Christopher Smith's Lyme Disease Bill 2557

General or non-medical topics with information and discussion related to Lyme disease and other tick-borne diseases.
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Spanky
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Re: Christopher Smith's Lyme Disease Bill 2557

Post by Spanky » Thu 22 Dec 2011 0:13

"Henry":
Spanky: It's like this. If one has Lyme disease and has had it for a long period of time -- as is the case for many people who claim that they have chronic Lyme disease-- there will be IgG antibody in the serum that is detectable by both ELISA and IgG Western blot by CDC criteria-- unless ones immune defense system is completely suppressed. To believe otherwise would be like suspending the law of gravitation. There is no such thing as seronegative Lyme disease.
No, I understand that. And I understand that you are suggesting that the interpretation methods used by IgeneX might, in the hands of some LLMDs, be used to justify treatment of cases of Lyme, that are NOT actually Lyme. Got that.

But is there reason to doubt the validity of their actual labwork? Or just the interpretation of that work?

But look...maybe I can explain the thought I have in mind by just relating what happened with me...

Like Claudia's guy I showed an IgM positive reaction (for OspA), late stage, according to the IgeneX test. Now...in discussing that with one doctor...I said to him, "okay, as I understand that...that is either a lab error or that, basically confirms, for all intents and purposes, (non-CDC, admitttedly) the three previous screens that were performed".

Unless you think that is a false result, it was Lyme. And given the odds of hitting three positive screens in a row...it almost had to be, mathematically.

And I asked him if there were any reason to think that IgeneX's results were that unreliable. And he didn't answer...but did want to discount, dismiss them.

And I am just saying...okay...but why?

In other words, if I am going to demand that ILADS docs provide reasons to discount the results of the four studies...then I think someone should also provide evidence as to why IgeneX's lab work is deemed so unreliable.

From what I remember...they always pass their tests.

Edited to add: To this day, the docs insist that, in my situation, there is really very little chance that it wasn't Lyme.

Now...if I understand what you you just said...no chance that it was Lyme.

Sooo...has to be. Can't be.

The theory meets the reality.

Henry
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Re: Christopher Smith's Lyme Disease Bill 2557

Post by Henry » Thu 22 Dec 2011 1:55

Spanky: Let me try one more time to explain the situation. The CDC criteria for a positive IgG Western blots requires the presence of 5 of the following 10 antigenic bands: 18 kDa; 23-25 kDa (OspC); 28 kDa; 30 kDa; 39 kDa; 41 kDa; 45 kDa; 58 kDa; 66 kDa; and/or 83-93 kDa. IGenex's criteria for a positive IgG Western blot requires the presence of only 2 of the following antigenic bands: 23-25 kDa (OspC); 31 kDa (OspA); 34 kDa (OspB); 39 kDa; and or 83-93 kDa. At one time, the CDC considered using the 31 kDa and 34 kDA bands as part of its criteria; however, extensive studies showed that these antigens are expressed by Borrelia only when grown on artificial laboratory media and in the midgut of the tick, not during human infection. Although they are sometimes expressed in patients with severe and long lasting Lyme-induced arthritis, antibodies against the other antigenic bands used in their criteria predominate, so that a positive IgG Western blot can usually be obtained in the absence of antibodies against the 31 kDa and 34 kDa bands. If antibodies against these bands were of diagnostic value, the FDA would not have approved the OspA based LYMErx vaccine for use in humans.

I will not get into the criteria for IgM Western blots since IgM Western blots are reliable only when used early during infection, i.e., within the first 30 days of infection. In the case of patients who believe that they have chronic Lyme disease, we are dealing with infections of longer duration so that an IgG Western blot is more appropriate for use.

I have no doubt that IGenex is doing their tests correctly and in accordance with standard protocols, which is why they pass approval. It is the CRITERIA that they use which is the problem. As I said previously, in their reports, they express their results with respect to both criteria. Most of the reports on IgG Western blots that I have seen were negative by CDC criteria, but positive by IGenex's criteria. In most cases, antibodies against only the 31 kDa, 34 kDa, and 41 kDa bands are detected in tests that they designate positive. That’s not enough to cut it. This is hardly good evidence that someone has Lyme disease.

