Correspondence
Treatment of Patients with Persistent Symptoms and a History of Lyme Disease
N Engl J Med 2001; 345:1424-1425November 8, 2001
- Article
To the Editor:
The study reported by Klempner et al. (July 12 issue)1 showed that patients with chronic Lyme disease are ill; it also showed that the antibiotics used (intravenous ceftriaxone for one month, followed by oral doxycycline for two months) did not lead to improvement. The study did not answer the question of whether better outcomes would have resulted from a longer duration of either intravenous ceftriaxone or oral doxycycline therapy or from treatment with different antibiotics for the same or a longer period. The assumption that ceftriaxone and doxycycline are equivalent and additive treatments for chronic Lyme disease is untested. The mechanisms of action of the two drugs and their intracellular concentrations differ markedly.
Klempner et al. cite studies that my colleagues and I have performed with tetracycline2 but do not discuss the pertinent observations — that tetracycline appears to be more effective than doxycycline, that intracellular-type antibiotics may be more effective than beta-lactams, and that the period of therapy required to achieve stable improvement is much longer than three months. We have since observed that other intracellular-type treatments appear to be effective for the treatment of chronic Lyme disease when they are used for longer periods.3 There is a need to treat other chronic infections (e.g., tuberculosis, leprosy, Q fever, and hepatitis C) for more than three months.
The study by Klempner et al. was a beginning. What we need now, as the next step in finding successful treatments for all patients who are ill with chronic Lyme disease, is additional trials to evaluate alternative antibiotic therapies and different periods of treatment.
3 ReferencesSam T. Donta, M.D.
Boston University Medical Center, Boston, MA 02119
sam.donta@bmc. org 1
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
Full Text | Web of Science | Medline2
Donta ST . Tetracycline therapy for chronic Lyme disease. Clin Infect Dis 1997;25:Suppl 1:S52-S56
CrossRef | Web of Science | Medline3
Donta ST. Treatment of chronic Lyme disease with macrolide antibiotics. In: Program and abstracts of the 8th International Conference on Lyme Borreliosis, June 20–24, 1999, Munich, Germany. abstract.
To the Editor:
The report by Klempner et al. raises an important question about a poorly understood condition: Does antibody-negative Lyme disease have a different response to treatment from that of antibody-positive disease? Although no improvement was associated with antibiotic treatment among the seropositive patients, among those who were seronegative, the proportions of patients who had improvement in the physical and mental components of the 36-item Short-Form General Health Survey (SF-36) were larger in the antibiotic group (41 percent and 36 percent, respectively) than in the placebo group (22 percent and 26 percent, respectively).
In a 1996 report of a new polymerase-chain-reaction (PCR) technique, Mouritsen et al. noted that all nine samples that were positive for Borrelia burgdorferi DNA by PCR were from patients who were seronegative for antibodies to B. burgdorferi.1 In the 29 samples from patients who were seropositive for antibodies, B. burgdorferi DNA was not detected. One reasonable explanation for this difference is that seronegative patients may have more difficulty clearing B. burgdorferi than patients with a robust antibody response.
1 ReferencesMark E. McCaulley, M.D.
43480 RCR 36, Steamboat Springs, CO 80487
mccaulley@springsips.com 1
Mouritsen CL ,Wittwer CT ,Litwin CM , et al. Polymerase chain reaction detection of Lyme disease: correlation with clinical manifestations and serologic responses. Am J Clin Pathol 1996;105:647-654
Web of Science | Medline
To the Editor:
The study by Klempner et al. appears to have been designed to fail. Why was a positive PCR test for B. burgdorferi a formal criterion for exclusion from a study intended to provide insight into the controversy over chronic Lyme disease? If there is a consensus that PCR positivity constitutes laboratory confirmation of active infection, and if patients with a positive result were excluded from this placebo-controlled study for ethical reasons, this point should have been emphasized.
Neuropsychiatric symptoms are a substantial part of chronic Lyme disease.1,2 The neuropsychological scales used in the study were insufficient to assess the impairments in executive functioning and the psychiatric dysfunction that are seen in patients with persistent Lyme disease. The SF-36 is a subjective assessment scale, based on the patient's opinion, and there was a paucity of objective measures to assess the patient's status. Furthermore, at base line, the placebo and antibiotic groups appeared to have significantly different scores on the primary outcome measures. These observations suggest that randomization may have been inadequate, thereby invalidating the results of the study.
2 ReferencesRobert Bransfield, M.D.
Riverview Medical Center, Red Bank, NJ 07701
rbransfield@monmouth.com Stephen Brand, Ph.D.
University of Rhode Island, Kingston, RI 02881Virginia Sherr, M.D.
47 Crescent Dr., Holland, PA 18966-21051
Fallon BA ,Nields JA . Lyme disease: a neuropsychiatric illness. Am J Psychiatry 1994;151:1571-1583
Web of Science | Medline2
Bransfield RC . Diagnosis, treatment, and prevention of Lyme disease. JAMA 1998;280:1049-1049
CrossRef | Web of Science | Medline
To the Editor:
Because Klempner and his colleagues used liberal enrollment criteria, it is likely that the groups they studied were rather heterogeneous. A more intensive analysis of subgroups might have revealed distinctive characteristics that could influence current medical practice or at least the design of future studies.
