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Volume 358:428-431  January 24, 2008  Number 4

An Appraisal of "Chronic Lyme Disease"


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 by Feder, H. M.
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To the Editor: Feder et al. (Oct. 4 issue)1 review the great controversy surrounding "chronic Lyme disease." For most patients with this diagnosis, the authors advocate against the use of antibiotics.

But before the decision is made not to use antibiotics for patients with post–tick-bite symptoms, anaplasma, babesia, bartonella,2 and ehrlichia must be ruled out. These tick-borne2 intracellular pathogens are difficult to diagnose and can establish long-term, persistent infection.3,4,5 Anaplasma, babesia, and bartonella are underdiagnosed: the nonspecific symptoms of infections with these organisms tend to be ascribed to the more easily identifiable Lyme disease, which often accompanies them.2,3,4,5,6 Indeed, when studied prospectively, 65 of 161 patients with Lyme disease (40%) were coinfected with babesia, and 11 of 161 (7%) with anaplasma.6 Accurate diagnosis of these infections helps steer successful treatment: babesia3 and bartonella5 are especially difficult to eradicate. Accurate diagnosis is also important, since babesia3 and anaplasma4 can spread through blood transfusion.

As Feder et al. note, "chronic Lyme disease" is often unrelated to borrelia. If symptoms occur after a tick bite in the absence of evidence of active borrelia infection or if they persist despite anti-borrelia treatment, another tick-borne infection should be suspected. If such an infection is found, the patient may indeed benefit from appropriate antibiotics.

Lawrence Mayer, M.D.
16 Hudson St.
Lexington, MA 02421

Susanne Merz, B.S.
Jungfrudansen 34
S-17156 Solna, Sweden


  1. Feder HM Jr, Johnson BJB, O'Connell S, et al. A critical appraisal of "chronic Lyme disease." N Engl J Med 2007;357:1422-1431. [Free Full Text]
  2. Adelson ME, Rao RV, Tilton RC, et al. Prevalence of Borrelia burgdorferi, Bartonella spp., Babesia microti, and Anaplasma phagocytophila in Ixodes scapularis ticks collected in northern New Jersey. J Clin Microbiol 2004;42:2799-2801. [Free Full Text]
  3. Krause PJ, Spielman A, Telford SR III, et al. Persistent parasitemia after acute babesiosis. N Engl J Med 1998;339:160-165. [Free Full Text]
  4. Dumler JS. Is human granulocytic ehrlichiosis a new Lyme disease? Review and comparison of clinical, laboratory, epidemiological, and some biological features. Clin Infect Dis 1997;25:Suppl 1:S43-S47. [CrossRef][ISI][Medline]
  5. Rolain JM, Brouqui P, Koehler JE, Maguina C, Dolan MJ, Raoult D. Recommendations for treatment of human infections caused by Bartonella species. Antimicrob Agents Chemother 2004;48:1921-1933. [Free Full Text]
  6. Krause PJ, McKay K, Thompson CA, et al. Disease-specific diagnosis of coinfecting tickborne zoonoses: babesiosis, human granulocytic ehrlichiosis, and Lyme disease. Clin Infect Dis 2002;34:1184-1191. [CrossRef][ISI][Medline]

To the Editor: Feder et al. fail to adequately inform readers about the science underlying the "chronicity" debate. Multiple researchers have documented Borrelia burgdorferi's ability to penetrate human cells. In demonstrating the presence of the organism inside neurons and glial cells, Livengood and Gilmore established that it can exist in an intracellular state within a protected site,1 characteristics favoring persistence and necessitating longer courses of antibiotics. B. burgdorferi's pleomorphic abilities also favor persistence. One study suggested that penicillin, ceftriaxone, and doxycycline are ineffective against the bacteria in its cystic form.2 The study by Yrjänäinen et al. revealed that B. burgdorferi can survive standard therapy, lending further credence to the theory of bacterial persistence.3 Krupp et al. found that retreatment was beneficial; 69% of the treatment group, as compared with 23% of the placebo group, had significant improvement in fatigue.4

"Clinical assessment remains the most important method for determining the efficacy of treatment."5 Persistent symptoms in patients with late Lyme disease suggest treatment failure and the need for a new approach.

