Lyme Wars: Conflicting Data - Part 3

http://www.bmj.com/cgi/eletters/335/7626/910#179199 

Raphael B. Stricker, MD

24 November 2007

We wish to address the inaccuracies and misstatements in the communication from microbiologist Susan O’Connell concerning the “Lyme Wars” article (3 November).

Dr. O’Connell states that the evidence-based guidelines of the International Lyme and Associated Diseases Society (ILADS) were not peer reviewed, citing a personal communication from an individual who is not associated with the publisher of the guidelines. Prior to publication, the ILADS guidelines underwent internal peer review by Expert Review of Anti- Infective Therapy, an independent medical journal (1). In contrast, the Lyme guidelines of the Infectious Diseases Society of America (IDSA) were self-published by IDSA in its own journal, Clinical Infectious Diseases (2). Self-publication implies a lack of independent peer review that probably contributed to the overly restrictive nature of the IDSA guidelines.

Dr. O’Connell maintains that the two-tier approach to Lyme antibody testing remains valid, and she gives two references to support her view (3,4). The first reference relies on data from 1988 and 1989 using “home- brew” Lyme antibody testing in patients with acrodermatitis and lymphocytic meningoradiculitis, and the sensitivity of this irrelevant test system was only 50-77% in patients with chronic disease (3). The second article contains the following statement: “Relatively few studies using currently available commercial tests have evaluated the performance of the recommended two-tier testing on well-characterized sera from patients with extracutaneous manifestations of Lyme borreliosis” (4). The few studies that have been performed found a consistently poor sensitivity of the two-tier test system essentially equivalent to a coin toss, as outlined in our recent letter to BMJ (5). Thus the two-tier approach endorsed by IDSA and Dr. O’Connell is inadequate for the diagnosis of Lyme disease.

Dr. O’Connell’s optimism about the wonderful new Lyme tests that are just around the corner is unwarranted. The only test that has become commercially available in recent years is the C-6 peptide ELISA, which was shown to have less sensitivity than the current two-tier test system (6). Until a “gold standard” test becomes available, physicians will need to rely heavily on their clinical judgment rather than commercial testing to support a diagnosis of Lyme disease.

Raphael B. Stricker, MD Past President, International Lyme & Associated Diseases Society San Francisco, CA 94108

Lorraine Johnson, JD, MBA Executive Director, California Lyme Disease Association Los Angeles, CA 90068

References

1. Cameron D, Gaito A, Harris N, et al. Evidence-based guidelines for the management of Lyme disease. Expert Rev Anti-Infect Ther 2004;2(1 Suppl):S1-13.

2. Wormser GP, Dattwyler RJ, Shapiro ED, et al. The clinical assessment, treatment, and prevention of Lyme disease, Human Granulocytic Anaplasmosis, and Babesiosis: Clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis 2006; 41:1089- 1134.

3. Wilske B, Fingerle V, Schulte-Sprechtel S. Microbiological and serological diagnosis of Lyme borreliosis. FEMS Immunol Med Microbiol 2007;49:13-21.

4. Aguero-Rosenfeld ME, Wang G, Schwartz I, Wormser GP. Diagnosis of Lyme borreliosis. Clin Microbiol Rev 2005;18:464-509.

5. Stricker RB, Johnson L. Lyme Wars: Let’s tackle the testing. BMJ 2007;335:1008.

6. Gomes-Solecki MJ, Meirelles L, Glass J, Dattwyler RJ. Epitope length, genospecies dependency, and serum panel effect in the IR6 enzyme- linked immunosorbent assay for detection of antibodies to Borrelia burgdorferi. Clin Vaccine Immunol 2007;14:875-9.

Competing interests: RBS serves on the advisory panel for QMedRx Inc.

*****

Raphael B. Stricker, MD

8 December 2007

Microbiologist Susan O’Connell gives us more examples of the inaccuracies and misstatements that have fuelled the “Lyme wars”. She turns conflicting data into weighty pronouncements about the diagnosis and treatment of Lyme disease.

