0 Lyme Disease Presents Differently In Women Compared To Men

Recently, Lauren A. Crowder, M.P.H. reported observations on some differences between women and men in response to Lyme disease in a poster at the International Conference on Emerging Infectious Diseases.

The short story: Women with Lyme disease display more clinical symptoms than do men with the disease and also are less likely to seroconvert following treatment, according to findings from a prospective cohort study involving 77 patients.


The study revealed the following observations:

• Significantly more women than men reported joint pain, muscle pain, headache, back pain, heart palpitations, nausea, vomiting, anxiety, numbness and tingling, and changes in vision during at least one of six preplanned study visits with a physician.
• At the initial study visit, a similar proportion of men and women (about 60% of each) tested negative for Lyme disease using the Centers for Disease Control and Prevention’s recommended two-tier testing criteria for serodiagnosis. At the first post-treatment interview, 70% of women who tested negative at the first pre-treatment visit remained negative, compared with only 35% of the men who initially tested negative.

Read more about this Lyme Disease Foundation funded study here:
http://www.internalmedicinenews.com/news/infectious-diseases/single-article/lyme-disease-presents-differently-in-men-and-women/1bf48578d5.html

And see the original source with study here:

SEE page 151 of ICEID 2012 Abstracts
March 11-14, 2012 | Hyatt Regency Atlanta | Atlanta, Georgia
(PDF) http://www.iceid.org/images/iceid_2012_finalprogram_final.pdf

Board 264. Another Difference between Boys and Girls: Sex-Based Differences in Lyme Disease.
L.A. Crowder, A. Rebman, V. Yedlin, M. Soloski, J.N. Aucott; Lyme Disease Research Foundation of Maryland, Lutherville, MD, USA, Johns Hopkins University, School of Medicine, Baltimore, MD, USA.

This isn't the first time, however, that someone observed a difference between men and women's immune responses in relation to Borrelia burgdorferi.

Let's take the time machine back to Sweden, in 2004...

Lyme borreliosis reinfection: might it be explained by a gender difference in immune response?
Sara Jarefors, Louise Bennet, Elin You, Pia Forsberg, Christina Ekerfelt, Johan Berglund, and Jan Ernerudh
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1782288/

This study had a different goal than Ms. Crowder's in that it was intended to measure the difference in immunological response between people of both genders who had only been infected once and those who had been reinfected with Lyme disease within a five year period.

The findings relevant to women in this case:

"...for the immunological response there were major differences between men and women. The women displayed higher spontaneous secretion of all cytokines measured, i.e. IL-4, IL-6, IL-10, IFN-γ and TNF-α. Spontaneous secretion, at an infection-free time-point, reflects the habitual immune status and may suggest what type of immunological defence an individual generally displays. For instance, allergy has been considered a Th2-type related condition and, accordingly, atopic individuals have higher spontaneous IL-4 expression than non-atopic controls.

Women of reproductive age are believed to handle infections better than men, having a stronger tendency to show Th1-type responses and expression of higher levels of pro-inflammatory cytokines, and they also develop higher antibody titres than men when vaccinated. However, the female immune response fluctuates with the menstrual cycle. In general, oestrogen has a stimulatory effect on the immune system whereas testosterone acts as a suppressor. When women enter the menopause their levels of oestrogen decrease and thereby the stimulatory effect diminishes, leading to an altered immune status. All except one of the women in our study were postmenopausal, and this could be a factor explaining why more women than men became reinfected with B. burgdorferi."

And...

"Serology was not performed on the individuals in this study because, at the time of EM diagnosis, only 30–40% of patients displayed antibodies to Borrelia. Studies following patients with culture-confirmed EM have shown that, although antibodies can be detected 10–20 years after initial infection, titres decline gradually during the first year."

A paper which cited the previous one discusses the functions of IL-10 in relationship to Borrelia burgdorferi:

Interleukin-10 alters effector functions of multiple genes induced by Borrelia burgdorferi in macrophages to regulate Lyme disease inflammation.
Gautam A, Dixit S, Philipp MT, Singh SR, Morici LA, Kaushal D, Dennis VA.