Claudia
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Re: Christopher Smith's Lyme Disease Bill 2557

Post by Claudia » Thu 22 Dec 2011 3:08

Henry wrote:

At one time, the CDC considered using the 31 kDa and 34 kDA bands as part of its criteria; however, extensive studies showed that these antigens are expressed by Borrelia only when grown on artificial laboratory media and in the midgut of the tick, not during human infection. Although they are sometimes expressed in patients with severe and long lasting Lyme-induced arthritis, antibodies against the other antigenic bands used in their criteria predominate, so that a positive IgG Western blot can usually be obtained in the absence of antibodies against the 31 kDa and 34 kDa bands. If antibodies against these bands were of diagnostic value, the FDA would not have approved the OspA based LYMErx vaccine for use in humans.
Henry, please post links to these studies. I couldn't find anything in Google Scholar but I am probably not using the correct terminology to get the results.

I did find this article from the JOURNAL OF CLINICAL MICROBIOLOGY, stating research that shows that approx. 10% of confirmed Lyme patients would be missed by dropping bands 31 and 34 and that antibodies against these bands were of strong diagnostic value because they are more specific than some of the other accepted bands, and a very high percentage of Lyme arthritis patients (71% in a referenced study) had strong reactivity to OspA (31 kDa) or OspB (34 kDa) or both:
JOURNAL OF CLINICAL MICROBIOLOGY,
June 1996, p. 1353–1354 Vol. 34, No. 6
American Society for Microbiology

Recommendation To Include OspA and OspB in the New Immunoblotting Criteria for Serodiagnosis of Lyme Disease

EILEEN HILTON,1* JAMES DEVOTI,1 AND SUNIL SOOD,2 Department of Medicine 1
and Department of Pediatrics, 2 Long Island Jewish Medical Center, Long Island
Campus for Albert Einstein College of Medicine, New Hyde Park, New York 11042

In October 1994, the Second National Conference on the Serologic Diagnosis of Lyme Disease recommended a two-step approach to serological testing. The first step was the performance of an enzyme-linked immunosorbent assay (ELISA); the second step was a confirmatory immunoblot. New criteria for the interpretation of a positive immunoblot were also recommended. The committee decided to omit the 31- and 34-kDa bands (OspA and OspB, respectively) from the choice of bands considered diagnostic for a positive immunoblot. Since we had previously included these in our diagnostic criteria for Lyme disease-positive immunoblots, we reviewed data for all patients attending a Lyme disease center with positive ELISAs and immunoblot assays for Lyme disease from 1 September 1992 to 31 December 1993. The criteria for a positive Western blot (immunoblot) were the presence of 5 of 12 bands, including the 10 recommended by the conference, and the presence of the 31- and 34-kDa protein bands. Of the 136 patients evaluated, 50 were considered to have Lyme disease. Of these 50, 4 (8%) would not have met immunoblot criteria for the diagnosis if the new recommendations were used. Had the 31- and 34-kDa bands been included as part of the diagnostic requirements for immunoblot, these patients would have been included. Although overdiagnosis of Lyme disease appears to be the more frequent problem, our concern is that the exclusion of the 31- and 34-kDa protein bands from the diagnostic criteria may result in the underdiagnosis of Lyme disease by those who would rely too heavily on serological confirmation. The addition of the 31- and 34-kDa bands to those recommended for confirmatory immunoblot should be reconsidered.

[SNIP]

There was agreement that the use of OspA and OspB (31-and 34-kDa) bands did not significantly add to the sensitivity or the specificity of the IgG Western blot, as these bands may develop only late in disease and other diagnostic bands would already be present when OspA and OspB antibodies appeared.

