Re: Some Interesting Materials on the NIH Study

a_weisman_at_yahoo.com
Date: 01/10/05 

Date: 10 Jan 2005 07:15:33 -0800

PART 5

LymeNet Newsletter Volume 6 Issue 10

NIH: Chronic Lyme Borreliosis Clinical Trial RFP - NIH/ALI
Source: Carl Henn, Contracting Officer <ch24v@nih.gov>
Release Date: 7 October, 1998
URL: http://web.fie.com/htdoc/fed/nih/gen/any/proc/any/10099808.htm

CHRONIC LYME BORRELIOSIS CLINICAL TRIAL SOL N01-AI-65296 DUE 110498
POC Mr. Carl Henn, Contracting Officer, 301-496-0993.

The National Institute of Allergy and Infectious Diseases, Division of
Microbiology and Infectious Diseases, is seeking sources capable of
conducting randomized, placebo-controlled, double-blind clinical
trials to demonstrate the efficacy of treatment with intravenous
ceftriaxone (2 grams per day for 30 consecutive days) followed by oral
doxycycline (200 mg per day for 60 consecutive days) for the treatment
of chronic Lyme borreliosis. The trials will involve defined cohorts of
patients, from regions of the United States in which Lyme disease is
endemic, that are either seropositive or seronegative for Lyme disease
(by the two-test CDC-Dearborn criteria) at the time of enrollment, and
who meet the inclusion and exclusion criteria established and approved
for this study. Primary analysis of the efficacy of the antibiotic
therapy used will be determined by improvement in the patient's
health-related quality of life, as measured by the SF-36 Health Survey;
it includes eight multi-item scales that measure physical functioning,
role-physical, bodily pain, general health, vitality, social
functioning, role-emotional, and mental health. Three additional
multi-item scales from the medical outcomes study (MOS) will be used to
measure cognitive functioning, pain, and role functioning; however,
they will not be used for primary analysis of efficacy. The SF-36
Health Survey (and additional MOS measures) will be administered to
study participants five times: at baseline (prior to therapy); at one
month (the end of intravenous therapy); at three months (the end of
intravenous and oral therapy); at six months; and at one year . Also,
at baseline and at defined intervals (as stipulated in the protocol
approved for use in these studies), specimens will be collected to test
for: (a) an immune response to Borrelia burgdorferi antigens in serum
and cerebrospinal fluid (CSF); (b) B. burgdorferi DNA in CSF; (c)
viable B. burgdorferi in CSF; (d) B. burgdorferi antigens in urine; and
(e) serum antibodies specific for possible co-infecting agents, e.g.,
Babesia microti and Ehrlichia species. Interested parties should
submit, no later than November 4, 1998, four (4) copies of a capability
statement addressing each of the areas outlined above. The statement
also should include information on numbers of eligible volunteers
likely to be enrolled per year (do not provide the names of prospective
volunteers or personal identifiers). A copy of the specific inclusion
and exclusion criteria approved for the study will be provided on
request. This Sources Sought Announcement is a request for information
to assist the NIAID in selecting additional sites for conducting the
studies described. It may or may not result in a solicitation.
Respondents are invited to discuss additional terms or conditions with
the NIAID by contacting: Carl Henn Contracting Officer Contract
Management Branch National Institute of Allergy & Infectious Diseases.

LymeNet Newsletter Volume 6 Issue 10
http://www2.lymenet.org/domino/nl.nsf/634e8a3fba016005852565e30012110d/6dfcd6c971b9e3e48525669f00017d16?OpenDocument

-----
Conference Abstract - April 28-30, 1997

Title:
Randomized, Double-Blinded, Placebo-Controlled, Multicenter Trials
of the Safety and Efficacy of Ceftriaxone and Doxycycline in the
Treatment of Patients with Seropositive and Seronegative Chronic LD
Authors:
Klempner M
Conference:
10th Annual International Scientific Conference on Lyme Disease &
Other Tick-Borne Disorders, National Institutes of Health,
Bethesda, MD April 28-30, 1997
Presenter:
Mark Klempner, M.D.
Tufts New England Medical Center

Abstract:
A description of the NIH supported clinical protocols for the
characterization and treatment of patients with Chronic Lyme Disease
(CLD) will be presented.
The objectives of these studies are to determine whether:
1. intensive antibiotic treatment benefits seropositive and
seronegative patients with CLD,
2. evidence of persistent infection with Bb can be found in patients
with CLD,
3. evidence of coinfection with other microorganisms can be found in
patients with CLD,
4. specific clinical or laboratory parameters improve in patients who
receive antibiotic therapy compared to patients who receive placebo,
and
5. specific parameters are predictive of a response to therapy should
it be observed.

