EVALUATION OF THE KLEMPNER ARTICLE:
Stellungnahme von Burrascano zur sogenannten Klempnerstudie
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AN ILADS POSITION PAPER The most important facts - Dr.Burrascano
The International Lyme and Associated Diseases Society (ILADS), an international multi-specialty medical organization, reviewed the article by Klempner et al. in an objective and didactic fashion using principles of evidence-based medicine.
The study design, patient selection criteria, data reporting and outcomes analysis were all subjected to scrutinyStudy design and scientific objectivity were analyzed in light of peer-reviewed medical literature on chronic Lyme disease and associated tick-borne illnesses.INTRODUCTION
Chronic and persistent sequellae of tick bites became common knowledge in both the scientific and lay communities
Well documented but seronegative Lyme disease has been widely reported in the medical literature
These observations raise doubt about the reliability of negative results using current Lyme disease tests
Active central nervous system (CNS) infection can exist despite negative spinal fluid tests for B. burgdorferi, including normal cell count and chemistry evaluations and absent Lyme antibody titers.
The absence of antibodies against B. burgdorferi in CSF cannot be relied on to rule out CNS infection with this organism
Consequently, the diagnosis of B. burgdorferi infection should be made primarily on clinical grounds, with current serologies playing only supportive roles.
Almost impossible to obtain a definition of cure
Despite this uncertainty, some physicians insist that 30-day courses of antibiotic therapy are curative even for later stage Lyme disease
This belief persists despite seminal studies documenting that 30-day courses of antibiotics do not eradicate disseminated B. burgdorferi infection from mice, chimps and dogs
Many humans with late stage Lyme disease also are not cured of their symptoms with 30-day courses of antibiotics.
A number of peer reviewed publications demonstrating persistent infection with B. burgdorferi in humans despite multiple and extended courses of antibiotic therapy
Persistent infection has been demonstrated repeatedly by polymerase chain reaction (PCR), histopathology and by culture
Culture positivity has even been found in patients who are seronegative for the Lyme spirochete
In light of such data, it would be illogical to assume that persistent symptoms in chronically ill Lyme disease patients are not related to active infection with B. burgdorferi.
In direct opposition to the extensive body of published data, some researchers have attributed chronic symptoms compatible with Lyme disease to alternative vague diagnoses, such as post-Lyme syndrome, fibromyalgia, or chronic fatigue syndromeRESULTS
Numerous methodological weaknesses are noteworthy in the study
First is the initial contention that the study was intended to be a double blind, placebo-controlled trial of long-term antibiotic treatment for chronic Lyme disease patients of both seronegative and seropositive status
Inappropriate selection and inadequate randomization of study patients
For example, evaluated patients were excluded from participation if they tested positive by polymerase chain reaction (PCR) for the presence of B. burgdorferi DNA
Barring from the study the very patients who may have been most likely to benefit from antibiotics
PCR was then reported in the body of the work as if it were a new finding
This may mislead readers to conclude that chronic Lyme disease patients do not frequently have intermittently positive PCR reactivity following treatment with antibiotics.
Failure to recognize that spirochetal infection cannot be excluded without adequate culture techniques.
Inappropriate study design with respect to the antibiotic treatment regimen
Treatment regimen consisting of one month of intravenous ceftriaxone at 2 gm daily followed by two months of oral doxycycline at 200 mg daily
These antibiotics differ markedly in their mode of action and bioavailability, with no scientific evidence backing the assumption that their effect is additive or that the combination qualifies as long-term treatment
Consequently the trial amounted to a short-term ceftriaxone protocol for re-treatment of patients who had, without apparent success, experienced comparable treatment in the past, thereby undermining the principal objective of the study
Many of the patients had already failed treatment with a short course of ceftriaxone, thus increasing the odds that they would do so again
This approach introduced significant selection bias into the study
Furthermore, the doxycycline dose used in the study (200 mg daily) was inadequate for CNS penetration.
The acceptable medication compliance rate was 75%, reducing the doxycycline dose to sub-therapeutic levels
Randomization seems to have been insufficient in this research
At baseline, the placebo and antibiotic groups appeared to have significantly different scores on the primary outcome measures, thereby invalidating the results of the study
Failure to explain positive cerebrospinal fluid findings,
For example, Klempner et al. found that over 25% of the enrollees had elevated CSF protein and that 8 had intrathecal production of B. burgdorferi antibodies
These clinical parameters may be consistent with active neuroborreliosis
Failure to report objective neurocognitive assessments;
The neuropsychological scales used in the study were insufficient to assess the cognitive impairments in executive functioning and the psychiatric dysfunctions that are seen in patients with persistent Lyme disease
The SF-36 is a subjective assessment scale, based on the patient's self-perception.
There was a paucity of objective measures to assess the patient's status
Exclusion of pertinent findings from the final report
For example, Klempner publicly alluded to his testing for CSF matrix metalloproteinases in these patients, but this was not reported in the study
The exclusion of possible Jarisch-Herxheimer reactions
Is a serious oversight, since any assessment of interval change in patient status could not be conducted properly without consideration of such a common phenomenon
Indeed, for patients with active B. burgdorferi infection, worsening symptoms due to Jarisch-Herxheimer reactions potentially could have been troublesome enough to prompt their withdrawal from the study unless this complication had been discussed with them in advanceThe complexities of B. burgdorferi pathogenesis were not fully taken into consideration
Altered morphologic forms of B. burgdorferi are present
These host adapted forms are referred to collectively as L-forms or spheroplasts, of which cystic forms and granules are sub-types,
Have been extensively documented in vitro and in vivo, both extracellularly and intracellularly
Host-adapted forms of B. burgdorferi are considered to be major factors in the relapsing and persistent nature of Lyme disease
B. burgdorferi spheroplasts have unique antibiotic sensitivities
Although the utility of ceftriaxone for Lyme disease has been documented, it has been similarly documented that this agent frequently does not fully eradicate human B. burgdorferi infections
These findings are critically important since chronic infections are highly dependent on intracellular asylum as a mode of persistence, and localization within eukaryotic cells protects B. burgdorferi from antibiotics
Surprising that the lead author agreed to use ceftriaxone in this study, since he previously authored a paper on the fibroblast-mediated protection of B. burgdorferi in vitro from concentrations of ceftriaxone achieved in vivo for the treatment of Lyme disease
Failure to assess co-infection status of study participants
Ixodes ticks transmit other pathogens that may have infected the study patients, such as Babesia, Ehrlichia and Bartonella species.
veröffentlicht mit freundlicher Genehmigung von J. Burrascano
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