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Re: Invincible borrelia?

Posted: Sun 31 Jul 2016 16:39
by Henry
Duncan: Just as I thought -- you assume too much and don't know what you are talking about.

Re: Invincible borrelia?

Posted: Sun 31 Jul 2016 16:54
by duncan
Please answer my questions, Henry.
1) Of the 300,000+ patients diagnosed annually for Lyme, how many were diagnosed via direct means?
2)How many Lyme patients participating in NIH-sponsored Lyme studies - that do not use EM's for culture - showed direct evidence of Bb infection?

I will help you: Whatever the numbers are, they will prove minute. So their relevance is marginal at best, and I suspect you know this.

Accordingly, why you introduced the notion of direct evidence of Bb infection in the RCT's remains a puzzler.

Edited to add: Moreover, didn't you write that there was NO evidence of a persistent infection? But isn't it true that many to most patients in the RCT's were sero-positive, and presented with symptoms?

Re: Invincible borrelia?

Posted: Sun 31 Jul 2016 17:25
by Henry
Duncan: The figure of 300,000 is an estimate based on insurance claims for patients that were treated for Lyme disease -- for whatever reasons that might be -- not on the results of laboratory testing. Many of these were patients living in endemic areas who presented to a physician with symptoms that they attributed to Lyme disease; in such cases, the physician exercised "clinical judgement" and treated them with oral antibiotics, without conducting laboratory tests. Health insurance companies often will pay for such treatment. After all, 28 days of treatment with oral doxycycline cost about $40 -- which not a big deal and which certainly is not going to "break the bank".

If you took the time to read the published papers concerning the now 5 clinical trials on the benefit of extended antibiotic therapy for the treatment of PTLDS, you will discover that all were open recruitment studies in which any individual who thought that they might have "chronic Lyme disease" was perfectly free to apply for enrollment. All who were eligible (read the eligibility requirements) were cultured and tested for Borrelia infection by PCR at the time of enrollment. None were found to be positive. So, it is incorrect to say -- and or assume-- that investigators did not look to see if these patients were infected. They did and could find no evidence to support such a possibility. Since they showed no significant and lasting benefit from the extended antibiotic therapy, which one certainly would expect if they were infected, it is reasonable to conclude that their symptoms are due to other causes that remain to be determined and may not be the same for all of these patients.

Re: Invincible borrelia?

Posted: Sun 31 Jul 2016 17:34
by duncan
Henry, you are still dancing around my questions. :D

I've read the studies.

Did you read Steere's July 1983 study (I think) divvying up, in a contrived and imo strange fashion, late manifestations of the disease into major and minor categories? Might the lingering effects of that effort play a role in the dismissive attitude of some researchers as to the severity and even legitimacy of some patient complaints?

I ask since researchers and clinicians who discard patient symptoms as so much fertile imagination, or ascribe them to the aches and pains of everyday life, are...well, suffice it to say I marvel that they are in the people business.

Re: Invincible borrelia?

Posted: Sun 31 Jul 2016 18:12
by Henry
Duncan: My response was to your question #2 above, as well as the false claim that no one is looking for infected patients in the extended antibiotic treatment studies that have been done. I have already responded to your question #1.

Re: Invincible borrelia?

Posted: Sun 31 Jul 2016 18:30
by Henry
Duncan: You are conflating again. The 300,000 figure came from health insurance company records on the number of people treated for Lyme disease, based on the number of claims they received. Such reports do not include clinical data. The figure obviously would be quite different from the numbers of cases reported to the CDC each year (about 30,000), which require clinical data and the results of lab tests to support the diagnosis of Lyme disease. Quite a different situation don't you think?

Re: Invincible borrelia?

Posted: Sun 31 Jul 2016 19:11
by duncan
Eh. Are you saying that the CDC or NIH or IDSA dispute the 300,000 estimate?

