Maintaining IgM Antibodies for Years, Poor Prognosis in LD

Medical topics with questions, information and discussion related to Lyme disease and other tick-borne diseases.
Claudia
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Maintaining IgM Antibodies for Years, Poor Prognosis in LD

Post by Claudia » Tue 5 Jul 2011 16:49

From 1999 American Nurses Association:

Lyme Disease

Antibody Production

IgM
Indicates new infection
First antibody produced
Peaks at approximately 4 weeks
Some individuals maintain IgM antibodies for many years; indicates a poor prognosis
Does not cross placental barrier

IgG
Indicates older infection
Are produced several weeks following infection
Peaks at 6-8 weeks
Crosses placental barrier

http://www.nursingworld.org/mods/archive/mod5/cely6.htm
Does anybody have any more information, found any studies or research about a history of IgM antibodies and a poor patient outcome? Please post them here. Thank you.

Claudia
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Location: Connecticut, USA

Re: Maintaining IgM Antibodies for Years, Poor Prognosis in

Post by Claudia » Fri 22 Jul 2011 15:30

I ordered this medical text book, published in 2008, after seeing it on Camp Other blog, primarily because my son's Lyme disease symptoms are predominately neuropsychiatric and I was interested in learning more information:
Neurology, American Academy of Neurology

Book Review: THE NEUROLOGICAL MANIFESTATIONS OF PEDIATRIC INFECTIOUS DISEASES AND IMMUNODEFICIENCY SYNDROMES
John J. Millichap, MD


THE NEUROLOGICAL MANIFESTATIONS OF PEDIATRIC INFECTIOUS DISEASES AND IMMUNODEFICIENCY SYNDROMES

edited by L.L. Barton and N.R. Friedman, 421 pp., Totowa, NJ, Humana Press, 2008, $139

Pediatric neuroinfectious diseases is an evolving and important neurologic subspecialty. The Neurological Manifestations of Pediatric Infectious Diseases and Immunodeficiency Syndromes is the only available text focused primarily on this subject. Doctors Leslie L. Barton, a pediatric infectious diseases specialist, and Neil R. Friedman, a pediatric neurologist, produced a complete reference with a target audience that includes residents, general pediatricians, pediatric critical care specialists, pediatric infectious disease specialists, and pediatric neurologists.

The book is organized into 8 sections. The first 6 refer to all major classes of infectious agents, while the last 2 include immunodeficiencies and general clinical management principles. Each neuropathogen is covered with a common format that provides both basic information for the generalist as well as specific evidence-based management for the pediatric neuroinfectious diseases specialist. There is a complete list of references at the end of each chapter. Important data are plentiful and displayed in 27 tables and multiple figures (8 MRIs, 7 photographs, 4 CTs, and 2 EEGs). There is a complete index for reference use, but the writing style also facilitates a cover-to-cover overview of the subspecialty.

The editors, and contributing authors, succeeded in fulfilling the needs of interested readers with variable backgrounds and expertise who encounter pediatric neuroinfectious diseases. Organization of the book by neuropathogen favors the perspective of the infectious disease specialist rather than that of the neurologist, who may categorize by diseases instead. Neurology residents and fellows will find this book useful for managing patients, but it is too detailed to be an appropriate resource for board review. The Neurological Manifestations of Pediatric Infectious Diseases and Immunodeficiency Syndromes will endure as the seminal text of the emerging subspecialty of pediatric neuroinfectious diseases.

http://www.neurology.org/content/73/19/e96.full
This book is part of a series of books on Infectious Disease, the series editor is from the National Institute of Allergy and Infectious Disease, National Institute of Health, and is geared towards medical professionals. So I would imagine that it was carefully edited for accurate and the most up to date content.

I was more than very interested to read this passage from the chapter on Borrelia burgdorferi, diagnosis section, page 281:
IgM antibody levels rise approximately 2 to 4 weeks after the onset of EM, peak at approximately 6 to 8 weeks, and become nondetectable 4 to 6 months after EM. Persistence of IgM may be an indicator of persistent infection or re-infection. IgG antibody levels rise 6 to 8 weeks after EM, peak at 4 to 6 months after EM, and remain elevated for life [4, 28].
This passage notes the following two references:

4. Rahn DW. Lyme disease: clinical manifestations, diagnosis, and treatment. Semin Arthritis Rheum 1991 Feb;20(4):201-18.