These studies are Phase III, randomized, double-blinded, placebo-
controlled, multicenter trials (two centers). 260 patients will be
enrolled in the studies and randomized to receive either antibiotic
therapy or placebo in a 1:1 ratio; antibiotics and placebo will be
administered both intravenously and orally. The antibiotic regimen will

be intravenous ceftriaxone 2 gms/day for 30 days followed by oral
doxycycline 200mg/day for 60 days. Placebos identical in appearance to
the intravenous and oral antibiotics will be administered by the same
routes and for the same duration to patients randomized to the placebo
group. Initial and serial analyses during treatment will include PCR of

plasma and CSF for borrelia and other organism DNA, borrelia urinary
antigen, and serum antibodies to organisms transmitted by Ixodes ticks.

Primary outcome analysis for the efficacy of antibiotic therapy will be

determined by improvement in the patient's health related quality of
life as measured by the SF-36 Health Survey. Other assessments will
include changes in pain and cognition using scales from the Medical
Outcomes Study, the fibromyalgia impact questionnaire,
neuropsychological tests, and nerve conduction studies for patients
with
neuropathic pain.

Unique ID: 97LDF032

http://www2.lymenet.org/domino/abstract.nsf/8c703fae46ce57c28525670a0009ab7e/bdacb8512816bcc88525660f00001243?OpenDocument

-----
Lyme Disease Advisory Panel Summary Report - September 4, 1996

The following summary report was submitted to NIAID by the
Lyme Disease Advisory Panel, following its first meeting on
August 14, 1996. This panel was convened by the Institute to
provide advice and guidance concerning the planning of
Lyme disease clinical trials.

Lyme Disease Advisory Panel Summary Report
September 4, 1996

Introduction

The Lyme Disease Advisory Panel would like to express its
gratitude to the NIAID staff for their excellent efforts in planning
and
organizing this meeting, to the investigators for excellent and
well-prepared presentations, and to the participants for invaluable
contributions to the discussions and deliberations.

A number of deliberations and discussion items arose among the
panel members and will be subdivided to the categories of the NIH
Intramural Proposal, presented by Dr. Adriana Marques, and the
New England Medical Center Extramural Proposal, presented by
Dr. Mark Klempner. These will be referred to as the Intramural
Protocol and the Extramural Protocol, respectively.

The Panel recognizes and appreciates that the protocols reviewed
at this meeting are considered to be "in evolution" by the
investigators and considers the comments of the panel to be within
the spirit of creating the best possible final protocol.

There was a consensus among the members to have two new
individuals available to the Panel, if possible. These individuals
would be a biostatistician and a neuropsychologist.

Comments on the Intramural Protocol

Choice and Duration of Antibiotic Treatment: Considerable
discussion arose over this issue. In conclusion, the Panel agreed
with the antibiotic regimen that has been chosen by the
investigators. Therefore, no change in the choice or duration of
antibiotic treatment was recommended. The Panel encourages the
intramural investigators to discuss any post-treatment evidence of
persistent infection with both the patients and their personal
physicians, so that informed decisions can be made about the
desirability of further treatment in these patients.

Number of Lumbar Punctures: Although it was recognized that
patient compliance may be an issue, it was strongly recommended
that attempts should be made to obtain the four lumbar punctures.

Additional Laboratory Tests: It was suggested that tests based
on the detection of Borrelia burgdorferi- specific immune
complexes and the presence of B. burgdorferi antigen in urine be
incorporated in these studies.

Comments on the Extramural Protocol

Choice of Antibiotics and Duration of Therapy: The Panel
agreed with the choice made by the investigators for this initial
study, realizing that the choice may be subject to change in future
studies. They agreed that this strategy was reasonable as a
starting point, since it includes agents (antibiotics) with good
activity against B. burgdorferi, has agents with satisfactory nervous
system penetration, and includes agents which achieve
satisfactory intracellular levels. The Panel is also aware that cost,
side effects, and pharmacokinetics are important considerations in
choice of antibiotics.

Inclusion Criteria: The Panel agreed that the inclusion criteria
require documentation that the previous diagnosis of acute Lyme
disease was made by a physician. The Panel agreed with the
investigators that patients with PCR-positive evidence for the
presence of B. burgdorferi DNA in plasma or spinal fluid should be
excluded from the protocol and referred to the NIH Intramural study.

Neuropsychological Evaluation: The Panel requested
standardization of the neuropsychological tests to be used in both
the Intramural and Extramural studies.

Length of Illness Prior to Entry into the Protocol: It was
suggested that no longer than four years be allowed for the
diagnosis of Lyme disease prior to entry into this protocol.

Concomitant Infections: The importance of testing for
concomitant Ehrlichia and Babesia infections was recognized and
endorsed.

