Guidelines for Diagnosis and Treatment German Borreliosis So

Medical topics with questions, information and discussion related to Lyme disease and other tick-borne diseases.
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panda
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Re: Guidelines for Diagnosis and Treatment German Borreliosi

Post by panda » Thu 11 Oct 2012 6:31

Serology Diagnostic Schemes

M. Tokarska-Rodak and M. Kozioł-Montewka(2012).
The Serology Diagnostic Schemes in Borrelia burgdorferi Sensu Lato Infections – Significance in Clinical Practice, in: Lyme Disease, Dr. Ali Karami (Ed.), ISBN: 978-953-51-0057-7

http://www.intechopen.com/books/lyme-di ... -in-clinic

http://cdn.intechweb.org/pdfs/28827.pdf

p. 80:
It was recommended that an IgM immunoblot be considered positive if two of the following three bands are present – OspC, (24 kDa), BmpA (39 kDa) and Flagelina (41 kDa). It was further recommended that an IgG immunoblot be considered positive if bands for antigen proteins are present: p17, p18, p21 (DbpA), OspC (p22, 23, 24, 25), OspD (p29), p30, OspA (p31), OspB (p34), p58, p83/100 and VlsE (Aberer, 2007; Deutsche Borreliose-Gesellschaft e.V, 2010; EUCALB, 2008, MMWR, 1995). Complete standardization of immunobloting protocols in Europe is unrealistic at present. Lyme borreliosis is not the same in all geographic areas due to different local prevalence of species and strains of B. burgdorferis.l. and to heterogeneity within those strains. Recommendations for the interpretation of Western blots have not always been applicable to populations in geographic areas other than where they were developed.
p. 89-90:
6. Conclusion
Highly immunogenic proteins produced in vivo after spirochete transmission into the human body are significant antigens for the diagnostics of B. burgdorferi s.l. infections. Antigens VlsE, BBA36, BBO323 and Crasp 3 demonstrate in vivo expression and comprise highly immunogenic epitopes, common for B. burgdorferi s.l., which are important IgG serological markers of advanced stages of borreliosis. Thus a serologic test with those antigens involved creates better potential to evaluate immune response with account for clinical status of the patient. The detection of antibodies directed against specific B. spielmani antigens suggests that this microorganism may be responsible for triggering borreliosis both as a single etiologic agent and with other Borrelia genospecies. The long-lasting persistence of the disease and thus long-term antigenic stimulation can be considered as a factor enabling the initiation of autoimmune reactions. This process can exist in a small percentage of patients with Lyme disease but the possibility of its inception cannot be completely negated.

Lorima
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Re: Guidelines for Diagnosis and Treatment German Borreliosi

Post by Lorima » Fri 12 Oct 2012 23:43

Thanks to all for the good information.

I said I'd look into EUCALB, and what I'm finding is interesting. It looks as if in 2000, many European experts, including those in EUCALB, were working together to formulate rules to interpret European Western blots (along with other aspects of European Lyme disease).
J Clin Microbiol. 2000 Jun;38(6):2097-102.
A European multicenter study of immunoblotting in serodiagnosis of lyme borreliosis.
Robertson J, Guy E, Andrews N, Wilske B, Anda P, Granström M, Hauser U, Moosmann Y, Sambri V, Schellekens J, Stanek G, Gray J.
Source
Public Health Laboratory, Southampton General Hospital, Southampton, United Kingdom.
Abstract
A European multicenter study of immunoblotting for the serodiagnosis of Lyme borreliosis showed considerable variation in results obtained from tests with a panel of 227 serum samples. Six laboratories used different immunoblot methods, and a wide range of bands was detected in all the assays. Multivariable logistic regression analysis of data from individual laboratories was used to determine the most discriminatory bands for reliable detection of antibodies to Borrelia burgdorferi sensu lato. These bands were used to construct individual interpretation rules for the immunoblots used in the six laboratories. Further analysis identified a subset of eight bands, which were important in all the laboratories, although with variations in significance. Possible European rules, all closely related, were formulated from these bands, although there was no single rule that gave high levels of sensitivity and specificity for all the laboratories. This is a reflection of the wide range of methodologies used, especially the use of different species and strains of B. burgdorferi sensu lato. The panel of European rules provides a framework for immunoblot interpretation which may be adapted in relation to the characteristics of Lyme borreliosis in local areas.
PMID: 10834959 [PubMed - indexed for MEDLINE] PMCID: PMC86736 Free PMC Article
But by 2006 many of these authors had adopted IDSA guidelines: Gerold Stanek and Franc Strle were authors of the 2006 IDSA guidelines, and now the EUCALB guidelines copy IDSA, with a few nods to the often-cited difference in the relative proportions of arthritic, neurologic, and cutaneous sequelae, between the US and Europe.