28. Ravel R. Spirochetal and Rickettsial Infections. In: Ravel R, ed. Clinical Laboratory Medicine 6th ed. St. Louis, MO: Mosby Inc.; 1995; 232-233.
I can't find free versions of these two reference papers. If anybody has a pdf hanging around somewhere, I'd be very interested in reading these. THANK YOU.

As an aside, this book was also very interesting to read because I was surprised to see how many infections can have similar neurological manifestations as those seen in CNS Lyme disease. The book is also a valuable source of references to articles on other tick-borne infections and disorders.

RitaA
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Re: Maintaining IgM Antibodies for Years, Poor Prognosis in

Post by RitaA » Sat 23 Jul 2011 16:21

Claudia,

Chances are that you are already aware of this, however I'm posting it on the off-chance that you are not:

http://www.ncbi.nlm.nih.gov/pmc/article ... 6-0052.pdf

West J Med. 1991 June; 154(6): 706–714.
PMCID: PMC1002871
Conferences and Reviews

Lyme Disease
DANIEL W. RAHN, MD, and STEPHEN E. MALAWISTA, MD, New Haven, Connecticut
In 1982, Burgdorfer and associates24 isolated the spirochete that bears his name from I dammini collected on Shelter Island, New York, and linked it serologically to patients with Lyme disease. Within months this organism had been cultured from specimens of blood, skin, and cerebrospinal fluid of patients, and specific IgM and IgG antibody responses had been delineated.25 26 Because of its infectious cause but inflammatory or "rheumatic" expression, Lyme disease, beyond intrinsic interest as a new nosologic entity, presents a unique human model for an infectious cause of a chronic rheumatic disease.27
(page 707):
Lyme disease is associated with characteristic immune abnormalities.7-10 At disease onset (ECM), most patients have evidence of circulating immune complexes.9"l0 At that time, the findings of elevated serum IgM levels and cryoglobulins containing IgM predict subsequent nervous system, heart, or joint involvement7'8; that is, early humoral findings have prognostic significance. Serial determinations of serum IgM can be a helpful laboratory indicator of risk of future disease activity. These abnormalities tend to persist during neurologic or cardiac involvement, but by the time arthritis is present, serum IgM levels are more often normal. By then, immune complexes are usually lacking in serum but are present uniformly in joint fluid,10 where their titers correlate positively with the local concentration of polymorphonuclear leukocytes.54 Mononuclear cells from peripheral blood show increasing proliferative responses to spirochetal antigens as the disease progresses, but the greatest reactivity is seen in synovial fluid cells from inflamed joints.52 Mononuclear cells exposed to spirochetes produce interleukin- 1, and interleukin-l has been found in fluid from inflamed joints.55 On biopsy a proliferative synovium is seen, often replete with lymphocytes and plasma cells that presumably are capable of producing immunoglobulin locally. Thus, an initially disseminated, immune-mediated inflammatory disorder becomes in some patients localized and propagated in joints.
(pages 710-711):
Figure 2.-The typical antibody response is shown in persons with untreated Lyme disease. Specific IgM antibodies usually become detectable 2 to 4 weeks after onset of disease. The subsequent appearance of specific IgG antibodies is frequently concurrent with systemic manifestations. IgM antibody levels typically decline over 4 to 6 months, even in untreated patients; a persistence of high IgM antibody levels is predictive of later manifestations of disease. IgG antibodies are almost always elevated during late disease (from Rahn and Malawista68).
Determination of specific antibody titers is currently the most helpful diagnostic test for Lyme disease. IgM antibodies against B burgdorferi usually appear two to four weeks after disease onset and reach a peak between the third and sixth week; specific IgG antibody titers rise more slowly and are generally highest months later when arthritis is present (Figure 2).2597 Persons with Lyme disease of more than six weeks' duration can be expected to have detectable specific antibodies. The tests used, however, are not yet standardized, and results from different commercial laboratories may vary.98 Although either immunofluorescence assays or enzyme-linked immunosorbent assays (ELISA) are offered, the ELISA technique offers the advantages of being more reproducibile, less subjective, and automatable. Such assays, however, cannot distinguish patients with active infection from those with previous immunologic exposure but without current infection. In our experience, the vast majority of persons with Lyme arthritis have a positive serologic response, and this finding makes antibody titers against B burgdorferi particularly useful in differentiating Lyme disease from other rheumatic syndromes, especially when ECM has been missed, forgotten, or absent.
(page 711):
The major goal of therapy in Lyme disease is to eradicate the causative organism. Like other spirochetal diseases, Lyme disease is most responsive to antibiotics early in its course. Treatment regimens have evolved over time, based on both controlled clinical data and on clinical experience. Because of the difficulty in proving that bacteria have been eradicated and the common persistence of some symptoms long after treatment, the end point of antibiotic therapy is not always clear. The treatment regimens presented here represent guidelines that will no doubt be refined in time (Table 2).
(page 712):
TABLE 2.-Antibiotic Regimens for Various Manifestations of Lyme Disease'