[SNIP]

In other studies from the United States, 71% of 80 patients with arthritis had strong IgG reactivity with
OspA (31 kDa) or OspB (34 kDa) or both (3–5)
. Although there have been some reports of cross-reactivity of human spirochetes, the 31- and 34-kDa outer surface proteins appear to be more specific for Lyme borreliosis than some of the other bands recommended for confirmation (6).

[SNIP]

However, there is concern that the exclusion of the 31-kDa (OspA) and 34-kDa (OspB) bands from the list of bands required to make the diagnosis of Lyme disease may result in underdiagnosis by clinicians who view the criteria in a strict sense. We found that that would have occurred in 8% (4 of 50) of cases at our center. We feel the addition of the 31- and 34-kDa bands to the group of bands used for confirmatory immunoblots should be reconsidered. Clinicians should, as always, exercise clinical judgment in the interpretation of any laboratory results.

http://www.ncbi.nlm.nih.gov/pmc/article ... 341353.pdf

RitaA
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Re: Christopher Smith's Lyme Disease Bill 2557

Post by RitaA » Thu 22 Dec 2011 4:19

Hi Claudia,

It's so nice to see you posting again. I hope your son is doing okay.

I did a quick search too. Please forgive me if I'm introducing an unreliable or controversial source of information into this discussion, but I don't believe I've come across this before (although I could simply be forgetting):

http://www.lymenet.de/labtests/brenner.htm
[snip]

A number of criticisms have been offered of the CDC criteria since their adoption in 1994.

The first is centered on the CDC's failure to make any qualitative distinction among the various bands that can show up on a patient's Western blot.

[snip]

On the other hand, certain other bands are considered highly specific for Bb -- the aforementioned
31 kDa band, for example, or
34 (OspB)
or
39 or OspC (anywhere between 22 and 25).

[snip]

A second criticism of the CDC Western blot criteria is that they fail to include the 31 and 34 kDa bands. This does indeed seem like an odd decision, since antibodies with these molecular weights correspond to the OspA and OspB proteins of B. burgdorferi, which are considered to be among the most species-specific proteins of the organism.

So why didn't Dressler et al. include them?

Answer: These bands tend to appear late if at all in Lyme disease patients, and did not show up with great frequency in the patients that the Dressler et al. group studied (though they did show up sometimes). As a result, they weren't deemed to have much diagnostic value and didn't find their way onto the CDC hot list. However, while the absence of either of these bands from a patient's immunoblot result does not rule out Lyme disease, their presence is hardly meaningless. Thus, many Lyme disease experts believe it is a serious mistake to exclude these two antibody proteins from the list of significant bands. The CDC's decision to do so seems particularly strange in light of the fact that it is the OspA component of Bb that is being used as the stimulating antigen in the ongoing experimental Lyme disease vaccine trials. As one immunologist remarked shortly after the 1994 CDC conference, "If OspA is so unimportant, then why the heck are we vaccinating people with it?"

[snip]

First, it is well established that early subcurative treatment of Lyme disease can abrogate the human immune response to B. burgdorferi [3]. Although this is not thought to be a common phenomenon ...
Note: I tried to limit the extract above to the discussion about bands 31 and 34 and seronegativity.

Bagge
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Re: Christopher Smith's Lyme Disease Bill 2557

Post by Bagge » Thu 22 Dec 2011 4:27

Claudia, I am reading the book "Lyme Disease: An Evidenced-based Approach", edited by John J. Halperin. Chapter four discusses in detail many aspects of the laboratory diagnostic testing for Bb infection written by B.J.B. Johnson. I noticed elsewhere that you had purchased a textbook and thought you may be interested in this newer book.

This is not my area of expertise, so I will not attempt to interpret or relay any of the textbook's explanations for the questions you asked Henry. However, in this chapter on testing, it does discuss the 31 and 34kDa issues you mention and refers to a study by Crowley and Huber, 2003, as well as other studies. Perhaps you can look up that study and it will help you. http://iai.asm.org/content/71/7/4003.short

Edited to add: the textbook also offers a different opinion with detailed supporting explanation about the items RItaA just posted from her source of lymenet.de.