Statistical Analysis: There was considerable discussion on the
numbers of patients required to detect a significant antibiotic
treatment effect, as well as the magnitude of the placebo effect to
be expected in studies such as these. The advice of
biostatisticians with expertise on these matters will be sought to
resolve these issues.

Other issues: Compliance with the treatment protocol and use of
concomitant drugs will be monitored. The addition of audiology
competency testing was suggested for the neuropsychological
evaluation. The suggestion was made that the investigators
engage in dialogue with others also conducting clinical studies on
chronic disease.

It was suggested that the term Post-Lyme Disease Syndrome
should be replaced by Chronic Lyme Disease in the protocols
being considered.

The Panel suggested that urine antigen also be determined in the
Extramural protocol patients (see discussion under Intramural
Protocol).

The Panel felt that future studies in primate models would be highly
complementary to the proposed studies. The conducting of these
studies was considered maximally important by the Panel.

Members of DMID Advisory Panel on Clinical Studies of
Chronic Lyme Disease

John E. Edwards, Jr., M.D. (Chair)
LAC Harbor-UCLA Medical Center
Torrance, California

Carl Brenner
Lyme Disease Coalition of New York
Hawley, Pennsylvania

Phyllis Mervine
Lyme Disease Resource Center
Ukiah, California

Justin Radolf, M.D.
Department of Internal Medicine
University of Texas Southwestern Medical Center
Dallas, Texas

Donald H. Gilden, M.D.
Department of Neurology
University of Colorado School of Medicine
Denver, Colorado

Fred A. Gill, M.D.
Bethesda, Maryland

J. Stephen Dumler, M.D.
Department of Pathology
The Johns Hopkins University School of Medicine
Baltimore, Maryland

Lyme Disease Advisory Panel Summary Report
http://www.x-l.net/Lyme/nihsep96.htm

-----
NIH News Release:

FOR IMMEDIATE RELEASE
Friday, June 28, 1996
John Bowersox
(301) 402-1663
Bowersox@nih.gov

NIAID Awards Contract for Post-Lyme Disease Syndrome Studies

The National Institute of Allergy and Infectious Diseases (NIAID) has
awarded a five-year contract to the New England Medical Center (NEMC)
in
Boston, Mass., to study the pathogenesis and treatment of post-Lyme
disease syndrome (PLDS). Mark Klempner, M.D., is the principal
investigator of the $4.2 million study.

"This research will help us answer important questions regarding the
nature of Lyme disease sequelae and the most effective treatment for
individuals affected by this syndrome," says NIAID Director Anthony S.
Fauci, M.D.

Lyme disease is caused by infection with the tick-borne spirochete
Borrelia burgdorferi. Since 1982, when the organism was first
identified
by NIAID scientists, more than 50,000 cases of Lyme disease have been
reported in the United States. Patients usually are treated
successfully
in the early stages of the disease with a two- to four-week course of
oral antibiotics. Additional treatment with intravenous antibiotics may

be required in some cases. Several months after patients with the
initial symptoms of Lyme disease have been treated, some of them
develop
PLDS, a condition also known as chronic Lyme disease and characterized
by persistent musculoskeletal and peripheral nerve pain, fatigue and
memory impairment.

"There is much uncertainty about the pathogenesis of PLDS. We don't
know
if it is caused by ongoing active infection with B. burgdorferi or
another tick-borne pathogen, or if PLDS symptoms result from
reinfection," says John R. La Montagne, Ph.D., director of NIAID's
Division of Microbiology and Infectious Diseases. "Inflammatory or
autoimmune responses occurring during early infection, prior to
treatment with antibiotics, may also play a role in PLDS. We also have
a
lot to learn about its clinical manifestations. This contract will
allow
us to define this syndrome more precisely and develop rational
strategies for treating it."

As contractor, NEMC researchers will work closely with NIAID staff, and

collaborate with scientists at New York Medical College, the University

of Minnesota School of Medicine, and Tufts University School of
Medicine. Studies on the cause or causes of PLDS and the evaluation of
potential therapies for patients with PLDS are planned. Treatment
success will be measured with a variety of tests that assess symptoms,
signs and laboratory manifestations of PLDS.

This contract award to NEMC follows a rigorous objective review
process,
during which all proposals received under an NIAID solicitation were
evaluated and scored by non-government Lyme disease experts. The new
study further expands NIAID's growing portfolio of Lyme disease
research
projects. NIAID currently supports a variety of investigator-initiated
studies of the pathogenesis, diagnosis and treatment of Lyme disease.
In
addition, intramural scientists from NIAID and other institutes at the
National Institutes of Health (NIH) are collaborating on Lyme disease
studies.

According to NIAID's Phillip Baker, Ph.D., the project officer for the
study, the NEMC researchers will work closely with NIH intramural
investigators.