[content of the table]

'*Current antibiotic regimens are based on both controlled clinical studies and clinical experience and will no doubt be refined in time. Antibiotic failures occur at all stages of disease, but, in general, the illness is most responsive to antibiotic therapy early in its course.
Claudia, if nothing else, I find some of the older articles and commentaries interesting to read because the authors admit to a degree of uncertainty, as well as the need for future refinements, that are now rarely acknowledged when it comes to both diagnosis and treatment.

Rita A

Claudia
Posts: 1448
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Location: Connecticut, USA

Re: Maintaining IgM Antibodies for Years, Poor Prognosis in

Post by Claudia » Sat 23 Jul 2011 16:31

Rita, these are excellent finds and the information is appreciated.
Claudia, if nothing else, I find some of the older articles and commentaries interesting to read because the authors admit to a degree of uncertainty, as well as the need for future refinements, that are now rarely acknowledged when it comes to both diagnosis and treatment.

Rita A
I have repeatedly been struck by this observation as well.

Have you ever read Polly Murray's book The Widening Circle? If not, I highly recommend reading it. Murray describes a rather shocking and inexplicable change; a dismissiveness, marginalizing and downplaying that suddenly took place, seeming out of nowhere and out of context to the momentum of discovery and scientific medical research evolving at the time.

RitaA
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Re: Maintaining IgM Antibodies for Years, Poor Prognosis in

Post by RitaA » Sat 23 Jul 2011 16:49

Claudia,

I have not yet read The Widening Circle -- but only because it hasn't been available when I have tried to order it online at Canadian bookstores. It's time I either order it from a U.S. distributor or put in a special order at my local bookstore. Thanks for the reminder.

Rita A

ChuckG
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Location: Berkeley

Re: Maintaining IgM Antibodies for Years, Poor Prognosis in

Post by ChuckG » Sun 24 Jul 2011 1:34

http://archderm.ama-assn.org/cgi/content/full/142/7/862

Clinical Relevance of Different IgG and IgM Serum Antibody Responses to Borrelia burgdorferi After Antibiotic Therapy for Erythema Migrans
Long-term Follow-up Study of 113 Patients

Martin Glatz, MD; Marjaneh Golestani, MD; Helmut Kerl, MD; Robert R. Müllegger, MD
Arch Dermatol. 2006;142:862-868.

ABSTRACT

Objectives To investigate the kinetics of anti–Borrelia burgdorferi antibodies for a minimum of 1 year after antibiotic therapy in patients with erythema migrans (EM) and to correlate antibody titer kinetics with clinical variables.
Design Retrospective study of serial anti–B burgdorferi antibodies in correlation to clinical variables.

"No significant correlations were found between a given IgM antibody titer profile and any clinical variable, a fact that has not been addressed specifically so far. Neither duration of EM or of extracutaneous signs and symptoms after therapy nor type or duration of therapy correlated with a particular serologic profile. Accordingly, 3 smaller previous studies14, 29-30 found no correlation between antibody responses and disease course after therapy. Thus, posttreatment antibody titers do not allow for the assessment of treatment efficiency. Persistent positive IgG or IgM antibody titers after therapy should not lead to further treatment as long as a patient does not have attributable clinical signs and symptoms.

