The Klempner Article
By Robert Bransfield,
M.D.
and
The recent article in the NEJM, “Two Controlled
Trials of Antibiotic Treatment in Patients with Persistent Symptoms and a
History of Lyme Disease,” by Klempner,
et. al., provides some
interesting data, but the proper interpretation of this data is of little
relevance to both clinical practice and guidelines related to chronic Lyme disease. It does, however, provide some interesting
insight about the significance of PCR and IgG testing
in Lyme disease and it demonstrates a poor quality of
life is associated with a history of Lyme disease. It
is also an excellent example of the failure of objectivity in a peer reviewed
article in a prestigious medical journal followed by misperceptions of the
significance of this article by the media, which results in the improper use of
this article by the insurance industry. An objective review of this article is
one issue, while the role of this article towards perpetuating false beliefs
about Lyme disease is an additional and more
significant issue.
Medicine today is much like law. Both have
adversarial qualities. Information is presented in a manner that is most
effective in arguing a point of view. When this technique is effective, guilt
is proven to be innocence; black is proven to be white, etc. The technique is
always the same. There is a series of statements and conclusions. Each
statement is a 10-degree twist on the truth, so small that it can go below the
radar of our ability to detect deception. After a series of complicated and
related statements, there is a 180-degree twist to the truth.
The twists to this article began many years ago, when
a few rheumatologists involved in Lyme disease
incorrectly attempted to apply their observations of acute Lyme
arthritis to explain late-stage Lyme disease and Lyme neuroborreliosis. The
problem was compounded when Lyme disease was
conceptualized from the perspective of an acute infection rather than
recognizing the persistent relapsing nature of this microbe. These and many
other similar twists set the stage for biasing the researchers to confirm their
prior views on the subject. A failure to recognize and comprehend that
tick-borne diseases were often complex interactive infections involving
multiple stealth and persistent pathogens as well as an excessive reliance upon
molecular mimicry hypotheses further added to the problem. As a result of these
and other errors, a twenty-first century problem is approached with a
nineteenth century view of infectious disease. The bias was further solidified
as patent issues, competing diagnostic systems, research grants, reputations,
lawsuits, and a need to defend prior consultant decisions provided to insurance
companies by high paid consultants further clouded scientific objectivity.
Anyone coming from this perspective would be highly motivated to design a study
arguing that persistent infection was not a significant issue in Lyme disease, and this is exactly what happened.
The study design guaranteed the study would fail. The
design of the research protocol is the most critical step in the project. This
study had very restrictive inclusionary and
exclusionary criteria. The vast majority of patients with chronic Lyme disease do not meet the criteria for inclusion into
the study, therefore the findings and stated conclusions have no relevance to
most patients with chronic Lyme disease (CLD.) The
other two NIH sponsored trials had much better study designs. I recall sitting
in a meeting several years ago at NIH when the study design of the NIH
intramural study was discussed. A pyramid was used as an analogy. At the bottom
of the pyramid were the patients who had some of the features of Lyme disease, with disagreement about whether or not these
patients truly had Lyme disease. The intent was to
select the patients at the tip of the pyramid who clearly had Lyme disease. This strategy was NOT used in the Klempner study. Patients who demonstrated DNA evidence for
the presence of Borellia burgdorferi
by PCR testing were excluded from the study. There was only one short sentence
in the journal article that discussed this, and this was the most significant
sentence in the entire article. PCR testing has been considered absolute proof
in the legal system. Why would a PCR positive patient ever be excluded? It was
stated that it would have been unethical to give a placebo rather than the antibiotic
treatment to a PCR positive patient. This is a clear endorsement that positive
PCR testing is considered confirmation of persistent infection with Bb.
Depression, a major symptom of the neuropsychiatric
manifestations of Lyme disease, was also an
exclusionary criterion. Even though both PCR and depression were exclusionary
criteria, the status of the study participants was measured by PCR testing on
the spinal fluid and the Beck Depression Scale. Other means of evaluating the
status of the patients were the SF-36 and other testing. Basically, the wrong
tests and tests that lacked objectivity were used to evaluate the status of the
patients. Although there were 12 authors, none were psychiatrists. Why? Neuropsychiatric symptoms are a major part of the later
manifestations of Lyme disease. How can a study,
which is supposed to study late stage disease, not have the input of a
psychiatrist with experience in working with Lyme
disease? The neuropsychological scales that were implemented in the study were
notably insufficient to adequately assess the psychiatric symptoms and the
executive functioning impairments, which are associated with persistent Lyme disease infections. The SF-36 scale was used. The
scores were quite low, reflecting a poor quality of life for these patients. In
addition, the SF-36 is only a subjective scale based solely upon patient
opinion and contains no objective criteria for the assessment of patients’
status.