It is striking that the use of placebo was associated with demonstrable improvement in the mental component of the SF-36 score in 46 percent of seropositive subjects and that this was the highest favorable response rate in the study. Although the lack of an untreated control group in the study limits the interpretation of this observation, the possibility of a substantial placebo effect is not unimportant. These chronically ill patients may have benefited solely from the sustained interest and attention of the investigators. This study should serve not only to discourage the indiscriminate use of antibiotics in patients with persistent symptoms and a history of Lyme disease but also to encourage ongoing support of such patients. Having removed one thread of hope — that antibiotics would be helpful — the study should not become a justification for telling patients that there is currently nothing that can be done for them.
David J. Wyler, M.D.
194 Ward St., Newton Centre, MA 02459
dwyler@mediaone.net Author/Editor Response
The authors reply:
To the Editor: Our study does indeed show that patients with persistent pain and neurocognitive symptoms after treatment for acute Lyme disease have substantial impairment of their quality of life. In contrast to Donta's interpretation that the patients did not have improvement, approximately one third of the patients treated with antibiotics had improved SF-36 scores and approximately one half had improved scores on the Fibromyalgia Impact Questionnaire. However, these results were not statistically different from those in the placebo group, suggesting that patients have symptoms that wane and wax spontaneously. In contrast to the findings in patients with the chronic infectious diseases that Donta cites as requiring prolonged therapy, we did not find evidence of persistent borrelial infection. Furthermore, when antibiotic therapy is given for tuberculosis, Q fever, or hepatitis C, objective responses are expected during the first three months of treatment. In contrast to Donta's uncontrolled studies, controlled trials of treatment for Lyme disease with the use of antibiotics that are excluded from the intracellular environment and those that are concentrated in the intracellular environment have had similar results.1-3 Furthermore, B. burgdorferi appears mainly within tissues in extracellular sites.4 Our studies suggest that trials of nonantibiotic therapies are warranted for this condition.
Contrary to McCaulley's comments, there was no significant difference between the responses of the seronegative patients and those of the seropositive patients. At the base-line screening and during treatment, we also did not find evidence of B. burgdorferi DNA in cerebrospinal fluid or blood samples from either the seronegative or the seropositive patients. We know of no evidence that in response to antibiotic treatment, seronegative patients “have more difficulty clearing B. burgdorferi” than do seropositive patients.
Bransfield et al. are correct that the detection of borrelial DNA by PCR in pretreatment blood and cerebrospinal fluid samples was a reason for excluding patients because such patients require antibiotic therapy. However, we screened over 1800 patients for this study, and no patient was excluded for this reason, since no patient was found to have a positive PCR assay or culture for borrelia — a result that confirms the absence of evidence of active infection in this clinical syndrome. We agree that the patients in our study exhibited neuropsychiatric symptoms in the absence of objective neurologic findings.5 All patients were given an extensive battery of neurocognitive tests in addition to the SF-36. A forthcoming analysis of these data should be sufficient to demonstrate any cognitive impairment, should it exist. The randomization protocol was adequate, since base-line values for the primary outcome measures in all patients were statistically equivalent in the placebo and antibiotic groups.6 Moreover, each patient served as his or her own control, since the clinical response was measured by calculating a change in health status for each patient.
Contrary to Wyler's comments, our criteria for enrollment were very stringent. Less than 10 percent of screened subjects actually qualified for the study. We agree that antibiotic therapy offers no long-term benefit, and further studies on pathogenesis and treatment are needed.
6 ReferencesArthur Weinstein, M.D.
Washington Hospital Center, Washington, DC 20010Mark S. Klempner, M.D.
Boston University School of Medicine, Boston, MA 021181
Dattwyler RJ ,Volkman DJ ,Conaty SM ,Platkin SP ,Luft BJ . Amoxycillin plus probenecid versus doxycycline for treatment of erythema migrans borreliosis. Lancet 1990;336:1404-1406
CrossRef | Web of Science | Medline2
Nadelman RB ,Luger SW ,Frank E ,Wisniewski M ,Collins JJ ,Wormser GP . Comparison of cefuroxime axetil and doxycycline in the treatment of early Lyme disease. Ann Intern Med 1992;117:273-280
Web of Science | Medline3
Dattwyler RJ ,Luft BJ ,Kunkel MJ , et al. Ceftriaxone compared with doxycycline for the treatment of acute disseminated Lyme disease. N Engl J Med 1997;337:289-294
Full Text | Web of Science | Medline4
Steere AC . Lyme disease. N Engl J Med 2001;345:115-125
Full Text | Web of Science | Medline5
Bujak DI ,Weinstein A ,Dornbush RL . Clinical and neurocognitive features of the post Lyme syndrome. J Rheumatol 1996;23:1392-1397
Web of Science | Medline6
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
Full Text | Web of Science | Medline
- Citing Articles (5)
Citing Articles
1
Kristin M Corapi, Samardeep Gupta, Matthew H Liang. (2008) Management of Lyme disease. Expert Review of Anti-infective Therapy 6:2, 241-250
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R. B. Stricker. (2007) Counterpoint: Long-Term Antibiotic Therapy Improves Persistent Symptoms Associated with Lyme Disease. Clinical Infectious Diseases 45:2, 149-157
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Raphael B. Stricker, Andrew Lautin, Joseph J. Burrascano. (2006) Lyme Disease: The Quest for Magic Bullets. Chemotherapy 52:2, 53-59
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Raphael B Stricker, Andrew Lautin, Joseph J Burrascano. (2005) Lyme disease: point/counterpoint. Expert Review of Anti-infective Therapy 3:2, 155-165
CrossRef5
Raphael B Stricker, Andrew Lautin. (2003) The Lyme Wars: time to listen. Expert Opinion on Investigational Drugs 12:10, 1609-1614
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