"Although these new studies will not supply all the answers with regard

to the etiology and treatment of PLDS," says Dr. Baker, "they should
provide meaningful information that can help us move toward the
development of effective solutions to this problem."

NIAID, a component of the NIH, conducts and supports research to
prevent, diagnose and treat illnesses such as AIDS and other sexually
transmitted diseases, tuberculosis, asthma and allergies. NIH is an
agency of the U.S. Public Health Service, U.S. Department of Health and

Human Services.

News Release - June 28, 1996
NIAID Awards Contract for Post-Lyme Disease Syndrome Studies, NIAID
http://www.niaid.nih.gov/newsroom/lyme.htm

-----
Clinical Trials in Progress

Chronic Lyme Disease Is It An Ongoing Infection?

NIAIDs Laboratory of Clinical Investigation has begun recruiting
patients for a study of chronic Lyme disease. The goal of this study is

to determine if persistent signs and symptoms of disease, especially
neurologic ones, are due to ongoing active borrelial infection or to
other pathogenic mechanisms. The study is designed to identify
objective
markers that could be used to substantiate and follow the persistence
of
Borrelia burgdorferi infection in people with presumed chronic Lyme
disease and others exposed to the bacterium. The extent of infection
and
the immune system response to it in patients with neuroborreliosis and
other exposed controls will be evaluated. This comprehensive study
should yield a prospective database upon which diagnostic criteria for
chronic Lyme disease can be established and future therapeutic trials
can be designed.

This study is divided in two parts. In the first part, results of
several different evolving tests for B. burgdorferi infection will be
compared between patients with suspected chronic neuroborreliosis
and five different control groups. The control groups include patients
with Lyme arthritis, persons who recovered from Lyme disease after
therapy, asymptomatic persons incidentally found to be seropositive for

B. burgdorferi who have not been treated, patients with multiple
sclerosis, and healthy volunteers. All study participants except for
the
multiple sclerosis patients and healthy volunteers must have documented

positive Lyme serology confirmed by Western blot.

In the second part of the study, patients with clinical suspicion of
chronic neuroborreliosis who have evidence of persistent infection by
polymerase chain reaction, antigen-capture, or other assays will be
offered four weeks of intravenous ceftriaxone therapy. The therapy will

be given on an outpatient basis, ideally under the supervision of the
referring physician. The participants will then return to NIH for
reevaluation at the end of treatment, and 3, 6, and 12 months later.

This study is being developed collaboratively with scientists in
NIAID's
extramural program, in the National Institute of Neurological Diseases
and Stroke, the National Institute of Mental Health, and the National
Institute of Deafness and Other Communication Disorders, and with Lyme
disease experts at institutions such as the State University of New
York
at Stony Brook, the New England Medical Center, and the Mayo Clinic.
Adriana Marques, M.D., is the principal investigator on the project,
and
Brenda Cuccherini, Ph.D, is co-investigator.

For more information, call 1-800-772-5464 x605, or send a
self-addressed
envelope to the following address: NIAID Chronic Lyme Disease Study,
Building 10, Room 11N228, 10 Center Dr., MSC 1888, Bethesda, MD 20892-
1888.

Chronic Lyme Disease Is It An Ongoing Infection?
Clinical Trials in Progress, January 1996
http://www.niaid.nih.gov/publications/dateline/0696/page6.htm

---------------
News articles on the NIH chronic Lyme disease study:

Subject: Time Magazine Article 7/28/97
Date: 22 Jul 1997 00:00:00 GMT
From: "Rita Stanley" <ritastan@worldnet.att.net>
Newsgroups: sci.med.diseases.lyme

JULY 28, 1997 VOL. 150 NO. 4

HEALTH

TICK, TICK, TICK...
IT'S PRIME TIME FOR LYME DISEASE. PULL UP YOUR SOCKS AND FOLLOW THE
CONTROVERSY

BY CHRISTINE GORMAN

Joseph Dipaoma, 58, of Bedford, N.Y., never saw the pinhead-size tick
that bit him. But there was no mistaking the angry red rash that
blossomed on his forearm. He had Lyme disease, which three weeks on
antibiotics quickly cured. Still, five years later, he sometimes
wonders
if the infection is really gone. "I get a lot of aches and pains," says

the part-time delicatessen worker. "In the back of my mind, there's
this
question: Could it be a residue of the Lyme? Or have I been standing
behind the counter too long?"

Twenty years after the first cases of Lyme disease were reported in and

around Old Lyme, Conn., the epidemic of tick-borne infections seems to
be taking a detour into the twilight zone. Doctors know how to diagnose

it--most of the time. They can even cure it--most of the time.
Pharmaceutical companies are working on two promising vaccines that
could be approved by the U.S. Food and Drug Administration later this
year. Biologists have even come up with some ingenious methods for
controlling the tick population that carries Lyme. But no one is
satisfied, not the victims who complain that their symptoms seem to
persist, not the doctors who are called upon to treat those victims,
not
the scientists who are being asked to solve a medical mystery that no
one has been able to define clearly. There are now so many mixed
messages about exactly what Lyme is and how it should be treated that
many people are left, like DiPaoma, wondering what to believe.

