Prolonged symptoms following treatment of Lyme disease – Should patients with persistent symptoms following standard treatment of Lyme disease receive additional antibiotics?, pages 62-63, lines 1445-1449 and 1464-1468: Four randomized, controlled trials are cited as evidence against repeated antibiotic treatment (references #317, 321, 319).

A careful statistical analysis of the trials and their design calls into question the conclusion that repeated antibiotic treatment has no benefit. DeLong et al. showed that two trials conducted by Klempner (reference #317) had sample sizes too small to detect true minimum clinically important differences, particularly in SF-36 scores.

The guidelines state that in study by Fallon et al. (reference #321) “A cognitive index score at week 24 did not differ between treatment and control groups.” While true that objective measures such as cognitive test results did not show differences between PTLDS patients and controls, it is important to note that PTLDS patients in the study had to invest considerably more effort to achieve the same test scores. This would argue against the notion “that this phenomenon, in whole or in part, represents anchoring bias…”. Additionally, the authors did note a positive effect on fatigue, similar to that observed in the Krupp trial (reference #319), and Fallon and co-authors highlighted the need for further study.

In reviewing these clinical studies, DeLong et al. concluded that “primary outcomes originally reported as statistically insignificant were likely underpowered.” At the very least, DeLong’s analysis should be cited in the IDSA guidelines as evidence that further study of repeated antibiotic use should be very carefully designed, executed, and interpreted.

Regarding continued or repeated antibiotic treatment for persistent symptoms, the guidelines state that “A body of literature conducted in animal models has raised hypotheses of microbiological persistence”. While correct, this statement is wholly disingenuous as it fails to reference any of the studies and, worse, neglects to acknowledge that experimental results are presented that support the hypotheses put forward. It also is stated that “Moreover, animal models cannot reproduce the human experiences of fatigue and pain, and it is unlikely that any animal study can give reliable insight into the biology of humans experiencing such symptoms following treatment of Lyme disease.” Again, this statement neglects a significant body of literature describing animal models of human fatigue and chronic pain.  Such studies have been instrumental in advancing our understanding of the pathogenesis of these human conditions and have spurred the development of novel treatments. This statement also fundamentally misrepresents the intent of the diverse animal studies conducted that provide evidence of persistence of spirochetes post-antibiotic treatment of infected animals. The purpose of using animal models as articulated by Monica Embers, Ph.D. (Division of Bacteriology and Parasitology, Tulane National Primate Research Center, Tulane University Health Sciences Center) is “to understand the etiology of post-treatment Lyme disease syndrome (PTLDS), namely whether or not the spirochetes persist post-treatment and could thus contribute to chronic symptoms.” Symptoms experienced by PTLDS patients are not restricted to fatigue and pain, so one cannot reasonably discount the results of animal findings supporting spirochetal persistence because they are purported not to recapitulate all the symptoms experienced by humans.

Recent human evidence that continued bacterial presence may contribute to long-term symptoms was published by Jutras et al. in a 2019 PNAS article. They found that B. burgdorferi peptidoglycan, a component of the cell wall, was recovered from 94% of synovial fluid samples from Lyme arthritis patients, with specific IgG responses. Many of these patients had previously been treated with antibiotics. As peptidoglycan is shed from actively growing live bacteria, it’s at least plausible and worth further inquiry to study whether bacteria persist in these patients. If not, one is left with a less plausible explanation that foreign bacterial antigens must remain in inflamed tissues for weeks, months, or even years after (presumed) effective antibiotic-mediated killing of B. burgdorferi. With such intriguing findings at least hinting at the possibility of persistent organisms in Lyme disease patients, the authors of the revised guidelines should consider specifically referencing these animal and human studies rather than covering the entire topic by citing one publication (reference #320) and summarily discounting the results presented in so many other peer-reviewed scientific journals.