What happened? This is a history-and-politics question, not a scientific one. The European disease didn't change, during that period. Only the academic view of it did. One possible way to find out why is to read through the history of the EUCALB members' publications and collaborations. So I will follow that line of investigation, but it will take a while. We need a European Pamela Weintraub to make an exhaustive journalistic study of the situation, but until then we'll have to settle for hints and clues.

Meanwhile, here are some details about the current EUCALB view:

http://meduni09.edis.at/eucalb/cms_15/i ... 4862e4f30b

Image

Notice that EUCALB considers it "essential" that suspected neurological Lyme patients be subjected to spinal tap (=CSF fluid sample), and that the findings be abnormal (white blood cells and antiBb antibodies high in CSF), in order to diagnose neurological disease.

But the DBG says that abnormal findings in CSF are unlikely, except in acute Lyme meningitis. In late neurological disease, the CSF will likely seem normal. ILADS also says this. There are numerous publications supporting this view.

The US mainstream (IDSA) has also largely given up looking for late neurological Lyme disease with abnormal CSF, by saying that late NLB is so rare in the US that it's not worth looking for it.

Who is EUCALB?

http://www.eucalb.com/
Media Ownership:
Gerold Stanek (IDSA 2006 guidelines author)

Editor: Jeremy Gray

Advisory board:
19 academics, including 2 IDSA 2006 guidelines authors:
Gerold Stanek
Frank Strle

http://www.ncbi.nlm.nih.gov/pubmed/20132258
Clin Microbiol Infect. 2011 Jan;17(1):69-79. doi: 10.1111/j.1469-0691.2010.03175.x.
Lyme borreliosis: clinical case definitions for diagnosis and management in Europe.
Stanek G, Fingerle V, Hunfeld KP, Jaulhac B, Kaiser R, Krause A, Kristoferitsch W, O'Connell S, Ornstein K, Strle F, Gray J.
[note from Lorima: all authors are members of EUCALB advisory board]
Source
Medical University of Vienna, Department of Hygiene and Applied Immunology, Vienna, Austria. gerold.stanek@meduniwien.ac.at
Abstract
Lyme borreliosis, caused by spirochaetes of the Borrelia burgdorferi genospecies complex, is the most commonly reported tick-borne infection in Europe and North America. The non-specific nature of many of its clinical manifestations presents a diagnostic challenge and concise case definitions are essential for its satisfactory management. Lyme borreliosis is very similar in Europe and North America but the greater variety of genospecies in Europe leads to some important differences in clinical presentation. These new case definitions for European Lyme borreliosis emphasise recognition of clinical manifestations supported by relevant laboratory criteria and may be used in a clinical setting and also for epidemiological investigations.