The battle lines are deeply drawn. Taking a page from AIDS activists,
several advocacy and educational groups are insisting that, among other

things, they be consulted in the design of scientific studies of Lyme.
Their input has not been entirely welcomed by the scientific community.

One outspoken program officer at the National Institutes of Health was
so vociferous in his criticism of the Lyme groups that he was barred
from having anything more to do with the disease. His cause was taken
up
three weeks ago in an op-ed piece in the New York Times that criticized

the lay groups and pleaded with them to "let scientists do their job."

A few facts are clear. Lyme disease is caused by one of a group of
corkscrew-shaped bacteria called spirochetes. It is spread when
infected
deer ticks, or other members of the genus Ixodes, bite their potential
hosts, which include field mice, wood rats and suburbanites. Lyme has
become endemic in the Northeastern U.S. It has also been found in
Canada, Europe and Australia. The initial infection is usually
accompanied by an expanding red rash, which generally, but not always,
resembles a bull's-eye. Caught early enough, the Lyme infection can be
completely cleared by taking oral antibiotics.

Things quickly get tricky, however, when you focus on the anomalies.
Sometimes the disease isn't caught soon enough. Sometimes the
spirochetes invade the nervous system, which is beyond the reach of
most
oral medications, in which case they must be flushed out with
antibiotics that are administered intravenously. Everyone agrees that
such complications occur. But some people think they are the exception,

while others believe they are the rule.

The debate gets downright vicious when the subject turns to "chronic
Lyme disease," a catch-all term that means different things to
different
people. Some patient advocates and their medical allies believe the
Lyme
spirochete tends to persist in the body even after standard antibiotic
treatment. This camp generally favors intravenous antibiotic therapy to

treat chronic Lyme. On the other hand, some academic researchers and
their allies argue that people with chronic Lyme fall into one of two
categories: they either have hypersensitive immune systems that have
overreacted to an earlier, no longer viable, Lyme infection--in which
case antibiotics are useless--or they never suffered from Lyme disease
in the first place and are ascribing to Lyme various aches and pains
that actually have nothing to do with the disease.

This difference of opinion has significant implications for treatment.
Intravenous antibiotics can cost tens of thousands of dollars,
especially if hospitalization is required. Moreover, there is a risk
that the catheters used to administer the drugs may become
contaminated,
leading to serious infections of the bloodstream and even the heart.
Clearly, intravenous antibiotics should not be withheld from people who

truly need them. Who truly needs them is, of course, what's in dispute.

The NIH is funding a $4.5 million study in an effort to sort out both
the best definitions and the best treatments for chronic Lyme disease.

Meanwhile, a group of biologists in central Texas may have come up with

at least a partial solution to the Lyme problem. "We call it the four-
poster," says John George, a tick specialist with the U.S. Department
of
Agriculture in Kerrville. It's a bin full of corn surrounded by
specially angled rollers. As deer push in to eat the corn, the rollers
coat the animal's head and neck with a pesticide that targets mites and

ticks. Pilot studies on 50-acre plots have produced a 95% drop in the
local tick population. "What's neat about this is that it's safe for
the
deer and doesn't involve wholesale spraying," George says. "We're
hoping
to try this out very soon in the Northeast." It may not seem very
sophisticated to the folks in Old Lyme, but at least it targets ticks
and not people.

TICK, TICK, TICK..., Time Magazine, 28 Jul 97
http://cgi.pathfinder.com/time/magazine/1997/dom/970728/health_tick.html
or
http://groups.google.com/groups?hl=en&lr=lang_en&safe=off&ic=1&th=99e554787be3c7e9,2&seekm=01bc964f%242024d9c0%24337b93cf%40default#p

-----
Science, Vol. 270, October 13, 1995, pp 228-229.

NIH GEARS UP TO TEST A HOTLY DISPUTED THEORY
Eliot Marshell

The National Institutes of Health (NIH) is preparing to fund a
$1-million-a-year study that it hopes will settle a dispute that has
riven a segment of the medical community in the past few years. At
issue: Is there a chronic form of Lyme disease that sometimes persists
after conventional antibiotic treatment, inflicting a variety of
symptoms such as muscle pain, fatigue, and memory loss on its victims?

A group of physicians and patient advocates believes the answer is an
emphatic "yes", and they have been agitating for the medical
establishment to take them seriously. The upcoming NIH study means
that
their claims will finally be put to the test. But many Lyme disease
researchers are skeptical of the need for this project.