Elizabeth L. Maloney, M.D.
25611 West Comfort Dr.
Wyoming, MN 55092


  1. Livengood JA, Gilmore RD Jr. Invasion of human neuronal and glial cells by an infectious strain of Borrelia burgdorferi. Microbes Infect 2006;8:2832-2840. [CrossRef][ISI][Medline]
  2. Kersten A, Poitschek C, Rauch S, Aberer E. Effects of penicillin, ceftriaxone, and doxycycline on morphology of Borrelia burgdorferi. Antimicrob Agents Chemother 1995;39:1127-1133. [Abstract]
  3. Yrjänäinen H, Hytönen J, Song XY, Oski J, Hartiala K, Viljanen MK. Anti-tumor necrosis factor-alpha treatment activates Borrelia burgdorferi spirochetes 4 weeks after ceftriaxone treatment in C3H/HE mice. J Infect Dis 2007;195:1489-1496. [CrossRef][ISI][Medline]
  4. 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. [Free Full Text]
  5. Moellering R Jr, Eliopoulos G. Monitoring the response of the patient to antimicrobial therapy. In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas, and Bennett's principles and practice of infectious diseases. 6th ed. Vol. 1. Philadelphia: Elsevier, 2005.

To the Editor: The patient community discussed in the article by Feder et al. does not suffer from "mild and self-limiting subjective symptoms." These symptoms are disabling, precluding employment and school attendance. Patients have severe pain and cognitive dysfunction. Antibiotics have helped many such patients reclaim their lives.

A careful reading of the article shows that a diagnosis of Lyme disease is all but impossible without certain objective symptoms. These symptoms determine which patients receive the diagnosis, are treated, and are enrolled in research studies. Table 1 of the article shows objective symptoms present in a minority of patients. Erythema migrans rash may be undetected or misdiagnosed in persons infected with B. burgdorferi. Thus, many infected persons do not receive the diagnosis.

Patients who are seronegative for B. burgdorferi often do not lack an antibody response. A patient may have a strong positive response (IgG or IgM) to two genus-species–specific immunoblot bands for B. burgdorferi and have negative serologic test results because of the existing test criteria. For these reasons, some doctors may treat patients without qualifying clinical or serologic evidence of Lyme disease. In my view, many of these patients are helped greatly by treatment.

Karen D. Holmes, B.S.E.E.
1381 Peggy Ave.
Campbell, CA 95008

To the Editor: The article by Feder et al. on the proper therapy of chronic Lyme disease addresses a very timely concern. Unfortunately, the authors' statement that there are no "scientific data" that support persistent B. burgdorferi infection in the face of negative serologic test results is erroneous. In 1988, we reported on 17 patients who had all had erythema migrans, received inadequate antibiotic therapy, had vigorous T-cell blastogenesis to borrelia antigens, and were seronegative on the basis of enzyme-linked immunoassay.1,2 The majority of these patients had improvement after definitive antibiotic therapy. Seronegative infection was confirmed by other laboratories using polymerase-chain-reaction (PCR) assays to document the presence of microbes in seronegative patients.3,4 Abrogation of a humoral response by removal of the bulk of microbial antigens has been seen in other settings, including infection with Treponema pallidum. Although the use of repeated courses of antibiotics for a putative borrelia infection is unsupported and may cause serious morbidity,5 persons with evidence of previously inadequately treated Lyme disease may be seronegative and may benefit from adequate antibiotic therapy. Fortunately, erythema migrans is now more readily recognized, and occult Lyme disease is rarer. In the absence of antibiotic treatment, most persons become seropositive.

David J. Volkman, M.D., Ph.D.
State University of New York at Stony Brook
Stony Brook, NY 11794


  1. Dattwyler RJ, Volkman DJ, Luft BJ, Halperin JJ, Thomas J, Golightly MG. Seronegative late Lyme borreliosis: dissociation of specific T- and B-lymphocyte responses to Borrelia burgdorferi. N Engl J Med 1988;319:1441-1446. [Abstract]
  2. Volkman D. Prophylaxis after tick bites. Lancet Infect Dis 2007;7:370-371. [CrossRef][ISI][Medline]
  3. Keller TL, Halperin JJ, Whitman M. PCR detection of Borrelia burgdorferi DNA in cerebrospinal fluid of Lyme neuroborreliosis patients. Neurology 1992;42:32-42. [Free Full Text]
  4. Oksi J, Uksila J, Marjamäki M, Nikoskelainen J, Viljanen MK. Antibodies against whole sonicated Borrelia burgdorferi spirochetes, 41-kilodalton flagellin, and P39 protein in patients with PCR- or culture-proven late Lyme borreliosis. J Clin Microbiol 1995;33:2260-2264. [Abstract]
  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. [Free Full Text]

To the Editor: The appraisal of chronic Lyme disease by Feder et al. requires reevaluation. The strong recommendations made by the authors are based on a relatively small number of subjects, do not reflect clinical evidence, and do not take into account the International Lyme and Associated Diseases Society (ILADS) clinical practice guidelines.

It is time the medical community acknowledged Lyme disease as another example of "clinical equipoise" — an absence of consensus within the clinical community — and established publishing standards accordingly.