© 2010 The Authors. Journal Compilation © 2010 European Society of Clinical Microbiology and Infectious Diseases.
PMID: 20132258 [PubMed - indexed for MEDLINE]
(1) these case definitions are the EUCALB definitions, posted in this message, above.
(2)As in the US, there is no distinction made between surveillance (i.e. epidemiology) and diagnostic case definitions.
http://www.ncbi.nlm.nih.gov/pubmed/21903253
Lancet. 2012 Feb 4;379(9814):461-73. Epub 2011 Sep 6.
Lyme borreliosis.
Stanek G, Wormser GP, Gray J, Strle F.
Source
Medical University of Vienna, Institute for Hygiene and Applied Immunology, Vienna, Austria. gerold.stanek@meduniwien.ac.at
Abstract
Lyme borreliosis (Lyme disease) is caused by spirochaetes of the Borrelia burgdorferi sensu lato species complex, which are transmitted by ticks. The most common clinical manifestation is erythema migrans, which eventually resolves, even without antibiotic treatment. However, the infecting pathogen can spread to other tissues and organs, causing more severe manifestations that can involve a patient's skin, nervous system, joints, or heart. The incidence of this disease is increasing in many countries. Laboratory evidence of infection, mainly serology, is essential for diagnosis, except in the case of typical erythema migrans. Diagnosed cases are usually treated with antibiotics for 2-4 weeks and most patients make an uneventful recovery. No convincing evidence exists to support the use of antibiotics for longer than 4 weeks, or for the persistence of spirochaetes in adequately treated patients. Prevention is mainly accomplished by protecting against tick bites. There is no vaccine available for human beings.
Copyright © 2012 Elsevier Ltd. All rights reserved.
PMID: 21903253 [PubMed - indexed for MEDLINE]
Testing in Germany evaluated 2012:
http://www.ncbi.nlm.nih.gov/pmc/article ... 595427.pdf
Clin Dev Immunol. 2012;2012:595427. Epub 2011 Dec 27.
Evaluating frequency, diagnostic quality, and cost of Lyme borreliosis testing in Germany: a retrospective model analysis.
Müller I, Freitag MH, Poggensee G, Scharnetzky E, Straube E, Schoerner Ch, Hlobil H, Hagedorn HJ, Stanek G, Schubert-Unkmeir A, Norris DE, Gensichen J, Hunfeld KP.
Source
Bacteriologic Infection Serology Study Group of Germany (BISSGG), Central Laboratory, Institute for Laboratory Medicine, Northwest Medical Centre, Academic Teaching Hospital, Medical Faculty, Johann Wolfgang Goethe-University, Steinbacher Hohl 2-26, 60488 Frankfurt am Main, Germany.
Abstract
BACKGROUND:
Data on the economic impact of Lyme borreliosis (LB) on European health care systems is scarce. This project focused on the epidemiology and costs for laboratory testing in LB patients in Germany.
MATERIALS AND METHODS:
We performed a sentinel analysis of epidemiological and medicoeconomic data for 2007 and 2008. Data was provided by a German statutory health insurance (DAK) company covering approx. 6.04 million members. In addition, the quality of diagnostic testing for LB in Germany was studied.
RESULTS:
In 2007 and 2008, the incident diagnosis LB was coded on average for 15,742 out of 6.04 million insured members (0.26%). 20,986 EIAs and 12,558 immunoblots were ordered annually for these patients. For all insured members in the outpatient sector, a total of 174,820 EIAs and 52,280 immunoblots were reimbursed annually to health care providers (cost: 2,600,850€). For Germany, the overall expected cost is estimated at 51,215,105€. However, proficiency testing data questioned test quality and standardization of diagnostic assays used.
CONCLUSION:
Findings from this study suggest ongoing issues related to care for LB and may help to improve future LB disease management.
PMID: 22242037 [PubMed - indexed for MEDLINE] PMCID: PMC3254124 Free PMC Article