In conclusion, the IgG and IgM immune response to B burgdorferi in patients with EM after therapy develops in 3 distinct profiles: persistence of a positive titer, persistence of a negative titer, or decline of a positive to a negative titer. Except for long duration or large size of EM before therapy, which predisposes a patient to persistence of a positive IgG antibody titer after therapy, no correlations exist among serologic profiles and clinical variables. In particular, the serologic profile seems to depend on neither the type or duration of antibiotic therapy nor the clinical course after therapy. Therefore, antibody testing during follow-up of patients with EM is unsuitable and unnecessary for the assessment of treatment response."

Claudia
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Re: Maintaining IgM Antibodies for Years, Poor Prognosis in

Post by Claudia » Sun 24 Jul 2011 3:11

Thank you, ChuckG, for adding this study to the discussion. It has a lot of information including extensive references to follow up on, so many thanks.

During the six years of his on-again(mostly) off-again treatment, my son's Western blots had only one band convert from IgM to IgG, which was band 41, but it also still continued to stay as an IgM, too, all along. During his yearly Western blots, he continued to maintain all the other bands as IgM's and over the years would produce totally new IgM bands, including three Bb specific ones: 34, 39 and 93. The other IgM bands are 58 and 66.

So one IgG conversion; and six maintained IgM's over the years.

Other than definitely being exposed to Bb, it seems that there should be some basic pattern or logic to how, when, and why these are expressed.

RitaA
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Joined: Thu 1 Jul 2010 8:33

Re: Maintaining IgM Antibodies for Years, Poor Prognosis in

Post by RitaA » Sun 24 Jul 2011 10:28

Claudia,

I'm not sure if you've seen this -- or if it even applies in your son's situation -- but it seems that IgM bands may persist even in people with favourable outcomes:

http://www.ncbi.nlm.nih.gov/pmc/article ... 350774.pdf
Temporal Study of Immunoglobulin M Seroreactivity to Borrelia burgdorferi in Patients Treated for Lyme Borreliosis

EILEEN HILTON,1* ANTHONY TRAMONTANO,1 JAMES DEVOTI,1 AND SUNIL K. SOOD2

Division of Clinical Research1 and Department of Pediatrics,2 Long Island Jewish Medical Center,
the Long Island Campus for Albert Einstein College of Medicine, New Hyde Park, New York 11040
Received 10 June 1996/Returned for modification 20 August 1996/Accepted 12 December 1996

Forty-six patients with late Lyme disease who were considered improved or cured following treatment were monitored by immunoglobulin M (IgM) immunoblotting (mean monitoring period, 27.6 months). There was a persistent IgM response in 32 (97%) of 33 initially positive patients. All but three showed a consistent number, type, and intensity of IgM bands over the entire follow-up period. IgM immunoblotting may not be useful for monitoring the response to treatment of Lyme borreliosis.
[snip]
Our study specifically assessed patients with late Lyme borreliosis who were stable and who improved after treatment in order to assess whether IgM could be used to monitor recurrences. We chose this population because its constituents had improved and were expected to have negative IgM serology results. We found that the majority of patients remain immunoblot positive after treatment. Moreover, the band patterns are remarkably consistent despite stable clinical improvement.

All patients in this study had late Lyme borreliosis and had not been treated until well after the initial infection. Thus, it appears that IgM antibodies can persist after treatment of late Lyme borreliosis. In contrast, the positive IgM immunoblots of most patients treated for early Lyme disease revert to negative.
Six of seven patients with Lyme facial palsy were immunoblot negative by 3 months posttreatment (8). Only about one-third of treated EM patients had persistently positive IgM immunoblots after 1 year (1, 5). The clinical significance of this difference in IgM antibody persistence is unclear. It is also possible that persistent subclinical or indolent infection with B. burgdorferi accounts for the persistence of IgM antibodies. However, given the clinical improvement and stability of the course of infection in these patients, if persistent antigenic stimulation is present, its clinical relevance is questionable.

Our results show that IgM antiborrelial antibodies may persist for months to years after therapy. Although IgM immunoimmunoblotting is generally accepted as a reliable aid for the diagnosis of early Lyme borreliosis, it may be of limited or no use in monitoring the progression of disease or response to therapy.
Rita

Claudia
Posts: 1448
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Re: Maintaining IgM Antibodies for Years, Poor Prognosis in

Post by Claudia » Sun 24 Jul 2011 15:41

RitaA wrote:

Claudia,

I'm not sure if you've seen this -- or if it even applies in your son's situation --
No, I hadn't seen this, and yes, it definitely applies to my son's situation.