The very existence of the trial is testimony to the persistence of
patient advocacy groups. They have lobbied Congress for many years to
support research into chronic Lyme symptoms, promoting the need for
long-term therapy. Their tactics have angered leaders such as Allen
Steere of Tufts University, who was the first to identify the U.S. Lyme

syndrome in the 1970s. The multimillion-dollar trial that NIH is
planning, he says, "would never have been funded" through the "normal
mechanisms" of investigator-initiated research. But Greg Folkers, a
spokesperson for the National Institute of Allergy and Infectious
Diseases, says, "This trial has been under discussion for several
years" - well before Congress recommended that NIH study new
antibacterial
strategies.

Steere, Alan Barbour - a microbiologist at the University of Texas,
San
Antonio- and other researchers believe that there's little evidence to
support the notion that there is an epidemic of chronic infection by
Lyme disease. Most so-called chronic cases, they believe, are not Lyme

disease at all; NIH's study could be a waste of money. But advocate
groups - particularly the Lyme Disease Foundation (LDF) of Hartford,
Connecticut, which includes physicians who treat patients - argue that
the disease is more elusive, more malignant, and more difficult to
treat
than academic scientists have acknowledged. They believe that the
traditional treatment advocated by physicians at leading medical
schools
such as Yale, Tufts, and the University of Connecticut - 2 to 4 weeks
of
oral antibiotics and, in rare cases when the central nervous system is
infected, 4 weeks of intravenous antibiotics - is in many cases
insufficient to wipe out the disease.

Joseph Burrascano Jr., a Long Island physician who specializes in
treating Lyme disease and has served as board member of the LDF, argues

that more aggressive therapy is often needed. He prescribes month-long

courses of antibiotics for many of his Lyme patients, including
intravenous therapy. Kenneth Liegner, a physician in Armonk, New York,

has also written that clinicians should expect " a revolution in our
conceptualization of this disease". Evidence is mounting, Liegner
says,that "subsets of patients" with as-yet-unconfirmed immune system
weaknesses do not benefit from routine therapy and may require
"prolonged antibiotic treatment".

Patient activists have seized on these arguments and are pushing for
studies which they believe will confirm a more radical attack on the
disease than has been recommended by the establishment so far. One
objective, says patient advocate Kenneth Fordyce, chair of the
governor's Lyme disease advisory committee of New Jersey, is to get
insurance companies to reimburse patients for antibiotic therapy that
lasts longer than the standard 28 days.

Disagreement between the activists and the medical establishment
erupted 3 years ago, when abstracts of a dozen papers submitted by
clinicians to a Lyme disease conference were rejected by the program
committee as lacking in scientific merit. The papers - most of which
discussed chronic Lyme cases - were reinstated over the objections of
several researchers after patient advocacy groups protested (Science, 5

June 1992, p. 1384).

After failing to convince athe establishment of its scientific views,

LDF took a route that has been well trodden by AIDS and breast cancer
activists: It mounted a lobbying campaign. NIH is now accepting
proposals for a trial that will examine whether patients with long-
lasting symptoms are truly infected with Lyme, and whether they benefit

from prolonged antibiotic therapy.

ORIGINS: OLD LYME. The tussle between the activists and the Lyme
disease establishment stems in large part from inadequate diagnostic
tests and limited understanding of how the culprit organism survives in

humans. The symptoms of Lyme disease in the United States were first
identified during the 1970s through Steere's studies of children in New

Emgland who were suffering from swollen knees and joints. Steere
determined that the syndrome - which was heavily focused around Old
Lyme, Connecticut - is a form of arthritis associated with bites from
deer ticks and a strange, bulls- eye rash, erythema migrans. It soon
became apparent that Lyme syndrome was similar to an infection that had

been described in Europe in the 19th century. In 1982, biologist Willy

Burgdorfer at NIH's Rocky Mountain lab in Montana nailed the infectious

agent: a spiral-shaped bacterium (a spirochete) of the Borrelia family,

mainly found in a small deer tick, Ixodes scapularis. In honor of
the
discoverer, the bacterium was named Borrelia burgdorferi.

Today, Burgdorfer says that the Lyme organism and other spirochetes -
slow-growing but potent organisms responsible for a variety of disease
including syphilis - deserve more attention from researchers.
Syphillis, for example , " has been known for ages... But with alll our

advanced technology, we are not in a postion to 100% prove that the
manifestations shown by a patient are due to chronic spirochetosis
(ongoing infection) or something else," such as late-appearing damage
from an infection that may have stopped much earlier. The same
uncertainties plague the diagnosis and treatment of Lyme disease,
Burgdorfer says.