When clinical equipoise exists, it is even more critical for the medical community to be able to evaluate conflicting positions, the basis for the medical evidence cited, study criteria, and professional agendas and conflicts of interest that may exist. Only by airing these different points of view will the medical and scientific communities reach a better understanding of controversial topics such as chronic Lyme disease.

Currently, medical experts in support of the ILADS clinical practice guidelines are rarely, if ever, included in the process of scientific reviews. In the spirit of good science, I would suggest that this be changed.

Daniel J. Cameron, M.D., M.P.H.
First Medical Associates
Mt. Kisco, NY 10549

To the Editor: As an infectious-diseases consultant practicing in a highly Lyme-endemic area for more than 30 years, I have often seen patients who, convinced that they have chronic Lyme infection, leave my office disappointed or even angry at my refusal to prescribe prolonged antibiotic treatment. The article by Feder et al. is a valuable resource that I have already installed on my desktop. I salute the authors' efforts to refute those who would offer potentially hazardous treatment that is not evidence based, bolstered by reams of meaningless data from "special" laboratories and from Web sites rife with testimonials but bereft of scientific evidence. The balance between compassion for patients in distress and adherence to the evidence is exemplary and should be a help to patients and to their physicians. Good intentions do not justify improper treatment.

Mark S. Drapkin, M.D.
Newton–Wellesley Hospital
Newton, MA 02462

The author replies: My colleagues and I agree with Mayer and Merz that Ixodes scapularis ticks can transmit Anaplasma phagocytophilum, Babesia microti, or rarely, both of these pathogens, and that in the right clinical setting, appropriate diagnostic testing for these agents is warranted.1 There is no evidence that these or any other ticks transmit bartonella.1 There is also no evidence for the existence of chronic anaplasma infection in humans, nor is there any published clinical evidence that an active tick-borne coinfection is the explanation for symptoms in the vast majority of patients with post–Lyme disease syndrome.2

Maloney raises several issues that we fully address in our article. B. burgdorferi, like other spirochetes, predominantly resides in the extracellular matrix. Moreover, patients with post–Lyme disease syndrome who received a 2-month course of doxycycline, an antibiotic that enters cells, had no greater improvement than those who received placebo.2

Holmes attaches undue significance to serologic reactivity that fails to meet conventional guidelines for seropositivity. It is important to recognize that reactivity to one or more antigens of B. burgdorferi on immunoblot occurs in more than 50% of the general population because of the production of cross-reactive antibodies directed at either other bacteria or nonbacterial antigens. Indeed, the principal reason that the U.S. Public Health Service recommended both two-tier testing and the use of evidence-based criteria for interpreting immunoblots in 1995 was to reduce the number of false positive results. Use of immunoblot criteria with poor specificity contributes to substantial numbers of misdiagnosed cases and furthers public misperceptions of Lyme disease.

We disagree with Volkman. Seronegativity is unexpected in patients with any manifestation of late Lyme disease (e.g., Lyme arthritis).1 Cell-proliferation assays do not provide adequate evidence for the existence of seronegative Lyme disease because this method has an unacceptably high rate of false positive results (in one study the specificity was only 33%3). Similarly, certain studies using PCR assays in patients with possible Lyme disease also failed to meet high-level standards for scientific evidence. False positive results for the detection of DNA of B. burgdorferi by PCR testing are well recognized.4 Approaches to improving the reliability of PCR tests include avoiding nested-primer protocols, sequencing amplicons to confirm their identity, and using positive controls with distinctive sequences. Positive results may be confirmed by amplification of multiple gene targets and testing in separate laboratories in different locations.

The term "clinical equipoise," used by Cameron, is difficult to justify in view of the published reports of five double-blind, randomized, placebo-controlled clinical trials that have convincingly demonstrated that antibiotic treatment of post–Lyme disease symptoms is not in the best interests of patients.5 Our article summarizes the consensus among clinicians who practice evidence-based medicine, such as Drapkin, whom we thank for his comments.

Henry M. Feder, Jr., M.D.
University of Connecticut Health Center
Farmington, CT 06030

for the Ad Hoc International Lyme Disease Group


  1. 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;43:1089-1134. [Erratum, Clin Infect Dis 2007;45:941.] [CrossRef][ISI][Medline]
  2. 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. [Free Full Text]
  3. Zoschke DC, Skemp AA, Defosse DL. Lymphoproliferative responses to Borrelia burgdorferi in Lyme disease. Ann Intern Med 1991;114:285-289. [ISI][Medline]
  4. Aguero-Rosenfeld ME, Wang G, Schwartz I, Wormser GP. Diagnosis of Lyme borreliosis. Clin Microbiol Rev 2005;18:484-509. [Free Full Text]
  5. Halperin J. Prolonged Lyme disease treatment: enough is enough. Neurology (in press).


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 by Feder, H. M.
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