Rather than PCR, a positive IgG
Western Blot test based upon five bands at only one laboratory was used as a
reference point. No studies have ever demonstrated whether the absence of IgG reactivity had diagnostic significance in late-stage
disease.
The study was designed to provide patients with
“intensive antibiotics.” Although one month of ceftriaxone
and two months of doxycycline would be considered
intensive for the treatment of many acute infectious diseases, few physicians
who shoulder the responsibility of treating chronic Lyme
disease would consider this to be an adequate retreatment
for a patient with late-stage Lyme disease who had
failed prior courses of significant treatment. Results from recent scientific
studies on dog models by Strubinger of chronic Lyme disease indicate persistent infection even after six
months of antibiotic treatment. Furthermore, experience in the treatment of
human infections caused by other persistent bacteria, such as Treponema pallidum, Mycobacterium
tuberculum, and Helicobacter pylori demonstrates that
prolonged antibiotic therapy and/or different combinations of antibiotics would
result in greater improvement than was observed in this study. Additionally,
while the study tested patients for tick-borne coinfections
like babesiosis or ehrlichiosis,
it failed to offer any treatment strategies.
The placebo and treatment groups appeared to start
with significantly different scores on the primary outcome measures. In the
group of seropositive patients, those in the placebo
group had significantly better scores on the MOS Cognitive measures and exhibited
fewer neurocognitive symptoms at base-line than the
patients in the antibiotic group. In addition, within the seronegative
group patients in the placebo group had significantly poorer scores on the
SF-36 Mental Component, the MOS Pain scale, and the Fibromyalgia
Impact Questionnaire. The categorization of patients into Improved, Unchanged,
and Worse on each of the outcome components seems to lose a certain amount of
information about the magnitude of change in functioning from base-line until
post-treatment and to be lacking in statistical power compared with other
procedures for analyzing these data. In view of these two points, it would seem
advisable to utilize Analysis of Covariance procedures to measure the impact of
treatment on the outcome measures after adjusting for patients’ baseline scores
on the measures of functioning. This procedure would take into consideration
the baseline differences between groups, would treat change in the outcome
measures as a continuous rather than a categorical variable, and would afford
more statistical power in testing differences between the placebo and
antibiotic groups. Since the symptoms of chronic Lyme
disease are different in different patients, some patients presented
impairments primarily in specific areas of functioning and change from
treatment would be expected in the specific areas that were problematic for
each patient. An analysis of change in the most problematic items on each of
these scales would provide a more sensitive assessment of potential treatment
effects. In addition, the small sample size raises concerns about statistical
power and further undermines the validity of the study.
The 35% improvement threshold when combined with the
other study design constraints would predict a failure even before initiating
the study. It should have been necessary to adjust the status assessment to
make allowances for the Jarish-Herxheimer rection, but this was not a part of the study design. It
would be important to know more details of the NIH NIAID Data Safety and
Monitoring Board’s termination of the study.
Since the patients with seronegative
Lyme disease showed better improvement on antibiotics
than their seropositive counterparts, it appears that
negative IgG reactivity is not a useful criterion to
deny the presence of persistent infection. If the investigators feel persistent
infection was not a cause of the patient’s current symptoms, then what else is
a truly more plausible explanation?
A disclaimer reviewing the potential conflicts of
interests of the authors was absent from the article and would have been most
appropriate in light of the significant political, financial, and ethical
controversies surrounding chronic Lyme disease. This
should have included disclosures of the authors’ Lyme
disease-related insurance consultations, roles as defendants in Lyme-related lawsuits, and their roles as paid expert
witnesses as well as their ownership of Lyme
disease-related patents, commercial diagnostic systems, and their financial
vaccine interests.
Along with three other related articles, the Klempner article was distributed on the Internet a month
before the date of publication. The reason for the early release is a subject
of considerable speculation. When the article was released, there was a
well-orchestrated flood of articles in the media, which mostly interpreted the
significance of the article out of context. Since the release, insurance
companies have already used the article as proof to deny coverage for the
treatment of Lyme disease.
In summary, the design of the research and the manner
in which the article was written and promoted in the media even before it was
published reflects many of the biases that have obstructed scientific
objectivity and medical progress surrounding Lyme
disease for decades. The study demonstrates that patients with a history of
exposure to Lyme disease in the past who probably do
not have active infection at the time of the study as demonstrated by negative PCR’s and a history of significant antibiotic treatment in
the past, do not respond to inadequate antibiotic treatments as measured by
incorrect and highly subjective criteria that are not representative of
symptoms associated with CLD administered by physicians who appear to not know
how to treat Lyme disease, some of whom have strong
conflicts of interest to the contrary in a study that was never completed. In
short, the study proves very little. It does, however, demonstrate that it is
very easy to waste large amounts of Federal money for something of little
benefit to taxpayers. In a backhanded way, it validates PCR testing as proof of
persistent infection. It suggests that IgG testing by