Source: http://www.ncbi.nlm.nih.gov/pubmed/21947773

To sum it up: IL-10 (an interleukin) which is produced in higher amounts in women than it is in men, is responsible for inhibiting the actions of some genes in Borrelia burgdorferi - but it is also responsible for empowering the actions of some genes, too.

What implication this has on infection in different genders remains to be seen and requires more study.

But what is already known about the role of inflammation in the presence of Borrelia burgdorferi is important to take note of here: Inflammation facilitates Borrelia burgdorferi's adaptation to its host; it stimulates antigenic variation and it leads to increased spirochetal burden in mice. So if this applies to humans: All that pain, swelling, and inflammation patients feel? It is good for the spirochetes, and it is bad for you.

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2 Paper: Course of Antibody Response In Lyme Borreliosis Patients Before And After Therapy

ISRN Immunology Volume 2012 (2012), Article ID 719821, 4 pages doi:10.5402/2012/719821 Research Article

Course of Antibody Response in Lyme Borreliosis Patients before and after Therapy

Elisabeth Aberer¹ and Gerold Schwantzer<sup>2

1</sup>Department of Dermatology and Venereology, Medical University of Graz, Auenbruggerplatz 8, 8036 Graz, Austria

²Institute for Medical Informatics, Statistics and Documentation, Graz, Medical University of Graz, 8036 Graz, Austria

Received 27 September 2011; Accepted 27 October 2011

Academic Editors: A. Clayton and S. Devi

Copyright © 2012 Elisabeth Aberer and Gerold Schwantzer. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

The early immune response (IR) in European Lyme borreliosis patients has not yet been studied in detail. The aim of the study was to analyse retrospectively the antibody development in 61 erythema migrans (EMs) patients depending on the duration of infection from tick bite by using a whole-cell lysate B. garinii immunoblot. The evolution of antibodies proved to be undulatory in untreated patients with two peaks for IgM at weeks 5 and 9 and for IgG at weeks 4 and 8. The analysis of IR courses after therapy identified patients constantly seropositive or seronegative and patients with repeated seroconversions with a switch, disappearance, or reappearance of anti-23 kD or anti-39 kD antibodies during the one-year period. We suggest that the antibody production in EM patients may be missed due to an undulatory IR. This phenomenon might be an as yet insufficiently researched aspect in Lyme borreliosis.

1. Introduction

Serological testing aids in the diagnosis of Lyme borreliosis (LB). IgM antibodies develop during the first 3 weeks after infection followed by IgG antibodies after 4–6 weeks [1]. However, to our knowledge, the early immune response (IR) in European patients has not yet been studied in detail.

In routine clinical practice, we observed patients whose IR switched from positive to negative and vice versa in the course of time. The aim of this study was to analyse the development and the course of the IR in European erythema migrans (EMs) patients with known duration of disease from tick bite and to follow up their antibody profile during a 12-month period after treatment.

2. Patients, Materials, and Methods

One hundred and two patients with EM were enrolled for clinical and serological diagnosis. Their mean age was 50 (SD16) years. Forty-seven patients were male and 55 female. The mean duration of EM was 23 (1–210) days. Eighty-seven patients had EM without and 15 patients EM with extracutaneous symptoms. As sixty-one (28 males and 33 females aged between 22 and 78 years) remembered their tick bite, the onset of their infection was known and only these patients were included in the study. These patients received antibiotic treatment with phenoxymethylpenicillin 1500 000 IE threetimes a day, 26 patients for 14 days and 35 patients for 20 days. No statistical difference in the clinical outcome of the differently treated groups was observed during the 12-month observation period as described in a previous study [2].

Blood samples were obtained from all 61 patients for serological testing at the initial visit before therapy and then thereafter at 3 weeks after first blood withdrawal. Sera were available from 46 patients 3 months after therapy, from 52 after 6 months, and from 53 after 12 months (Table 1).

Table 1: Number of investigated patients’ sera.

