LTRS. TO EDITOR- NEJM ARTICLE ON CHRONIC LYME DISEASE

LTRS. TO EDITOR- NEJM ARTICLE ON CHRONIC LYME DISEASE

An Appraisal of "Chronic Lyme Disease"

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
lmayer@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. 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 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]
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]
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 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
holmeskd@sbcglobal,net

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
volkmans@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 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
cameron@lymeproject,com

I put all that stuff at the top of the new ActionLyme.org homepage.

On Apr 22, 11:05 pm, lipanz <lipanzmari...@aol,com > wrote:
> An Appraisal of "Chronic Lyme Disease"
>
> 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
> lma...@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. 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 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]
> 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]
> 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 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
> holme...@sbcglobal,net
>
> 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
> volkm...@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 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
> came...@lymeproject,com

Kathleen