The weak understanding of the organism's biology is compounded by the
lack of a good diagnostic test. Blood tests for human Lyme infection
have been unreliable, often yielding false positives, and, some
physicians say, many false negatives. It was only in October 1994,
Barbour notes, that leaders of public health agencies from around the
United States met in Michigan to establish common standards for testing

and confirming the presence of Lyme infection.

Because it was hard to diagnose cases with certainty, it was also hard

to sort out the effects of different therapies. The confusion has been

increased by the widening spectrum of symptoms attributed to Lyme
infection. Initially, Steere focused on clear-cut indicators - the
rash
and swollen joints. But subtle effects have now been added to the
list,
including injury to the eyes, the heart, the nervous system, and the
brain.

A POLARIZED COMMUNITY. As the list of possible ill effects grew, so
did the number of patients who felt they were suffering from Lyme
disease. Their ranks stood at fewer than 1000 in 1982, but, according
to the Centers for Disease Control and Prevention, rose to more than
13,000 in 1994. To Steere, the increase is a sign that Lyme disease
"has become an overdiagnosed and overtreated illness". To back up this

contention, Steere conducted a study, published in the Journal of the
American Association in 1993, in which he reported that 57% of 788
cases referred to the clinicas Lyme disease patients by other
physicians
were not infected with Borrelia.

Many other academics - such as Durland Fish and Eugene Shapiro of Yale

- agree with Steere that clinical practice has gone overboard. They
believe many physicians are classifying vaguely defined illnesses as
Lyme disease and selecting antibiotic therapy as the most convenient
solution, particularly for prolonged and ill-defined ailments, such as
diffuse pain (fibromyalgia) and fatigue. One of the major problems in
this field, says Shapiro, "is not Lyme disease itself but the
misdiagnosis of Lyme disease and anxiety about Lyme disease".

At the other pole are physicians who think Steere and his medical
school colleagues ignore the subtlety and persistence of B. burdorferi.

Burrascano, in a 1993 Senate hearing denounced the "conspiracy...of
university-based" scientists who he said were using their clout to
promote the "outdated" idea that "Lyme is a simple, rare illness that
is...easily cured by 30 days or less of antibiotics". Burrascano
points
out that the Lyme bacterium is difficult to detect in the blood after
the initial infection even if it has beenn left untreated. The
aggressive treaters of Lyme disease have long argued that the
spirochete
hides within cells, deep in joints and connective tissue, in the eyes,
and in the relative isolation of the cerebrospinal nerve system.
These
locations are inaccessible to routine antibiotic therapy, they argue,
and long-term infections require the use of intravenous, potent
antibiotics over many months.

Somewhere in the middle of the Lyme battleground are physicians like
neurologist Patricia Coyle, a clinician at the Health Science Center of

the State University of New York, Stony Brook, who see merit in
Burrascano's arguments but doubt that many patients are afflicted with
chronic infections. Coyle, who works in a speical clinic at Stony
Brook that sees 1600 Lyme patients a year, says key questions about
Lyme
infection remain unanswered.

First, Coyle asks: "Does the spirochete go into the cells or not? We
don't know." However, she says in vitro studies suggest that it does,
and that it may escape antibiotics that way. Second, Coyle would like
to know to what extent and how often the spirochete penetrates the
central nervous system. Also, she would like to confirm which
antibiotics are best at attacking it there. Third, she would like to
learn whether the organism enters a quiescent period after infection.
While scientists have been exploring these issues in laboratory
studies,
Coyle argues that it is important and "very practical" to carry out a
large clinical trial, because it's risky in dealing with infections to

extrapolate from bench to bedside.

These are just the kinds of questions that NIH's clinical trial will
address. The aim is to recruit patients who have previously been
diagnosed and given routine therapy for Lyme disease, but whose
symptoms
persist. They will be carefully screened to fit criteria - as yet
undefined - of confirmed Lyme patients. And they will be assigned
blindly to one of several treatment regimens, including a placebo
group, to be followed for several years, probably at more than one
center. "One of the big unanswered questions", says John LaMontagne of

the National Institute of Allergy and Infectious Diseases, "is whether
or not Borrelia produces some sort of permanent neurological damage
that
cannot be reversed".

Researchers such as Barbour and Steere are concerned that the trial -
if not well designed - could end up an expensive disappointment. But
Barbour agrees it may serve a useful purpose. The debate among
clinicians about what causes long-term symptoms and how to cure them
"needs to be settled", he says. "People are spending millions of
dollars on antibiotics," hoping to be rid of all kinds of symptoms.
Adds Burgdorfer: "Once we have the answers to these questions, all the
other stuff...the politics...the quarreling among the scientists, will
disappear." In a community so split, that may be a forlorn hope.

