To the Editor: Feder et al. (Oct. 4 issue)1 review the greatcontroversy surrounding "chronic Lyme disease." For most patientswith this diagnosis, the authors advocate against the use ofantibiotics.
But before the decision is made not to use antibiotics for patientswith post–tick-bite symptoms, anaplasma, babesia, bartonella,2and ehrlichia must be ruled out. These tick-borne2 intracellularpathogens are difficult to diagnose and can establish long-term,persistent infection.3,4,5 Anaplasma, babesia, and bartonellaare underdiagnosed: the nonspecific symptoms of infections withthese organisms tend to be ascribed to the more easily identifiableLyme 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%) withanaplasma.6 Accurate diagnosis of these infections helps steersuccessful treatment: babesia3 and bartonella5 are especiallydifficult 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 unrelatedto borrelia. If symptoms occur after a tick bite in the absenceof evidence of active borrelia infection or if they persistdespite anti-borrelia treatment, another tick-borne infectionshould be suspected. If such an infection is found, the patientmay indeed benefit from appropriate antibiotics.
Lawrence Mayer, M.D. 16 Hudson St. Lexington, MA 02421 lmayer{at}axigenmail.com
Susanne Merz, B.S. Jungfrudansen 34 S-17156 Solna, Sweden
References
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]
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]
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]
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]
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]
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. Multipleresearchers have documented Borrelia burgdorferi's ability topenetrate human cells. In demonstrating the presence of theorganism inside neurons and glial cells, Livengood and Gilmoreestablished that it can exist in an intracellular state withina protected site,1 characteristics favoring persistence andnecessitating longer courses of antibiotics. B. burgdorferi'spleomorphic abilities also favor persistence. One study suggestedthat penicillin, ceftriaxone, and doxycycline are ineffectiveagainst the bacteria in its cystic form.2 The study by Yrjänäinenet al. revealed that B. burgdorferi can survive standard therapy,lending further credence to the theory of bacterial persistence.3Krupp et al. found that retreatment was beneficial; 69% of thetreatment group, as compared with 23% of the placebo group,had significant improvement in fatigue.4
"Clinical assessment remains the most important method for determiningthe efficacy of treatment."5 Persistent symptoms in patientswith late Lyme disease suggest treatment failure and the needfor a new approach.
Elizabeth L. Maloney, M.D. 25611 West Comfort Dr. Wyoming, MN 55092
References
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]
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]
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]
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 articleby Feder et al. does not suffer from "mild and self-limitingsubjective symptoms." These symptoms are disabling, precludingemployment and school attendance. Patients have severe painand cognitive dysfunction. Antibiotics have helped many suchpatients reclaim their lives.
A careful reading of the article shows that a diagnosis of Lymedisease 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 ofthe article shows objective symptoms present in a minority ofpatients. Erythema migrans rash may be undetected or misdiagnosedin persons infected with B. burgdorferi. Thus, many infectedpersons do not receive the diagnosis.
Patients who are seronegative for B. burgdorferi often do notlack an antibody response. A patient may have a strong positiveresponse (IgG or IgM) to two genus-species–specific immunoblotbands for B. burgdorferi and have negative serologic test resultsbecause of the existing test criteria. For these reasons, somedoctors may treat patients without qualifying clinical or serologicevidence of Lyme disease. In my view, many of these patientsare helped greatly by treatment.
Karen D. Holmes, B.S.E.E. 1381 Peggy Ave. Campbell, CA 95008 holmeskd{at}sbcglobal.net
To the Editor: The article by Feder et al. on the proper therapyof chronic Lyme disease addresses a very timely concern. Unfortunately,the authors' statement that there are no "scientific data" thatsupport persistent B. burgdorferi infection in the face of negativeserologic test results is erroneous. In 1988, we reported on17 patients who had all had erythema migrans, received inadequateantibiotic therapy, had vigorous T-cell blastogenesis to borreliaantigens, and were seronegative on the basis of enzyme-linkedimmunoassay.1,2 The majority of these patients had improvementafter definitive antibiotic therapy. Seronegative infectionwas confirmed by other laboratories using polymerase-chain-reaction(PCR) assays to document the presence of microbes in seronegativepatients.3,4 Abrogation of a humoral response by removal ofthe bulk of microbial antigens has been seen in other settings,including infection with Treponema pallidum. Although the useof repeated courses of antibiotics for a putative borrelia infectionis unsupported and may cause serious morbidity,5 persons withevidence of previously inadequately treated Lyme disease maybe 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 antibiotictreatment, most persons become seropositive.
David J. Volkman, M.D., Ph.D. State University of New York at Stony Brook Stony Brook, NY 11794 volkmans{at}optonline.net
References
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]
Volkman D. Prophylaxis after tick bites. Lancet Infect Dis 2007;7:370-371. [CrossRef][ISI][Medline]
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]
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]
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 Federet al. requires reevaluation. The strong recommendations madeby the authors are based on a relatively small number of subjects,do not reflect clinical evidence, and do not take into accountthe International Lyme and Associated Diseases Society (ILADS)clinical practice guidelines.