Henry, you did not provide an answer as to the number - or even portion? - of the estimated 300,000 patients afflicted annually with Lyme that were diagnosed via direct means. If you prefer, you can provide insight into the portion of 30,000 reported Bb cases attributed to direct metrics.

Nor did you even remotely answer my second question.

Come to think of it, you also neglected to address my last two questions.

Now, a new question: What is the recommended protocol for a clinician to test for Lyme disease in a suspected Bb patient, and was that protocol employed for study participants?

Re: Invincible borrelia?

Posted: Sun 31 Jul 2016 21:06
by dlf
This discussion has taken a decidedly silly turn. Duncan, of course we all know that aside from the EM cultured patient cases, there has been little to no research done on patients with direct detection evidence of Borrelia and we also know that Borrelia are next to impossible to culture after treatment unless they are also treated with anti-tumor necrosis factor alpha. PCR testing is also incredibly insensitive and pretty much, "hit or miss". If Henry doesn't already know this, he should.

I also am completely confounded by Henry's disingenuous assertions about the patients in the treatment trials he is so fond of quoting. Of course none of them had direct evidence of bacterial persistence. It was an exclusion criteria. If any had been found to have such evidence, they would have been automatically excluded.

Two Controlled Trials of Antibiotic Treatment in Patients with Persistent Symptoms and a History of Lyme Disease
Mark S. Klempner, M.D., Linden T. Hu, M.D., Janine Evans, M.D., Christopher H. Schmid, Ph.D., Gary M. Johnson, Richard P. Trevino, B.S., DeLona Norton, M.P.H., Lois Levy, M.S.W., Diane Wall, R.N., John McCall, Mark Kosinski, M.A., and Arthur Weinstein, M.D.
N Engl J Med 2001; 345:85-92July 12, 2001DOI: 10.1056/NEJM200107123450202 ... articleTop
Patients were excluded if they had hypersensitivity to the study medications, had previously received parenteral antibiotic therapy for 60 days or more for their current symptoms, had active inflammatory synovitis, had a coexisting condition that could have accounted for their symptoms, or were unable to discontinue medications that could interfere with the evaluation of their response to the treatment regimen (e.g., narcotic analgesics or prednisone in a dose of 10 mg per day or more). Patients with a positive polymerase-chain-reaction (PCR) test for B. burgdorferi DNA in plasma or cerebrospinal fluid at base line were also excluded.
Any more recent studies undertaken on treatment in patients with PTLDS also require that no objective evidence of infection be found in patients, as outlined in the "proposed" definition for 'PLDS' in the 2006 IDSA Lyme guidelines.

So, this leads me back to the original post that started this thread. Usually, we don't see hv808ct and Henry post on a topic unless they have some ulterior motive, (whatever it might be). Any guesses as to what they are fishing for????

hv808ct wrote:
Among Lyme activists, these are some of the evolving reasons for treatment failures:

1. Treatment was too short
2. Co-infections
3. Physical seclusion (e.g., intracellular, which Bb doesn’t do)
4. Toxins (which Bb doesn’t produce)
5. Morphological changes (i.e., round bodies)
6. Antigenic variation of surface proteins
7. Antibiotic resistance (not seen in Bb)
8. Immunosuppression by Bb products
9. Biofilms
10. Persister cells following antibiotic treatment

Did I forget any? Of course, most bacterial and parasitic pathogens employ one or more of the above strategies, and yet remain susceptible to antimicrobial drugs and adaptive immune responses.
Dealing with these one by one.......

1. Treatment was too short. Yes, this is a common plausible reason. However, one could also add that the treatment was with the wrong antibiotic, or that a single antibiotic might not be appropriate, or that the dose of the antibiotic given was too small and therefore not effective, or that using a one size fits all strategy is simply not appropriate. Duration of illness and severity of symptoms before treatment are also important considerations. Additionally, not all people metabolize antibiotics similarly. Although the treatment in the study below was for Coxiella burnetii, the issue of antibiotic concentrations being variable in patients would also be a factor for other diseases including Lyme.