Dr. O’Connell cites the Lyme guidelines of the Infectious Diseases Society of America (IDSA) and the American Academy of Neurology (AAN) as if these were independent documents that support narrow treatment recommendations for Lyme disease (1,2). In reality, these guidelines were developed by overlapping panels with the respective IDSA and AAN chairmen serving on both panels, assuring that the guidelines would be “like-minded” (3). In fact, the wording in the two guidelines is so similar that it precludes any sense of independent thought by the panel members. The IDSA tactic of using interlocking and exclusionary panels to induce other medical societies to rubber-stamp its Lyme guidelines helps to explain why IDSA is under investigation for anti-competitive practices in its Lyme guidelines development process (4).

Dr. O’Connell states that “five double-blind randomised control studies failed to demonstrate long term benefits and showed significant risks from prolonged antibiotic therapy for patients with persistent symptoms following Lyme disease” (5-9). Of the studies cited, two (Klempner et al. and Kaplan et al.) describe the same patients and are not independent (5,7). The studies by Krupp et al. and Fallon et al. in fact demonstrated significant improvement in fatigue, cognitive function and/or physical function with longer courses of antibiotics in patients with chronic Lyme disease (6,8). The recent study by Oksi et al. was underpowered to draw conclusions about treatment efficacy because the study only enrolled 152 out of the required 200 patients necessary for adequate data analysis (9). Of note, the prevalence of an erythema migrans rash in the study patients was only 28%, significantly lower than the figure touted by the IDSA guidelines as a ubiquitous marker of Lyme disease.

Dr. O’Connell claims that our analysis of the insensitivity of commercial Lyme testing has been addressed by Porwancher and colleagues (10). In spite of the mathematical gymnastics employed by those authors, the insensitivity of commercial Lyme testing remains an undisputed fact that has harmed thousands of Lyme patients who are denied appropriate diagnosis and treatment based on these inaccurate tests (11,12). Once again, it is misleading for Dr. O’Connell to tell us about the marvelous Lyme tests that are just around the corner while denying care for patients in her National Health Service based on the insensitive commercial tests that are currently available.

Dr. O’Connell’s allegation that the evidence-based guidelines of the International Lyme and Associated Diseases Society (ILADS) were not peer reviewed is based on a misunderstanding of the review process. Although the guidelines were not subject to external review that is often employed for original scientific articles, they were subjected to in-house peer review by the editorial staff of the journal. In view of the prestigious membership of the journal’s editorial board at the time, this form of peer review by an independent journal trumps the nebulous review process of the self-published IDSA guidelines described in our previous communication (13). As a result, the ILADS guidelines provide a more balanced evidence-based approach to the complex issues surrounding the diagnosis and treatment of Lyme disease and associated tick-borne disorders (14).

Raphael B. Stricker, MD Past President, International Lyme & Associated Diseases Society San Francisco, CA 94108

Lorraine Johnson, JD, MBA Executive Director, California Lyme Disease Association Los Angeles, CA 90068

References

1. Wormser GP, Dattwyler RJ, Shapiro ED, Halperin JJ, Steere AC, Klempner MS et al. The clinical assessment, treatment and prevention of Lyme disease, human granulocytic anaplasmosis and babesiosis: Clinical Practice Guidelines by the Infectious Diseases Society of America. Clin Infect Dis 2006;43:1089-1134.

2. Halperin JJ, Shapiro ED, Logigian, E, Belman AL, Dotevall L, Wormser GP et al. Practice Parameter: Treatment of nervous system Lyme disease (an evidence-based review) Neurology 2007;69:1-12.

3. Stricker RB, Johnson L. Practice Parameter: Treatment of nervous system Lyme disease (an evidence-based review). Neurology, November 1, 2007. Available at http:// www.neurology.org/cgi/eletters/69/1/91.

4. Stricker RB, Johnson L. Lyme disease: A turning point. Expert Rev Anti-Infect Ther 2007;5:759-762.

5. Klempner MS, Hu LT, Evans J et al. Two controlled trials of antibiotic treatment in patients with persistent symptoms and a history of Lyme disease. N Engl J Med 2001;345:85-92.

6. Krupp LB, Hyman LG, Grimson R et al. Study and treatment of post Lyme disease (Stop-LD). A randomized double-masked clinical trial. Neurology 2003;60:1923-1930.

7. Kaplan RF, Trevino RP, Johnson GP et al. Cognitive function in post-treatment Lyme disease. Do additional antibiotics help? Neurology 2003;60:1916-1922.

8. Fallon BA, Keilp JG, Corbera KM et al. A randomized, placebo- controlled trial of repeated IV antibiotic treatment for Lyme encephalopathy. Neurology 2007; Oct 10 epub.