It is time the medical community acknowledged Lyme disease asanother example of "clinical equipoise" — an absence ofconsensus within the clinical community — and establishedpublishing standards accordingly.
When clinical equipoise exists, it is even more critical forthe medical community to be able to evaluate conflicting positions,the basis for the medical evidence cited, study criteria, andprofessional agendas and conflicts of interest that may exist.Only by airing these different points of view will the medicaland scientific communities reach a better understanding of controversialtopics such as chronic Lyme disease.
Currently, medical experts in support of the ILADS clinicalpractice guidelines are rarely, if ever, included in the processof scientific reviews. In the spirit of good science, I wouldsuggest that this be changed.
Daniel J. Cameron, M.D., M.P.H. First Medical Associates Mt. Kisco, NY 10549 cameron{at}lymeproject.com
To the Editor: As an infectious-diseases consultant practicingin a highly Lyme-endemic area for more than 30 years, I haveoften seen patients who, convinced that they have chronic Lymeinfection, leave my office disappointed or even angry at myrefusal to prescribe prolonged antibiotic treatment. The articleby Feder et al. is a valuable resource that I have already installedon my desktop. I salute the authors' efforts to refute thosewho would offer potentially hazardous treatment that is notevidence based, bolstered by reams of meaningless data from"special" laboratories and from Web sites rife with testimonialsbut bereft of scientific evidence. The balance between compassionfor patients in distress and adherence to the evidence is exemplaryand should be a help to patients and to their physicians. Goodintentions 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 andMerz that Ixodes scapularis ticks can transmit Anaplasma phagocytophilum,Babesia microti, or rarely, both of these pathogens, and thatin the right clinical setting, appropriate diagnostic testingfor these agents is warranted.1 There is no evidence that theseor any other ticks transmit bartonella.1 There is also no evidencefor the existence of chronic anaplasma infection in humans,nor is there any published clinical evidence that an activetick-borne coinfection is the explanation for symptoms in thevast 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 residesin the extracellular matrix. Moreover, patients with post–Lymedisease syndrome who received a 2-month course of doxycycline,an antibiotic that enters cells, had no greater improvementthan those who received placebo.2
Holmes attaches undue significance to serologic reactivity thatfails to meet conventional guidelines for seropositivity. Itis important to recognize that reactivity to one or more antigensof B. burgdorferi on immunoblot occurs in more than 50% of thegeneral population because of the production of cross-reactiveantibodies directed at either other bacteria or nonbacterialantigens. Indeed, the principal reason that the U.S. PublicHealth Service recommended both two-tier testing and the useof evidence-based criteria for interpreting immunoblots in 1995was to reduce the number of false positive results. Use of immunoblotcriteria with poor specificity contributes to substantial numbersof misdiagnosed cases and furthers public misperceptions ofLyme disease.
We disagree with Volkman. Seronegativity is unexpected in patientswith any manifestation of late Lyme disease (e.g., Lyme arthritis).1Cell-proliferation assays do not provide adequate evidence forthe existence of seronegative Lyme disease because this methodhas an unacceptably high rate of false positive results (inone study the specificity was only 33%3). Similarly, certainstudies using PCR assays in patients with possible Lyme diseasealso failed to meet high-level standards for scientific evidence.False positive results for the detection of DNA of B. burgdorferiby PCR testing are well recognized.4 Approaches to improvingthe reliability of PCR tests include avoiding nested-primerprotocols, sequencing amplicons to confirm their identity, andusing positive controls with distinctive sequences. Positiveresults may be confirmed by amplification of multiple gene targetsand testing in separate laboratories in different locations.
The term "clinical equipoise," used by Cameron, is difficultto justify in view of the published reports of five double-blind,randomized, placebo-controlled clinical trials that have convincinglydemonstrated that antibiotic treatment of post–Lyme diseasesymptoms is not in the best interests of patients.5 Our articlesummarizes the consensus among clinicians who practice evidence-basedmedicine, such as Drapkin, whom we thank for his comments.
Henry M. Feder, Jr., M.D. University of Connecticut Health Center Farmington, CT 06030 hfeder{at}nso2.uchc.edu
for the Ad Hoc International Lyme Disease Group
References
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]
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]
Zoschke DC, Skemp AA, Defosse DL. Lymphoproliferative responses to Borrelia burgdorferi in Lyme disease. Ann Intern Med 1991;114:285-289. [ISI][Medline]
Aguero-Rosenfeld ME, Wang G, Schwartz I, Wormser GP. Diagnosis of Lyme borreliosis. Clin Microbiol Rev 2005;18:484-509. [Free Full Text]
Halperin J. Prolonged Lyme disease treatment: enough is enough. Neurology (in press).
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