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Spanky
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Re: Christopher Smith's Lyme Disease Bill 2557

Post by Spanky » Thu 22 Dec 2011 4:39

"Henry":
Let me try one more time to explain the situation. The CDC criteria for a positive IgG Western blots...
Yes, thanks, Henry. But I think that I actually do understand that situation, fairly well. All too well.
I have no doubt that IGenex is doing their tests correctly and in accordance with standard protocols, which is why they pass approval.
Thanks very much for that. That is the way that I have always interpreted the situation. But good to hear it confirmed. Thanks.

But I am personally left with a situation, personal history, that my doctors say, basically, don't know what else it could be other than Lyme...

...and my own calculation of the odds of hitting three positive screens in a row...would tend to make me think that they are most likely right...

...and then, what I think that I hear you saying...is that I couldn't have Lyme without a positive Western Blot...

Now, seems to me...somebody's got to be mistaken.

My docs say it has to be...you say it cannot be.

That's just great, isn't it? You see?

I am just trying to share my own experiences to convey a sense of what a Lyme patient encounters...has to deal with.

Henry
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Re: Christopher Smith's Lyme Disease Bill 2557

Post by Henry » Thu 22 Dec 2011 15:09

Spanky and others: The best source of background information on this issue is the chapter by Barbara Johnson entitled, " Laboratory Diagnostic Testing for Borrelia burgdorferi infection", in "Lyme Disease: An Evidence-Based Approach", by J.J. Halperin. Of major concern to me is why one would expect to find antibodies against 31 and 34 kDa and NOT most --if not all-- of the other proteins bands used in the CDC criteria since those proteins are known to be produced in abundance by Borrelia during human infection? I and others find that puzzling. Any explanations? Since Barbara Johnson is an expert on the diagnosis of Lyme disease, I must defer to her sound judgement on this matter. Quite frankly, if I had a serological diagnosis based on the detection of only antibodies vs 31 and 34 kDA protein bands, I would ask my physician to look for other explanations for my symptoms besides Lyme disease. In my opinion, the probability of having Lyme disease under such circumstances would be very low indeed. No wonder some of the therapeutic approaches being used to treat such patients, which are based on the assumption of a persistent infection, have such poor success.

Henry
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Re: Christopher Smith's Lyme Disease Bill 2557

Post by Henry » Thu 22 Dec 2011 15:26

One last point I failed to address: Although the no longer manufactured LYMErx vaccine was an OspA-based vaccine, it was not designed to provide protective immunity against Borrelia in humans after immunization, as most commonly used vaccines are designed to do for other infections. As I mentioned previously, OspA (31 kDa) is produced by Borrelia when ground on artificial media and in the mid-guts of ticks, which is where Borrelia take up residence in infected ticks. When ticks take a blood meal, either the temperature of the blood or something in the blood causes the surface antigens of Borrelia to change from OspA to OspC; this permits Borrelia to migrate from the midgut to the salivary glands of ticks where they then can be transmitted to humans while the tick is still taking a blood meal. This whole process takes about 36-48 hours, in the mouse model (mice are more susceptible to Borrelia infections) and probably a few hours longer in the human model of infection. Immunization with an OspA-based vaccine like LYMErx generates antibodies in the blood against OspA that are then taken up by ticks during their blood meal. The presence of such antibody in blood causes Borrelia to be neutralized or killed in the midgut of the tick so that the tick is then unable to transmit Lyme disease to humans. Thus, the LYMERrx vaccine is a transmission-blocking vaccine, rather than one designed to confer protective immunity in the manner of a conventional vaccine. A variant of this approach is now being used as an oral OspA-based food-baited vaccine to prevent the transmission of borreliosis within the wild mouse population to reduce the incidence of Lyme disease in endemic areas. Field studies show that this approach has great promise.