Jean-Marc Rolain, Marie-Noëlle Mallet and Didier Raoult. Correlation between Serum Doxycycline Concentrations and Serologic Evolution in Patients with Coxiella burnetii Endocarditis J Infect Dis. (2003) 188 (9): 1322-1325 doi:10.1086/379082
Twelve months after therapy began, we noted that the serum concentration of doxycycline varied from 0.06 to 12.92 μg/mL. This wide heterogeneity in doxycycline levels was also found in patients with small, asymptomatic, abdominal aortic aneurysms [11]. This marked interpatient variation is difficult to explain, although low serum doxycycline concentrations might occur with the use of some psychotropic drugs and/or alcohol. Moreover, because doxycycline was administered orally, it is also possible that, for some patients, certain foods or drugs, such as antacids, inhibited the bioavailability of doxycycline [12, 13]. Because doxycycline can cause various adverse effects, such as epigastric burning, nausea, vomiting, or hyperpigmentation of the skin after exposure to the sun, lack of compliance of patients may also explain the wide variation in serum doxycycline concentrations. Moreover, one may hypothesize that bioavailability of the drug differs from patient to patient because of weight or clearance of the drug and, thus, that dosage of doxycycline needs to be adjusted for each patient. In our experience, the same standard dose of doxycycline was given to all patients whether they weighed 50 or 110 kg. Interestingly, we found that the mean serum doxycycline concentration in our patients increased during long-term administration of drugs [14]

It is possible to speculate that patients with higher serum doxycycline concentrations were treated more efficiently. The positive correlation between serum doxycycline concentrations and decreases in C. burnetii phase 1 antibody titers found in this study is in accordance with this hypothesis. A decrease in phase 1 IgG antibody titers <1:800 remains the main predictive criterion of clinical cure [3]. In general, the antibody titers decrease slowly with treatment [3]. However, the kinetics of antibody titer decrease in patients treated with doxycycline may vary, suggesting that some patients should be treated for >18 months to be cured. Moreover, the differences found in the present study show that patients with serum doxycycline concentrations <5 μg/mL had a lessened decreases in antibody titers, suggesting that treatment was not sufficiently effective. One may hypothesize that higher doses of doxycycline would be more effective in the treatment of Q fever endocarditis. Forslin et al. [15] have demonstrated that, when the oral dose of doxycycline increases, the serum concentration increases accordingly.

Considering the low and erratic levels produced by the usual 200-mg dose of doxycycline, it is possible that higher doses (400 mg) may be justified in the treatment of some cases of Q fever endocarditis, especially for patients who are infected with strains with higher MICs against doxycycline.
Pharmacodynamics of doxycycline
Cunha, B.A. et al.
Clinical Microbiology and Infection , Volume 6 , Issue 5 , 270 - 273
http://www.clinicalmicrobiologyandinfec ... 6/fulltext

Tetracycline and glycylcycline pharmacokinetics and pharmacodynamics represent a relatively under-investigated but interesting area of antimicrobial chemotherapy. Until recently our understanding was poor and little progress had been made until tigecycline entered clinical development. We are still unclear as to the relative importance of serum versus tissue levels in predicting outcomes for the tetracyclines and glycylcyclines but this may be important given their large volumes of distribution. Much work could be done to improve our pharmacokinetic/pharmacodynamic knowledge of these agents, and as tigecycline enters clinical use it is to be hoped that this experience will add to our knowledge in the area.

Karlsson M, Hammers S, Nilsson-Ehle I, Malmborg AS, Wretlind B. Concentrations of doxycycline and penicillin G in sera and cerebrospinal fluid of patients treated for neuroborreliosis. Antimicrobial Agents and Chemotherapy. 1996;40(5):1104-1107.