9. Oksi J, Nikoskelainen J, Viljanen M et al. Duration of antibiotic treatment in disseminated Lyme borreliosis: a double-blind randomized, placebo-controlled multicenter study. Eur J Clin Microbiol Infect Dis 2007;26:571-581.

10. Stricker RB, Johnson L. Lyme Wars: Let’s tackle the testing. BMJ 2007;335:1008.

11. Johnson L, Stricker RB. Treatment of Lyme disease: A medicolegal assessment. Expert Rev Anti-Infect Ther 2004;2:533- 57.

12. Stricker RB. Counterpoint: Long-term antibiotic therapy improves persistent symptoms associated with Lyme disease. Clin Infect Dis 2007;45:149-57.

13. Stricker RB, Johnson L. Lyme wars: The battle continues. BMJ Online, November 24,2007. Available at http://www.bmj.com/cgi/ eletters/335/7626/910.

14. Cameron D, Gaito A, Harris N, Bach G, Bellovin S, Bock K et al. Evidence-based guidelines for the management of Lyme disease. Exp Rev Anti Infect Ther 2004;2(suppl1) S1-13.

Competing interests: RBS serves on the advisory panel for QMedRx Inc. In December 2007 he joined the editorial board of Expert Review of Anti-Infective Therapy.

*****

http://www.bmj.com/cgi/eletters/335/7626/910#179199

Joel Spinhirne, President
Verim Research

The least convincing response to this article to date has come from Donald Poretz, the president of a professional society, the Infectious Disease Society of America (IDSA), which is currently under investigation for unfair trade practices(1).

This letter continues the IDSA’s pattern of misstatement of fact. Contrary to Poretz' claim that, "In more than 20 years there has not been one scientifically valid study published in the peer-reviewed medical literature that proves that the benefit of long-term antibiotic treatment outweighs the risks", in 1997 one of the IDSA's own journals published a study showing the benefit of antimicrobial therapy of longer than three month duration(2). Rather than follow this paper with subsequent studies investigating the benefits of therapy extending beyond three months, the IDSA repeatedly endorses poorly performed clinical studies, none of which examined therapy beyond three months. The initial investigator of the 1997 paper published his follow-up paper in a European journal(3). This study again showed benefits of therapy longer than three months.

Suggesting borreliosis is actually another unexplained illness, as Poretz does, is entirely dependent upon the physician’s inability or unwillingness to recognize the most likely cause of the presenting illness, persisting infection. There is no test or procedure that comes close to reliably indicating a patient is not infected with Borrelia burgdorferi. Any diagnosis denying infection lacks a scientific basis.

Contrary to Poretz’ claims, there is a startling absence of validated studies showing quantification of harm caused by antimicrobial treatment, let alone correlation of this harm with borreliosis treatment.

The study most often cited by the IDSA to justify non-treatment of borreliosis, at its fundamental level, demonstrated nothing.(4) The investigators reported their inability to detect anything of significance. The question then becomes how hard did they look for treatment effect? While the IDSA has long encouraged ignoring patient self-reporting, this study was entirely dependent on patient self-reports measured with an extremely insensitive measurement tool. There were zero post-treatment objective measures reported nor the result of any physician interview or examination. In addition, the number of subjects was exceedingly small and limited to subjects who had previously failed treatment much like the one being tested.

At some point the critical reader needs to ask why the IDSA needs to ignore or misstate so much to make their case. And, at some point the “do no harm” shibboleth is entirely unconvincing. Competent mainstream medical care dictates antimicrobial therapy of a duration necessary to control the causative infection. Tens of thousands, maybe more, patients reporting benefit, and no harm, from more than three months of antimicrobials is evidence — and the best evidence we have.

1. Hamilton E. Lyme Disease Guidelines Focus Of Antitrust Probe. The Hartford Courant. November 17, 2006.

2. Donta ST. Tetracycline therapy for chronic Lyme disease. Clin Infect Dis 1997;25 Suppl 1:S52-6.

3. Donta ST. Macrolide therapy of chronic Lyme Disease. Med Sci Monit 2003;9(11):PI136-42.

4. Klempner MS, Hu LT, Evans J, et al. Two controlled trials of antibiotic treatment in patients with persistent symptoms and a history of Lyme disease. N Engl J Med 2001;345(2):85-92.

Tweet