Patients’ sera that had been stored at −20°C were retested at the same time and antibody response was measured by a whole-cell lysate immunoblot (IB) according to the manufacturer’s instruction (Borrelia garinii, MRL Diagnostics, Cypress, CA). Interpretation of the IB bands was performed by a single technician. Criteria for a positive IB, as indicated in the manufacturer’s manual, were 1 of 2 bands (23 and 39 kD) for IgM and 4 of 7 bands (21, 23, 37, 39, 41, 45, and 93 kD) for IgG. Data obtained were entered in a computerized database and graphically displayed.

3. Results and Discussion

3.1. Development of Immune Response

Twenty-five of 61 (41%) sera showed IgM antibodies in IB before therapy. The IR started in week 1 after tick bite and peaked in week 5, when 5 of the 7 tested sera (71%) reacted positively (Figure 1).

In the following weeks there was a wavelike decrease of seropositive reactions. Furthermore, from week 8 there was a second increase in seropositivity peaking at week 9. IgG antibodies were positive in 13/60 (21%) patient sera (one serum could not be analysed because of a smear). The IR started from week 2 and peaked at week 4, where 75% (3 of the 4 tested sera) reacted positively (Figure 1).

Similar to the IgM antibody trend, the IgG IR decreased in the following weeks. However, there was a second increase of IgG IR that peaked in week 8.

Figure 1: Development of immune response from tick bite (weeks).

The development of the IR to an infection with B. burgdorferi (Bb) s.s. in EM patients from the United States was studied by Aguero-Rosenfeld and showed that 43% of the patients had positive IgM antibodies before therapy [3].

Due to the heterogeneity of borrelia strains in Europe, differences between IR on the two continents are expected since the Bb s.s. species provokes a stronger immune reaction than the dominant European species B. afzelii. Patients with culture-confirmed B. burgdorferis.s. erythemas from the USA were more often seropositive (35.3%) at presentation compared with 22.4% culture-confirmed B. afzelii erythemas [4].

In another European study with recombinant ELISA, German Lyme borreliosis patients yielded positive IgG antibodies in 22% and IgM antibodies in 61.5% for phase I of LB [5].

Both the IgM and IgG IR showed an undulatory distribution with antibodies coming and going in untreated patients over weeks. A similar periodicity is known in other bacterial infections, like relapsing fever with recurrent bacteraemias [6].

Syphilis can be reactivated by different conditions like HIV infection, showing seroconversion of the unspecific VDRL [7].

3.2. Course of Immune Response after Treatment

With respect to the course of IR after therapy, 21 of 61 (34%) patients did not show IgM seroconversion (constantly negative), whereas 12 (20%) were constantly positive. In the remaining 28 patients, different kinds of IgM seroconversion occurred. Nine patients (15%) (Figure 2, patients 1–9) seroconverted from positive to negative and 6 (11%) (Figure 2) (Figure 2, patients 16–22) seroconverted to positive and than back to seronegative during the 12 months. Six patients (10%) (Figure 2, patients 23–28) showed repeated seroconversions of IgM antibodies that presented as a switch of anti-23 kD to anti-39 kD antibodies and vice versa or the dis- or reappearance of either anti-23 kD or anti-39 kD antibodies.

 Figure 2: IgM antibody response in immunoblot before and  up to 12 months after therapy. Filled circles: positive IgM antibody response; empty circles: negative IgM antibody response; blank spaces: no serum available. BT: before therapy; AT: after therapy; 3, 6, 12 months after start of therapy.

Thirty-eight of the 60 patients (63%) were constantly IgG negative and 3 patients (5%) constantly positive in IB. Nineteen patients seroconverted within the observation period. Their data are presented in Figure 3. Six patients (10%) (patients 1–6) seroconverted from initially positive to negative and 2 (3%) (Figure 3, patients 7 and 8) from negative to positive.

Seven patients (12%) (Figure 3, patient 9–15) who were primarily negative seroconverted to positive and then back to seronegative during the observation period.

Figure 3: IgG antibody response in immunoblot before and up to 12 months after therapy. Filled circles: positive IgG antibody response; empty circles: negative IgG antibody response; blank spaces: no serum available. BT: before therapy; AT: after therapy; 3, 6, 12 months after start of therapy.

