Lyme Disease Practice and Research

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I am writing in response to a recent letter to the editor of Medical Minerva signed by Dr. Gary Wormser and a number of his colleagues, which challenged the design of a double-blind randomized placebo-controlled clinical trial (RCT) that I reported in 2008.[1] My report presenting the results of the RCT described the severity of chronic Lyme disease (CLD) and openly acknowledged the obstacles to completing a trial in actual practice.[2] I clearly described the RCT as “exploratory”, citing a higher than expected dropout rate due to the severity of the illness itself. Additional patients were dropped because of a higher than expected number that could have been reinfected.

In their letter to the editor of Medica Minerva April 2009, Dr. Wormser and his colleagues questioned the trial’s use of the Asch et al case definition for CLD. [1] My RCT was able to confirm that individuals meeting the Asch et al case definition exist in actual practice and that their quality of life (QOL) is poor compared to that of the general population.[3] Asch et al had reported in a retrospective cohort that 34% of 215 consecutively treated LD patients presented with “symptoms of arthralgia, cardiac or neurologic involvement with or without fatigue” a mean of 3.2 years after onset of illness.

The QOL for CLD patients using the Asch et al case definition in this RCT was as poor as for the CLD patients described in the Klempner and Fallon RCTs as measured by the SF-36 scale.[4] Klempner had characterized the QOL for patients with CLD as: “equivalent to those observed in patients with congestive heart failure or osteoarthritis and were more than 0.5 SD greater than the impairment observed in patients with type 2 diabetes or a recent myocardial infarction.”[4]

Dr. Wormser et al also questioned the adequacy of the initial antibiotic treatment that the patients enrolled in my RCT had received. My RCT could not ensure that each CLD patient had received adequate initial treatment, but neither could any of four National Institutes of Health (NIH) sponsored RCTs offer any reassurances of that kind.[5, 6] My RCT enrolled CLD patients had previously been treated with—at minimum-- the 2 to 4 weeks of antibiotics recommended by the Infectious Diseases Society of America (IDSA). There was no way to determine whether their previous treatment had been “adequate”, since no lab tests currently available can objectively and accurately determine when or if a Lyme patient has been “cured”.

What was clear, however-- based on clinical examination, reviewing medical records, and taking careful medical histories-- was that these patients remained ill despite having previously received no less than the minimum recommended amount of treatment. The patients in my RCT had received, on average, at least two previous courses of antibiotic treatment and had been ill an average of 7 months.[2] The Klempner et al RCTs described CLD patients’ ill an average of 4.7 years despite an average of three treatments without ever raising questions about the adequacy of the initial treatment.[5, 6] The Fallon et al RCT described average treatment delays of 2 years and an average duration of illness of 9 years without raising questions regarding the adequacy of initial treatment.[5, 6]

My RCT begins to address only the first two of the eight limitations of the Klempner RCTs which I have raised in analytic reviews.[5, 6] Those limitations are: 1) The design of RCTs did not address the range of treatment options available in an actual practice, 2) The findings cannot be generalized to actual practice, 3) The power of the evidence is inadequate to draw definite conclusions, 4) The evidence is too heterogeneous to make strong recommendations, 5) The risk to an individual of facing a long-term debilitating illness has not been considered, 6) The risk to society of a growing chronically ill population has not been considered, 7) Treatment delay has not been considered as a confounder, and 8) Co-infections have not been considered as a confounder.

My RCT’s conclusion that the “symptoms of CLD can be severe and a significant gain in the QOL for subjects randomized to amoxicillin without serious adverse events is consistent with the goal of improving patient’s QOL and consequently worthy of further study” remains exploratory.[2] Neither my RCT nor the four NIH-sponsored RCTs resolves the problem of CLD in actual practice.

  1.  Wormser GP, Shapiro ED, Halperin JJ, Porwancher RB, O'Connell S, Nadelman RB,
           Strle F, Radolf JD, Hovius JW, Baker PJ et al: Analysis of a flawed double-blind,
           placebo-controlled, clinical trial of patients claimed to have persistent Lyme disease
           following treatment. Minerva Med 2009, 100(2):171-172.

  2.  Cameron D: Severity of Lyme disease with persistent symptoms. Insights from a double-blind
            placebo-controlled clinical trial. Minerva Med 2008, 99(5):489-496.

  3.  Asch ES, Bujak DI, Weiss M, Peterson MG, Weinstein A: Lyme disease: an infectious and
           postinfectious syndrome. J Rheumatol 1994, 21(3):454-461.

  4.  Cameron DJ: Clinical trials validate the severity of persistent Lyme disease symptoms.
           Med Hypotheses 2008, 72:153-156.

  5.  Cameron DJ: Generalizability in two clinical trials of Lyme disease.
           Epidemiol Perspect Innov 2006, 3:12.

  6.  Cameron DJ: Insufficient evidence to deny antibiotic coverage to chronic
           Lyme disease patients. Med Hypotheses 2009, 72:688-691.