The communications from DeLong et al
1- DeLong A.K.
- Blossom B.
- Maloney E.
- Phillips S.E.
Potential benefits of retreatment highlight the need for additional Lyme disease research.
and Fallon et al
2- Fallon B.A.
- Petkova E.
- Keilp J.G.
- Britton C.B.
Ongoing discussion about the US clinical Lyme trials.
express concerns about the findings, implications, and methods used in the 4 published treatment trials for persistent symptoms in patients previously treated for Lyme disease.
The following can be concluded from the 4 treatment trials
3- Klempner M.S.
- Hu L.T.
- Evans J.
- et al.
Two controlled trials of antibiotic treatment in patients with persistent symptoms and a history of Lyme disease.
, 4- Kaplan R.F.
- Trevino R.P.
- Johnson G.P.
- et al.
Cognitive function in post-treatment Lyme disease. Do additional antibiotics help?.
, 5- Fallon B.A.
- Keilp J.G.
- Corbera K.M.
- et al.
A randomized, placebo-controlled trial of repeated IV antibiotic therapy for Lyme encephalopathy.
, 6- Krupp L.B.
- Hyman L.G.
- Grimson R.
- et al.
Study and treatment of post Lyme disease (Stop-LD). A randomized double-masked clinical trial.
and the various subsequent commentaries.
7- De Long A.K.
- Blossom B.
- Maloney E.L.
- Phillips S.E.
Antibiotic retreatment of Lyme disease in patients with persistent symptoms: a biostatistical review of randomized, placebo-controlled, clinical trials.
, 8- Fallon B.A.
- Petkova E.
- Keilp J.G.
- Britton C.B.
A reappraisal of the U.S. clinical trials of post-treatment Lyme disease syndrome.
, 9- Klempner M.S.
- Baker P.J.
- Shapiro E.D.
- et al.
Treatment trials for post-Lyme disease symptoms revisited.
None of the trials showed (and none of the investigators concluded) that additional retreatment with antibiotics led to a benefit for quality of life as assessed by a standard survey to assess this parameter (36-item Short Form Health Survey). The only issue for which there could be the slightest doubt is whether there was, in fact, a modest beneficial effect on fatigue. Given the uncertainty of whether a 0.7-point reduction in the score obtained on the fatigue severity scale used in the study by Krupp et al
6- Krupp L.B.
- Hyman L.G.
- Grimson R.
- et al.
Study and treatment of post Lyme disease (Stop-LD). A randomized double-masked clinical trial.
represents a clinically meaningful reduction in fatigue,
1- DeLong A.K.
- Blossom B.
- Maloney E.
- Phillips S.E.
Potential benefits of retreatment highlight the need for additional Lyme disease research.
, 9- Klempner M.S.
- Baker P.J.
- Shapiro E.D.
- et al.
Treatment trials for post-Lyme disease symptoms revisited.
it would seem more appropriate to evaluate the impact on fatigue simply on the basis of the percent reduction in the score.
In the study by Krupp et al,
6- Krupp L.B.
- Hyman L.G.
- Grimson R.
- et al.
Study and treatment of post Lyme disease (Stop-LD). A randomized double-masked clinical trial.
the fatigue score in the ceftriaxone-treated group decreased by 22% to a value of 4.4 at the 6-month time point versus a reduction of 9% in the placebo-treated group to a value of 5.5 (
P = .01). If a score of 4 or more is indicative of severe fatigue, as stated by Krupp et al,
6- Krupp L.B.
- Hyman L.G.
- Grimson R.
- et al.
Study and treatment of post Lyme disease (Stop-LD). A randomized double-masked clinical trial.
then on average both groups continued to have severe fatigue. In the study by Fallon et al,
5- Fallon B.A.
- Keilp J.G.
- Corbera K.M.
- et al.
A randomized, placebo-controlled trial of repeated IV antibiotic therapy for Lyme encephalopathy.
in which the duration of ceftriaxone treatment was 10 weeks, 2.5 times as long as the 4-week course in the study by Krupp et al,
6- Krupp L.B.
- Hyman L.G.
- Grimson R.
- et al.
Study and treatment of post Lyme disease (Stop-LD). A randomized double-masked clinical trial.
the reduction in fatigue in the ceftriaxone-treated group at 6 months was 15% (5.2 to 4.4) versus 15% in the placebo-treated group (5.5 to 4.7). The identical response rate found in both groups in the study by Fallon et al
5- Fallon B.A.
- Keilp J.G.
- Corbera K.M.
- et al.
A randomized, placebo-controlled trial of repeated IV antibiotic therapy for Lyme encephalopathy.
does not confirm that fatigue is selectively reduced in antibiotic-treated patients, and as in the study by Krupp et al,
6- Krupp L.B.
- Hyman L.G.
- Grimson R.
- et al.
Study and treatment of post Lyme disease (Stop-LD). A randomized double-masked clinical trial.
both groups on average continued to have severe fatigue. Furthermore, any conclusions based solely on the study by Krupp et al
6- Krupp L.B.
- Hyman L.G.