Four patients (7%) (Figure 3, patients 16–19) showed repeated seroconversion with at least 2 changes. The seroconversion itself presented as a loss of detectable antibodies from a previous maximum of up to 5 bands (23, 37, 39, 41, 45, and 93 kD) to 1 band.

When observed closely, none of the patients with a repeated seroconversion had any features that could distinguish them from the other patients with either persistent antibodies or seronegative individuals. There was also no relation between IgM and IgG seroconversion. Clinically, no correlation to the duration of treatment or to the presence of extracutaneous signs could be drawn.

A recent survey on the development of the IR, measured by ELISA, in Austrian EM patients over a minimum of 1 year after treatment showed 3 distinct courses: persistent positive, persistent negative, and positive to negative patients [8]. In this study, there were also patients with a change from negative to positive antibodies (3% IgM, 4% IgG), but this was not attributed to the original EM as seroconversion occurred after a median of 350 (for IgM) and 349 days (for IgG) after EM. In our study, IB was found to be more sensitive than ELISA; therefore only IB results were analyzed and the IR could be studied in more detail.

In our patients, the appearance of IgM antibodies only detected after 6 months (patients 21 and 22) and IgG antibodies only at 3 months (patients 9 and 10) cannot be related to the previous infection. Moreover, an isolated IgM seroreaction has been observed to be unspecific [9, 10].

Isolated positive serum IgM titers were seen in about 20% of children with a febrile illness, enterovirus meningitis, or headache [9]. In another article 2,6% of sera submitted for B. burgdorferi serology expressed unspecific anti-p41 IgM antibodies by ELISA. Confirmation test with IB showed that some sera also reacted with p39 or OspC antigen. No conclusive evidence for borrelia infection could be drawn [10].

The first appearance of antibodies after 6 and 12 months in our study (patients 14 and 15 for IgM, and 7 and 8 for IgG) might indicate a new infection in these patients.

Although the undulatory character of the IR before therapy in our patients could not be determined in every single patient, the findings after treatment might reflect a similar situation also in untreated patients before therapy. So, we suggest that a single serological finding is a snap shot and gives evidence of an infection. On the other hand, the true infection might be missed by negative IR, as might be the case in the ~40% seronegative EM patients.

Serological findings do not distinguish between active and previous disease. Borrelia DNA can persist in urine for even 1 year after treatment [11], and antibodies to Bb may persist for up to 20 years after appropriate therapy [12]. Bearing in mind the characteristics of cyclic patterns in other bacterial infections, the undulatory IR noted in our study may be an as yet insufficiently researched aspect in Lyme borreliosis.

Conflict of Interests

The authors declare that there is no conflict of interests.

Acknowledgments

The authors greatly acknowledge Jasmina Custovic, M.D., for collecting and analysing the data which were also partly shown in her thesis (development of the immune response in erythema migrans with special significance of the p18 antigen) and Mrs. Ingrid Krainberger for her excellent laboratory support during the study.