Tests employed were those used routinely for the serodiagnosis of LB in the participating laboratories. Figure 1 gives an overview on the frequency of the various test systems used by the participants during the surveys. The laboratories most frequently performed a two-tier protocol, beginning with a sensitive EIA or CLIA screening (mean: N = 312 (81.9%), SD = 6.9) followed by immunoblot or line blot confirmation of the results (mean: N = 282 (74.0%), SD = 9), in compliance with the current recommendations of the CDC and most European scientific expert opinions [13, 21, 22]. On average, for direct immunoglobulin class-specific analysis of samples, IgG- and/or IgM-EIA were used by 259 (SD = 6) and 298 (SD = 9) of the participants, respectively, during the six surveys. An immunoblot confirmatory assay for IgG- and/or IgM- antibodies was performed by 239 (SD = 6) and 238 (SD: N = 7) of the laboratories, respectively.

snip

To improve the value of LB serology in the routine microbiological laboratory, promotion of better interassay standardisation of the commercially available test kits is necessary [13, 35, 42] by implementing standards and procedures as suggested earlier by the Centers for Disease Control and Prevention (CDC) and the Association of State and Territorial Public Health Laboratory Directors (ASTPHLD) conference on the serological diagnosis of LB [43]. [Note from Lorima: this is the infamous 1994 Dearborn conference where the CDC officially adopted Dressler/Steere's 1993 5 band criteria] Most importantly, more detailed and independent clinical evaluation of assays should be legally required before placing such products on the market [19].[/color]
In other words, this German group wants even more compliance with the CDC's [=Steere/Dressler] 1994-95 criteria than there is now, even though it sounds as if the two-tier test dominates the system already, and the disease definitions updated in 2011 say testing is "essential" for diagnosis of non-EM Lyme, in parallel with the IDSA guidelines.

In summary, it seems likely that EUCALB is the primary importer of IDSA/CDC diagnostic standards into Europe. And, no help for European Lyme patients can be expected from EUCALB.
"I have to understand the world, you see."
Richard Feynman

duncan
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Re: Guidelines for Diagnosis and Treatment German Borreliosi

Post by duncan » Sat 13 Oct 2012 10:36

These are terrific finds, and very helpful. The footprint in Germany of the IDSA, although troubling, is not surprising. Now I'm wondering what the WHO has to say.

X-member
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Re: Guidelines for Diagnosis and Treatment German Borreliosi

Post by X-member » Sat 13 Oct 2012 16:45

This is from ECDC (European Center for Disease Prevention and Control):

"Eurosurveillance, Volume 16, Issue 27, 07 July 2011

Review articles

Lyme borreliosis in Europe

A Rizzoli ()1,2, H C Hauffe1,2, G Carpi1, G I Vourc’h3, M Neteler1, R Rosà1
1.Department of Biodiversity and Molecular Ecology, Research and Innovation Centre, Fondazione Edmund Mach, San Michele all'Adige (Trento), Italy
2.Both authors contributed equally to this work.
3.Unité d’Epidémiologie Animale, Institut National de la Recherche Agronomique (INRA), St Genès Champanelle, France"

http://www.eurosurveillance.org/ViewArt ... leId=19906

A quote:

"Diagnostic methods

Direct detection of B. burgdorferi sl
Although the diagnosis of LB is primarily based on the most obvious clinical sign, erythema migrans, diagnosis of other forms of LB require confirmation by means of a diagnostic test [52]. A wide range of methods have been developed for the direct detection of B. burgdorferi sl in clinical tissue specimens, including microscopic examination, detection of B. burgdorferi-specific proteins or nucleic acids, and cultivation. Although culture is the most commonly used method of direct detection, success rate depends on sample type. While mean recovery rates of Borrelia from skin biopsies of patients with erythema migrans and acrodermatitis chronica atrophicans are up to 70% [43], those for cerebrospinal fluid (CSF) are much lower. Future diagnostic methods may include PCR-based molecular techniques that can rapidly confirm clinical diagnosis of LB, and identify Borrelia genospecies in tissue specimens or cultured isolates [53]. However, even molecular methods have not yet been standardised since protocols and gene targets vary between laboratories and more clinical validations are needed [53]. Importantly, a negative PCR result does not necessarily indicate the absence of Borrelia [54]; therefore, the use of a PCR-based assay to confirm diagnosis of LB in the absence of serological evidence of Borrelia infection is not currently recommended.