NIH Gears Up To Test a Hotly Disputed Theory, Science, 13 Oct 95
sci.med.diseases.lyme:
Lyme conflict- part of the story-repost Science Article
http://groups.google.com/groups?hl=en&lr=lang_en&safe=off&ic=1&th=17d14980e714842d,1&seekm=19990526173111.09180.00006614%40ng35.aol.com#p

---------------
Information on the NIH chronic Lyme disease study posted on the
sci.med.diseases.lyme USENET newsgroup:

Subject: Opinion - Chronic Lyme Study
Date: 09 Mar 1999 00:00:00 GMT
From: steve.mclain@dol.net (Steve J. McLain)
Newsgroups: sci.med.diseases.lyme

I recently attended a review of the NIH Chronic Lyme study. I'm
posting
information about the enrollment criteria, study criteria and contacts
separately.

In this post I am presenting with the kind permission of the principal
investigator Mark Klempner, M.D., some of the data from the review.
For
those interested in hearing more, Dr. Weinstein will be presenting an
update of the study at the LDF Medical Conference in New York on
Saturday April 10.

I also want to offer some opinions and observations, and hopefully
start
a thread of discussion about the study.

First of all the data:

The majority of the enrolled patients report improvement in their Lyme
symptoms from antibiotic treatments prior to enrollment. In the
analysis of the first 45 patients enrolled in the study 53% reported
improvement in joint pain (arthralgia), 27% reported improvement in
muscle pain (myalgia) and 42% reported improvement in their energy
level
(fatigue and malaise) during or after prior antibiotic therapy for CLD.
Over 75% reported improvement in one or more symptom with prior
antibiotic treatment.

The western blot test is picking up some seropositive patients who are
negative by ELISA. Of the 45 patients enrolled, 2 (4.4%) were ELISA
negative and IgG western blot positive. There were 7 (15.6%) that were
indeterminate by ELISA and positive by IgG western blot. These tests
use the CDC/Dearborn criteria for the western blot.

New objective tests to distinguish chronic Lyme patients from control
groups are being developed. Dr. Klempner recently published a paper
reporting that a 130 kilodalton CSF matrix metalloproteinase without
MMP-9 is found in 78% of untreated patients with neuroborreliosis
(confirmed by CSF antibody index > 1.2 or positive PCR). This pattern
was found in only 6% of control patients and thus may be a useful
marker
for neuroborreliosis. Now they have found that 64% of patients
enrolled
in the Chronic Lyme study also have 130 kilodalton CSF matrix
metalloproteinase without MMP-9, i.e. the same pattern. He also
discussed efforts to better characterize chronic Lyme patients by
developing new objective tests based on serum and CSF cytokines.

I was impressed by the scientific breadth of the study and the personal
commitment that Dr. Klempner and Dr. Weinstein have made to recruiting
patients and obtaining a definitive outcome. I believe that the
principal investigators will reach whatever conclusions the data takes
them too. I see no evidence of a hidden agenda in this study.

I believe that there is a good chance that this study will demonstrate
that this group of patients is antibiotic responsive. The enrolled
patients are so impaired on the SF-36 Health survey that even modest
improvement should be detectable, i.e. the study should be very
sensitive. The majority of enrolled patients report a positive
response
to antibiotics in the past, and the enrollment criteria exclude those
who have been treated longer than 60 days with IV antibiotics. I think
this exclusion is a good idea because in my opinion these patients are
less likely to show a benefit from the length of treatment given in
this
study.

Some have argued that the enrollment criteria are too strict and
exclude
many patients with Chronic Lyme disease. This is a personal concern of
mine. I am ill with what I believe to be antibiotic responsive chronic
Lyme disease. I have objective evidence exposure to Lyme disease and
active symptoms, but I do not meet the enrollment criteria. I've
thought about this issue a lot and discussed it with others more
knowledgeable about study design. There is a delicate balance in
choosing enrollment criteria that capture patients that one is
reasonably sure were exposed to Lyme disease without excluding the very
group that one is trying to study. The seronegative group (EM
enrollment criteria) helps in this regard - it has patients with a wide
range of antibody response. They are only seronegative in the sense of
the overly strict (in my opinion) Dearborn/CDC criteria. Many have one
or more bands by western blot.

Obviously, enrolling in the study is a very personal decision that
should be done in consultation with your doctor. I would not encourage
someone with neurological problems that are progressively worsening to
enroll in this study. In my opinion, patients in that category with
evidence of Lyme disease should seek immediate agressive antibiotic
treatment. I DO want to encourage people to consider enrolling if they
have persistant symptoms that are relatively stable. I believe that
multiple benefits could come from this study. We may get conclusive
evidence regarding the antibiotic responsiveness of this group of
patients including whether any current tests are predictive of
responsiveness. We will undoubtedly learn more about the disease that
will aid in development of better tests and perhaps even treatments.

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