References

1. B. Wilske, “Serodiagnosis of lyme borreliosis,” Zeitschrift fur Hautkrankheiten, vol. 63, no. 6, pp. 511–514, 1988.
2. E. Aberer, P. Kahofer, B. Binder, T. Kinaciyan, H. Schauperl, and A. Berghold, “Comparison of a two- or three-week regimen and a review of treatment of erythema migrans with phenoxymethylpenicillin,” Dermatology, vol. 212, no. 2, pp. 160–167, 2006.
3. M. E. Aguero-Rosenfeld, J. Nowakowski, S. Bittker, D. Cooper, R. B. Nadelman, and G. P. Wormser, “Evolution of the serologic response to Borrelia burgdorferi in treated patients with culture-confirmed erythema migrans,” Journal of Clinical Microbiology, vol. 34, no. 1, pp. 1–9, 1996.
4. F. Strle, R. B. Nadelman, J. Cimperman et al., “Comparison of culture-confirmed erythema migrans caused by Borrelia burgdorferi sensu stricto in New York State and by Borrelia afzelii in Slovenia,” Annals of Internal Medicine, vol. 130, no. 1, pp. 32–36, 1999.
5. K. P. Hunfeld, M. Ernst, P. Zachary, B. Jaulhac, H. H. Sonneborn, and V. Brade, “Development and laboratory evaluation of a new recombinant ELISA for the serodiagnosis of Lyme disease,”Wiener Klinische Wochenschrift, vol. 114, no. 13-14, pp. 580–585, 2002.
6. C. Larsson, M. Andersson, J. Pelkonen, B. P. Guo, A. Nordstrand, and S. Bergström, “Persistent brain infection and disease reactivation in relapsing fever borreliosis,” Microbes and Infection, vol. 8, no. 8, pp. 2213–2219, 2006.
7. A. McMillan, H. Young, and J. F. Peutherer, “Influence of human immunodeficiency virus infection on treponemal serology, in patients who have been treated for syphilis,” Journal of Infection, vol. 21, no. 1, pp. 95–103, 1990.
8. M. Glatz, M. Golestani, H. Kerl, and R. R. Müllegger, “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,” Archives of Dermatology, vol. 142, no. 7, pp. 862–868, 2006.
9. R. Bennet, V. Lindgren, and B. Zweygberg Wirgart, “Borrelia antibodies in children evaluated for Lyme neuroborreliosis,” Infection, vol. 36, no. 5, pp. 463–466, 2008.
10. E. Ulvestad, A. Kanestrøm, L. J. Sønsteby et al., “Diagnostic and biological significance of anti-p41 IgM antibodies against Borrelia burgdorferi,” Scandinavian Journal of Immunology, vol. 53, no. 4, pp. 416–421, 2001.
11. E. Aberer, A. R. Bergmann, A. M. Derler, and B. Schmidt, “Course of Borrelia burgdorferi DNA shedding in urine after treatment,” Acta Dermato-Venereologica, vol. 87, no. 1, pp. 39–42, 2007.
12. R. A. Kalish, G. McHugh, J. Granquist, B. Shea, R. Ruthazer, and A. C. Steere, “Persistence of immunoglobulin M or immunoglobulin G antibody responses to Borrelia burgdorferi 10–20 years after active Lyme disease,” Clinical Infectious Diseases, vol. 33, no. 6, pp. 780–785, 2001.

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0 Failure of Topical Antibiotics to Prevent Disseminated Borrelia burgdorferi Infection

Last week, I posted an article on how topical azithromycin could help prevent Lyme disease infection. And now, this new abstract has turned up on PubMed...

Failure of Topical Antibiotics to Prevent Disseminated Borrelia burgdorferi Infection Following a Tick Bite in C3H/HeJ Mice. Wormser GP, Daniels TJ, Bittker S, Cooper D, Wang G, Pavia CS. J Infect Dis. 2011 Sep 19. [Epub ahead of print]

Abstract

A prior study in mice has shown that the timely application of topical antibiotics to the skin at the tick bite site could eradicate Borrelia burgdorferi infection. That study, however, did not evaluate antibiotic preparations that are considered suitable for use in humans. In this murine study, topical application of 2% erythromycin and 3% tetracycline preparations that are acceptable for use in humans was found to be ineffective in eliminating B. burgdorferi from the tick bite site or in preventing dissemination to other tissues. Reasons for the discrepant findings are discussed.

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I find it very odd that they would choose erythromycin as a topical antibiotic for Borrelia burgdorferi - there is research that shows that Borrelia burgdorferi is resistant to erythromycin. I would have never thought to make that a choice for treatment. Tetracycline makes more sense.

How many previous studies of topical antibiotics for treating early Lyme disease have there been, and what have the outcomes been? How many have been done using suitable human antibiotic preparations versus ones only effective in animal subjects?

It seems to me that the researchers who filed this patent might already have a good idea of what might work - is this the same formulation that was used in the study I posted last week?

Composition C
Composition [mg]
Component per unit [1 g]
Azithromycin 150
Dermacryl 79 50
Klucel MF 25
Miglyol 812 50
Ethanol 94% (w/w) ad 1 g

Or is it different?

Results: There is no infection of Lyme disease detectable when composition C is applied to the area where the ticks were allowed to feed. The topical application of Formulation C results in antibody titers, which are not different from naïve mice (KELA values between 10 and 40), whereas the infected mice show KELA values of 160 to 400.

