganglia were seen in 12 patients and 10 controls, no significant difference. Subependymal lesions were detected in patients down to the age of 25 and in the controls down to the age of 43. The number of lesions was correlated to age both in patients, rho = 0.83, P<0.01, rho =" 0.61," x =" 42,3" x ="43," x =" 53,5" n="20;" n="5," n =" 220)">12 species). Penicillin solution is one unfavorable condition that induces RBs. This antibiotic that inhibits bacterial cell wall synthesis cures neither the second "Great Imitator" (Lyme borreliosis) nor the first: syphilis. Molecular-microscopic techniques, in principle, can detect in animals (insects, ticks, and mammals, including patients) helices and RBs of live spirochetes. Genome sequences of B. burgdorferi and Treponema pallidum spirochetes show absence of >75% of genes in comparison with their free-living relatives. Irreversible integration of spirochetes at behavioral, metabolic, gene product and genetic levels into animal tissue has been documented. Irreversible integration of spirochetes may severely impair immunological response such that they persist undetected in tissue. We report in vitro inhibition and destruction of B. burgdorferi (helices, RBs = "cysts") by the antibiotic Tigecycline (TG; Wyeth), a glycylcycline protein-synthesis inhibitor (of both 30S and 70S ribosome subunits). Studies of the pleiomorphic life history stages in response to TG of both B. burgdorferi and Treponema pallidum in vivo and in vitro are strongly encouraged.
114: Persistence of borrelial DNA in the joints of Borrelia burgdorferi-infected mice after ceftriaxone treatment HETA YRJÄNÄInen 1 , JUKKA HYTÖNen 1 , PAULIINA HARTIALA 1 , JARMO OKSI 2 and MATTI K. VILJANEN Departments of 1Medical Microbiology and Immunology and 2 Medicine, University of Turku, Turku, Finland
Correspondence to Heta Yrjänäinen, Department of Medical Microbiology and Immunology, University of Turku, Kiinamyllynkatu 13, FIN-20520 Turku, Finland. e-mail: firstname.lastname@example.org Copyright Journal compilation © 2010 APMIS
We have earlier shown that Borrelia burgdorferi-infected and ceftriaxone-treated mice have viable spirochetes in their body, since immunosuppressive treatment allows B. burgdorferi to be detected by culture. However, the niche of the persisting spirochetes remained unknown. In the present study, we analyzed the tissues of B. burgdorferi-infected and ceftriaxone-treated mice by culture and PCR to reveal the foci of persisting spirochetes. C3H/HeN mice were infected via intradermal needle injection with B. burgdorferi s.s. N40. The mice were treated as follows: (i) short (5 days) and (ii) long (18 days) course of ceftriaxone at 2 weeks of infection and killed after either 10 or 30 weeks, or (iii) the mice received ceftriaxone for 5 days at 18 weeks of infection and were killed 21 weeks after the treatment. All samples of ceftriaxone-treated mice were culture negative, whereas all untreated controls were culture positive. Importantly, B. burgdorferi DNA was detected in the joints of 30–100% of the treated mice. In conclusion, these results combined with earlier results suggest that the joint or a tissue adjacent to the joint is the niche of persisting B. burgdorferi in ceftriaxone-treated mice.