Indirect diagnosis of B. burgdorferi sl
The complexity of the antigenic composition of B. burgdorferi sl and the temporal appearance of antibodies to different antigens at successive time intervals after Borrelia infection means the development of a serological test with high sensitivity and specificity is a challenge. The most commonly used serological methods for the detection of antibodies to B. burgdorferi sl include indirect immunofluorescent antibody assay (IFA) and an enzyme-linked immunosorbent assay (ELISA) [54]. Nevertheless, specific antibodies are often not detectable in the early stage of infection with the use of currently available test methods.

In more than 50% of cases, diagnosis of LB can be made on the basis of an expanding erythema (confirmed after a one-week follow-up). In the absence of erythema migrans at least one other clinical manifestation must be noted and confirmed using serological diagnosis of Borrelia in blood or CSF. According to the most recent German Society for Hygiene and Microbiology (Deutsche Gesellschaft für Hygiene und Mikrobiologie, DGHM) guidelines [43], serological diagnosis for patients in Europe should follow a two-step procedure: (i) ELISA and if reactive, followed by (ii) an immunoblot, if possible using recombinant antigens (p100, p58, p41i, VlsE, OspC, DbpA), including those expressed primarily in vivo (VlsE and DbpA), instead of whole-cell lysate antigen blots. OspC and VlsE are the most sensitive antigens for IgM antibody detection [54]. European standardisation of these diagnostic tests and new markers for detecting active infections are urgently required [55]. "
One more quote (that maybe is interesting for someone?):
In general, in almost all LB cases, the disease is resolved with short courses of antibiotics [51,57], although longer courses are recommended for relapses or more serious and/or chronic forms. Some authors advocate that all symptomatic LB cases should be treated in order to avoid progression to later stages of the disease, and suggest that the earlier treatment begins, the less likely it is that more severe forms will follow [58]. However, overtreatment is considered a problem by others [51], although thus far, drug resistance has been noted only in vitro [59].

Lorima
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Re: Guidelines for Diagnosis and Treatment German Borreliosi

Post by Lorima » Sat 13 Oct 2012 19:32

Thanks, Duncan, for mentioning WHO.
And thanks Carina for the ECDC information. More from them, below.

From WHO (World Health Organization):

Here's their current quick info for travelers:
http://www.who.int/ith/diseases/lyme/en/index.html

Here's a report from WHO, dated 2006:
http://www.euro.who.int/__data/assets/p ... E89522.pdf

page 24: 

In addition, in-depth education about clinical symptoms, diagnosis, treatment, risk factors, surveillance, etc. should be provided to health personnel not only in endemic areas but also in potential new risk regions.

7.6. Surveillance and monitoring

Several initiatives have been taken lately to address LB in Europe and to promote monitoring and the sharing of information. The European Union concerted action on Lyme borreliosis (EUCALB) targets professional groups, ranging from scientific researchers to public health workers. Their web site provides up-to-date information about scientific publications and other LB activities around Europe. The Network for Communicable Disease Control in Northern Europe (Epinorth) consists of infectious disease control institutes in Denmark, Norway, Iceland, Sweden, Finland, the Russian Federation, Estonia, Latvia and Lithuania. The aim of this network is to share information and register data on major infectious diseases, including LB, in this region.
Bad news there: they think EUCALB is reliable, so the "in-depth education" will be consistent with EUCALB's wrong beliefs.

Moving on, here's something from a "fact sheet" for health professionals, from the ECDC, which Carina references above:

http://www.ecdc.europa.eu/en/healthtopi ... onals.aspx

Image

Note that they repeat the US CDC's error about "very strong" seropositivity being characteristic of late disease, and the resulting requirement for highly positive serology. 
Which, of course, comes from Steere's papers (later reinforced by Wormser, Aguero, and B. Johnson), repeatedly claiming to show that all late cases are seropositive by two-tier testing, by the simple expedient of requiring seropositivity for diagnosis. Once the US CDC adopted Steere's disease definition, the whole charade was carved in stone. 