Especially, the tissue and serum samples taken from different parts of the mice 56 days after the tick bite show no Borrelia burgdorferi organisms when cultivated and no specific antigenes are detectable. Tissue probes are taken from heart tissue, bladder, joint and ear. The group of mice topically treated with Formulation C show complete absence of B. burgdorferi , whereas B. burgdorferi is detected in untreated mice, which are exposed to tick-feed.

The recultivation conditions of B. burgdorferi are suitable to detect B. burgdorferi in any morphological form known to date. Surprisingly, Formulation C was able to eradicate B. burgdorferi in a way, that no infectious agents of B. burgdorferi are detected in the target tissues of B. burgdorferi.

How were these tissue probes completed and could they have missed any bacteria? What about the parenchyma of the brain, since this is low passage N40 they're talking about? (Problematic in rodent studies - should be studied in other animals.) I wonder about the methodology...

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5 Abstract: A tick mannose-binding lectin inhibitor interferes with the vertebrate complement cascade

A tick mannose-binding lectin inhibitor interferes with the vertebrate complement cascade to enhance transmission of the lyme disease agent. Schuijt TJ, Coumou J, Narasimhan S, Dai J, Deponte K, Wouters D, Brouwer M, Oei A, Roelofs JJ, van Dam AP, van der Poll T, Van't Veer C, Hovius JW, Fikrig E. Cell Host Microbe. 2011 Aug 18;10(2):136-46.

Source: http://www.ncbi.nlm.nih.gov/pubmed/21843870?dopt=Abstract

Comments:

It occurs to me that a lot of the concern from the Lyme patient community over the use of vaccines could be eliminated if R & D shied away from human vaccine development.

Mice and other animals in the woods could ingest oral vaccines which could prevent the transmission of Borrelia burgdorferi to reservoir hosts on which ticks feed. Not only that, but this could have an extended effect of helping pets, too.

I think creating oral vaccines to block transmission of Bb to animals and pets is a good idea.

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0 Including the Middle

This was passed on to me in email. The original author's name is Lon Sarver, so credit goes to him and not me. 

Including the Middle

That there is no One True Way does not mean that all ways are equally valid, or that there are no false ways.  Similarly, there may be no one thing that works for everyone, but it does not follow that therefore, everything works for someone.  There are things that don’t work for anyone.

Just because you are a free adult, and do not require my consent to engage in whatever it is that you do (assuming it doesn’t impact me or mine), this does not mean that I have to agree that whatever you’re doing is a good thing.  Even less does it mean I have to approve, or withhold criticism.

I can’t tell you that you don’t like or enjoy something.  I can tell you that, in my experience or understanding, something is actually, objectively harmful.  I can’t tell you that you and other consenting adults cannot do whatever it is you’re consenting to do, but I can object when I see collateral effects impacting me or mine.

You see the distinction, yes?  I’m not arguing tastes, or debating rights in the abstract.  I’m questioning whether or not you’ve thought this through, whether or not you understand the unintended consequences of your actions. 

Consent is not a magic spell to negate ill effect, nor is tolerance or pluralism a barrier that prevents what you do over there from affecting me over here.  Hell, the more interconnected society becomes, the more likely I am to be impacted by people I never meet.  We can argue the extent of this, but not (I think) the fact of it.

So here’s the deal:  I won’t tell you what or who to like, or what’s best for you.  I won’t ask you to tailor your tastes or preferences to defer to mine.  I will tell you if I think you’re factually wrong, or if what you’re doing doesn’t seem to match up with the reasons why you’re doing it.  Feel free to tell me to butt out.  Hopefully, I’ll do it with grace.

If I’m saying that what you’re doing is somehow harmful, trust that I’m not judging you on some measure of Good or Evil, Worthy or Worthless.  Try and take it in the spirit of questioning the effects of your actions, not your intentions.  I’ll probably be a bit more stubborn, here, in proportion to how much I feel that my life is impacted by those effects.  We may not agree on that, but at least let’s agree on what we disagree about.

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Any thoughts on this? 

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