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Spanky
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Re: Christopher Smith's Lyme Disease Bill 2557

Post by Spanky » Thu 22 Dec 2011 15:43

"Henry";
"... and NOT most --if not all-- of the other proteins bands used in the CDC criteria since those proteins are known to be produced in abundance by Borrelia during human infection? I and others find that puzzling. Any explanations"?
Well, isn't the question, though, what degree of confidence to place in serological results?

I mean, what do you mean when you say "seronegative Lyme doesn't exist"...unless you test positive according to the CDC, you don't have Lyme?

What do you make of this, then?

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC229622/


Clin Microbiol. 1997 March; 35(3): 537–543.

PMCID: PMC229622

Interlaboratory comparison of test results for detection of Lyme disease by 516 participants in the Wisconsin State Laboratory of Hygiene/College of American Pathologists Proficiency Testing Program.

L L Bakken, S M Callister, P J Wand, and R F Schell

Department of Continuing and Vocational Education, University of Wisconsin, Madison 53706, USA.


Abstract
In 1991, we reported that 55% of laboratories participating in the Wisconsin Proficiency Testing Program could not accurately identify serum samples from Lyme disease patients containing antibody against Borrelia burgdorferi. The purpose of this study was to determine whether the accuracy of Lyme disease test results reported by approximately 500 participants in the Wisconsin State Laboratory of Hygiene/College of American Pathologists Lyme Disease Survey had improved. From 1992 through 1994, 50 serum samples were sent to participants of the survey. Each laboratory received 28 serum samples from individuals with Lyme disease according to the case definition of the Centers for Disease Control and Prevention and 22 serum samples from healthy individuals. Unfortunately, the serodiagnosis of Lyme disease by participants had not improved. The specificity of the Lyme disease assays steadily decreased from approximately 95% to approximately 81% during the 3-year period of the survey. False-positive test results approached 55% with some of the serum samples from healthy donors. A serum sample containing antibody against Treponema pallidum was reported as positive by 70% of the participants. In addition, the sensitivity fluctuated between 93 and 75%, depending upon the conjugate used by the laboratories. These results suggest that stronger criteria must be applied for approving and continuing to approve commercially available kits for the serodiagnosis of Lyme disease.
Quite frankly, if I had a serological diagnosis based on the detection of only antibodies vs 31 and 34 kDA protein bands, I would ask my physician to look for other explanations for my symptoms besides Lyme disease. In my opinion, the probability of having Lyme disease under such circumstances would be very low indeed.
Well, just to be clear, I certainly didn't mean to suggest that was the case in my situation...and I don't think anyone else did, either.

But as I said, before...I have a nice, interesting dilemna...highly positive screens...3 in a row...negative blots according to CDC standards..3 in a row...and a case history highly suggestive of Lyme.

Now...if you calculate the odds of hitting 3 screens in a row...and enter the post-test result number as the next, you will reach numbers near 99+%.

http://www.acponline.org/clinical_infor ... alculator/

Something tells me serology isn't exactly meant to 'rule in', 'rule out'...

Henry
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Re: Christopher Smith's Lyme Disease Bill 2557

Post by Henry » Thu 22 Dec 2011 16:09

Spanky: I would place my confidence in recommendations of the CDC and FDA. They derive a lot of their data from specimens and tests conducted at numerous State public health laboratories.

There's another interesting dilemma. I believe -- and hope that I am not mistaken-- that you had a negative ELISA test, but a positive IgG Western blot for 31 and 34 kDa. Since the ligand used in the ELISA is laboratory grown B. burgdorferi that is loaded with 31 and 34 kDA, it should have been positive. Obviously, as I've been trying to point out, there is something wrong here, especially if antibodies against the remaining abundant antigens used in the CDC criteria are not being detected. If I were a betting person, I wouldn't put my money on Lyme disease.

One last thing: A Western blot is not recommended if the ELISA is negative. I think the above illustrates why.

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