From my experience and the reports of other non-IDSA Lyme disease observers, this will keep most patients with late neuro disease from ever being diagnosed or treated. Because all the serological test development is measured against the current two-tier test as the gold standard, with all improvements aimed at eliminating false positives (because false negatives are said to be almost non-existent), failure at detecting very late LD is built into the system.

Peer reviewers, and the US and Euro CDCs, really must be asleep at the switch. Haste is implicated. But I think it's mostly caused by excessive deference to authority, which simply overrides scientific common sense. 

I'm sorry not to be able to offer reasons for optimism. But I think it's better to figure out what's really going on.
"I have to understand the world, you see."
Richard Feynman

duncan
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Re: Guidelines for Diagnosis and Treatment German Borreliosi

Post by duncan » Sun 14 Oct 2012 12:11

Very quick turnaround on the WHO data! I did not intend for you to hunt it down, but I greatly appreciate that you did. Thank you, Lorima.

I do not think the findings are any reason for pessimism. Just realism about the entrenched positions with which progress must first contend. It's unfortunate.

In one of the old Charlie Brown comic strips, Lucy observed something along the lines, "There's a lot of unlearning that needs to be done." The quip, IMO, could apply here.

X-member
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Re: Guidelines for Diagnosis and Treatment German Borreliosi

Post by X-member » Sun 14 Oct 2012 16:29

Duncan:
"There's a lot of unlearning that needs to be done."
I agree!

X-member
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Re: Guidelines for Diagnosis and Treatment German Borreliosi

Post by X-member » Sun 14 Oct 2012 16:57

I have seen (at least in Sweden, Norway and in Halperins book) that many experts, have considered neuroborreliosis to be where most of the problems are.

And many people therefore have only talked about neuroborreliosis. But most cases with neuroborreliosis are diagnosed early (Rita have posted information and numbers from Norway about this in this forum), so the studies (on neuroborreliosis) has (almost) only been done on cases with early (stage 2) Lyme borreliosis.

I have said it before (to admin and in many places in this forum), studies on late (stage 3) Lyme borreliosis, have to been done on cases with late Lyme borreliosis. It doesn't matter where in the body the (late, disseminated) infection is located. At least that is what I understand when I read information, studies or guidelines from more skilled European experts.

And then, studies have to be done on those cases (that already had late Lyme borreliosis when the first treatment was given) that are not cured with the treatment.

Edit to add:

"Definition of European Lyme Neuroborreliosis"

http://www.lymeneteurope.org/forum/view ... f=7&t=4174

A quote:
More than 95% can be classified as early LNB (stage II), defined as signs and symptoms lasting for <6 months. Less than 5% have late LNB (stage III) with duration between 6 months and several years [12]. The natural course of early LNB is often self-limiting [13], whereas late LNB has a chronic course that probably reflects persistent survival of bacteria in nervous tissue.
Last edited by X-member on Sun 14 Oct 2012 17:09, edited 1 time in total.

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Re: Guidelines for Diagnosis and Treatment German Borreliosi

Post by X-member » Sun 14 Oct 2012 17:01

Rita has posted some (in my eyes) very interesting information in the topic below:

"LTT for Borrelia Detects Active Lyme Borreliosis"

http://www.lymeneteurope.org/forum/view ... f=5&t=4281

Perhaps Henry can help us with this?

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Spanky
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Re: Guidelines for Diagnosis and Treatment German Borreliosi

Post by Spanky » Sun 14 Oct 2012 17:12

"Carina":
Perhaps Henry can help us with this?
OH...MY...GAWD...

:lol: :lol: :lol:


NO clue...

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