- Grimson R.
- et al.
Study and treatment of post Lyme disease (Stop-LD). A randomized double-masked clinical trial.
are open to question, because in that study 9 (33.3%) of the 27 placebo-treated patients did not receive intended treatment (n = 6) or were ineligible to have been enrolled in the first place (n = 3). Losses of more than 20% substantially reduce the validity of any study findings.
10Sample size slippages in randomized trials: exclusions and the lost and wayward.
On the basis of the available data, we agree with the conclusions of the investigators of the 4 trials
3- Klempner M.S.
- Hu L.T.
- Evans J.
- et al.
Two controlled trials of antibiotic treatment in patients with persistent symptoms and a history of Lyme disease.
, 4- Kaplan R.F.
- Trevino R.P.
- Johnson G.P.
- et al.
Cognitive function in post-treatment Lyme disease. Do additional antibiotics help?.
, 5- Fallon B.A.
- Keilp J.G.
- Corbera K.M.
- et al.
A randomized, placebo-controlled trial of repeated IV antibiotic therapy for Lyme encephalopathy.
, 6- Krupp L.B.
- Hyman L.G.
- Grimson R.
- et al.
Study and treatment of post Lyme disease (Stop-LD). A randomized double-masked clinical trial.
that none of the studies supported the use of additional antibiotic therapy with parenteral ceftriaxone and that parenteral therapy has significant risks. In the study by Fallon et al,
5- Fallon B.A.
- Keilp J.G.
- Corbera K.M.
- et al.
A randomized, placebo-controlled trial of repeated IV antibiotic therapy for Lyme encephalopathy.
more than one quarter of antibiotic-treated subjects experienced a serious adverse event. Further research is warranted to assess other potentially clinically effective therapies. However, because there is no convincing evidence to indicate that post-treatment Lyme disease symptoms are due to a persistent infection
3- Klempner M.S.
- Hu L.T.
- Evans J.
- et al.
Two controlled trials of antibiotic treatment in patients with persistent symptoms and a history of Lyme disease.
or that antimicrobial treatment is of benefit,
3- Klempner M.S.
- Hu L.T.
- Evans J.
- et al.
Two controlled trials of antibiotic treatment in patients with persistent symptoms and a history of Lyme disease.
, 4- Kaplan R.F.
- Trevino R.P.
- Johnson G.P.
- et al.
Cognitive function in post-treatment Lyme disease. Do additional antibiotics help?.
, 5- Fallon B.A.
- Keilp J.G.
- Corbera K.M.
- et al.
A randomized, placebo-controlled trial of repeated IV antibiotic therapy for Lyme encephalopathy.
, 6- Krupp L.B.
- Hyman L.G.
- Grimson R.
- et al.
Study and treatment of post Lyme disease (Stop-LD). A randomized double-masked clinical trial.
approaches that do not involve extended antibiotic therapy should be pursued actively.
11The pain of “chronic Lyme disease”: moving the discourse in a different direction.
, 12- Batheja S.
- Nields J.A.
- Landa A.
- Fallon B.A.
Post-treatment Lyme syndrome and central sensitization.
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Ongoing discussion about the US clinical Lyme trials.
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Article info
Footnotes
Funding: None.
Conflict of Interest: MSK has received research grants from the Centers for Disease Control and Prevention and National Institutes of Health. PJB has no conflicts of interest associated with the work presented in this manuscript. EDS is a board member of the American Lyme Disease Foundation, for which no compensation is received, and has received compensation from UpToDate for reviewing medical records for the Metropolitan Life Insurance Company and providing medicolegal testimony. AM is co-inventor on a patent application for a test for the detection of anti-Borrelia burgdorferi antibodies in which one of the antigens is based on the IR6 peptide (no money has been paid to her or to her institution): VOVO LIPS test for Lyme disease, US Provisional Application No. 61/312,520 filed March 10, 2010 (HHS Reference No. E-036- 2010/0-US-01). RJD has received research grants from the National Institutes of Health; is part owner of and has stock in Biopeptides Corp, no product of which is referred to in this article; has received payment for providing expert testimony in malpractice cases; and holds patents on vaccine and diagnostic technology with SUNY at Stony Brook and Biopeptides. JJH has served as an expert witness in several medicolegal cases concerning Lyme disease and has equity in Abbott, Bristol-Myers Squibb, Johnson & Johnson, and Merck; no products from these companies are referred to in this article. GPW has received research grants from the Centers for Disease Control and Prevention, National Institutes of Health, Immunetics, Inc, BioRad, DiaSorin, Inc, and BioMerieux; has equity in Abbott; has been an expert witness in malpractice cases involving Lyme disease; is an unpaid board member of the American Lyme Disease Foundation; and been an expert witness regarding Lyme disease in a disciplinary action for the Missouri Board of Registration for the Healing Arts; and is a consultant to Baxter for Lyme vaccine development.
Authorship: All authors had access to the data and played a role in writing this manuscript.
Copyright
© 2014 Elsevier Inc. Published by Elsevier Inc. All rights reserved.