He had the EM in July of 2001 and didn't get diagnosed and begin antibiotic treatment until October, 2005:
Temporal Study of Immunoglobulin M Seroreactivity to Borrelia burgdorferi in Patients Treated for Lyme Borreliosis:

All patients in this study had late Lyme borreliosis and had not been treated until well after the initial infection. Thus, it appears that IgM antibodies can persist after treatment of late Lyme borreliosis. In contrast, the positive IgM immunoblots of most patients treated for early Lyme disease revert to negative.
I did ask our neurologist about the IgM bands and he stated that most of his patients with Lyme disease are IgM. This would make sense in that it would likely be the late-stage and treatment failure patients that would end up seeking care from a neurologist, and have the most difficult recovery and need for long-term treatment/re-treatment. Thus the observation of "poor prognosis" probably in those patients whose doctors strictly followed the IDSA guidelines for their treatment.

This, relating to the mention of persistent infection also makes sense:
Temporal Study of Immunoglobulin M Seroreactivity to Borrelia burgdorferi in Patients Treated for Lyme Borreliosis:

The clinical significance of this difference in IgM antibody persistence is unclear. It is also possible that persistent subclinical or indolent infection with B. burgdorferi accounts for the persistence of IgM antibodies. However, given the clinical improvement and stability of the course of infection in these patients, if persistent antigenic stimulation is present, its clinical relevance is questionable.

Our results show that IgM antiborrelial antibodies may persist for months to years after therapy. Although IgM immunoimmunoblotting is generally accepted as a reliable aid for the diagnosis of early Lyme borreliosis, it may be of limited or no use in monitoring the progression of disease or response to therapy.
My son has had a favorable response to antibiotic treatment:
Temporal Study of Immunoglobulin M Seroreactivity to Borrelia burgdorferi in Patients Treated for Lyme Borreliosis:

Our study specifically assessed patients with late Lyme borreliosis who were stable and who improved after treatment in order to assess whether IgM could be used to monitor recurrences. We chose this population because its constituents had improved and were expected to have negative IgM serology results. We found that the majority of patients remain immunoblot positive after treatment. Moreover, the band patterns are remarkably consistent despite stable clinical improvement

RitaA
Posts: 2768
Joined: Thu 1 Jul 2010 8:33

Re: Maintaining IgM Antibodies for Years, Poor Prognosis in

Post by RitaA » Sun 24 Jul 2011 19:11

Claudia,

The delay in your son's diagnosis and treatment is so unfortunate -- and obviously not an isolated occurrence if his neurologist has other patients with persisting IgM bands. I suspect that neurologists probably end up seeing a fair number of late-stage Lyme disease patients who may defy diagnosis (possibly forever) because a tick-borne illness is so rarely considered in the differential diagnosis. I know this to be true from personal experience and from hearing firsthand accounts by other Canadians. There is no shortage of examples (whether anecdotal or case studies) where patients have been diagnosed with other (usually atypical forms) of neurological disorders, only to have that diagnosis eventually overturned. This tends to happen when the usual progression of symptoms doesn't occur (e.g. with a misdiagnosis of ALS, PD or GB) or because a person ends up with so many health issues that it becomes clear something else is going on. Sadly, what that something else is may never be determined if no thought is given to the possibility of tick-borne illnesses. That needs to change, and there's nothing like word-of-mouth (especially between healthcare providers) to get the message out. It's happening ever so slowly in Canada, and I imagine it may take years -- and possibly decades -- for tick-borne illnesses to be on the radar screen for most healthcare providers in the world.

The best news is that your son has responded to antibiotics even though it's been a long haul that could not have been easy for anyone in your family. I really hope your son's recovery can be maintained, but if antibiotics are required again, there's a very good chance that he'll respond favourably to retreatment. I've read about a number of people who thought they recovered only to relapse again, requiring additional antibiotics more than once. Some folks were eventually able to do without antibiotics, and I'm hoping your son has reached this stage as well. Wouldn't that be wonderful?

I sure am hoping that your son is able to maintain his recovery. Even though he and others (like myself) may never be included in any published statistics, it's good to spread the word that it is possible to get better with time and -- more importantly -- adequate treatment.

Rita

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