Oral doxycycline versus intravenous ceftriaxone for European Lyme neuroborreliosis: a multicentre, non-inferiority, double-blind, randomised trial
Ljøstad, Unn et al.
The Lancet Neurology , Volume 7 , Issue 8 , 690 - 695 ... 4/fulltext
Of 118 patients who underwent randomization, 102 completed the study (mean clinical score at baseline 8·5 [SD 4·1]). 4 months after the start of treatment, mean score improvement in the doxycycline group (n=54) was 4·5 (95% CI 3·6 to 5·5) points and that in the ceftriaxone group (n=48) was 4·4 (3·4 to 5·4) points (95% CI for difference between groups −0·9 to 1·1; p=0·84). 26 (48%) patients in the doxycycline group and 16 (33%) in the ceftriaxone group had total recovery (95% CI for difference between groups −4% to 34%; p=0·13). Side-effects possibly related to treatment were reported in 21 (37%) and 26 (46%) patients in these groups, respectively (−28% to 9%; p=0·30). Three patients discontinued ceftriaxone treatment owing to adverse events.

Oral doxycycline is as efficient as intravenous ceftriaxone for the treatment of European adults with Lyme neuroborreliosis.
So, in this case, 26 (48%) patients in the doxycycline group and 16 (33%) in the ceftriaxone group had total recovery. Does anyone actually think those are very good results????? Seems to me that they are both highly "inefficient"!!!

2. Co-infections

Yup, this is a big confounding issue!

3. Physical seclusion (e.g., intracellular, which Bb doesn’t do)

You may want to modify the part of your statement in brackets. See references below:

Borrelia burgdorferi (Lyme Disease)
The most active agents in vivo are ceftriaxone, clarithromycin, and the tetracyclines (8,119). The basis for the occasional discrepancy between in vitro and in vivo results of antimicrobial susceptibility tests for B. burgdorferi is unknown. The organism may persist intracellularly where antibiotic agents may vary widely in their effectiveness (53, 111, 117). For example, B. burgdorferi has been shown to persist within fibroblasts where they may avoid the antimicrobial effects of ceftriaxone (53). The organism may also interact with host factors to alter its pathogenicity. For example, addition of cytokines to the culture medium enhances the pathogenicity of B. burgdorferi (60, 61).
Intracellular localization of Borrelia burgdorferi within human endothelial cells.
Y Ma, A Sturrock, and J J Weis
Infect. Immun. February 1991 59:2 671-678 ... id=1987083

Alan G. Barbour, Durland Fish. The Biological and Social Phenomenon of Lyme Disease. (1993)

Although spirochetes are predominantly extracellular pathogens, they invade endothelial layers to pass into tissues, including the brain [55].

55. L. E. Comstock and D. D. Thomas, Infect. Immun. 57, 1626 (1989); J. C. Garcia-Monco, B. F. Villar, J. C.
Alen, J. L. Benach, J. Infect. Dis. 161, 1187 (1990); A. Szczepanski, M. B. Furie, J. L. Benach, B. P. Lane, H. B.
Fleit, J. Clin. Invest. 85, 1637 (1990); Y. Ma, A. Sturrock, J. J. Weiss, Infect. Immun. 59, 671 (1991).

Microbes Infect. 2006 Nov-Dec;8(14-15):2832-40. Epub 2006 Sep 22.
Invasion of human neuronal and glial cells by an infectious strain of Borrelia burgdorferi.
Livengood JA, Gilmore RD Jr.
SourceCenters for Disease Control and Prevention, Division of Vector-borne Infectious Diseases, 3150 Rampart Road, CSU Foothills Campus, Fort Collins, CO 80522, USA. ... 790600311X

Aside from the studies that show Borrelia can actually localize intracellularly, there are also areas of the body that can be considered immune privileged. i.e. for example, the eyes.

Additionally, this is an interesting take on the issue of disease pathogenesis based on immune signaling orchestrated from intracellular vesicles and organelles.

Petnicki-Ocwieja T, Kern A. Mechanisms of Borrelia burgdorferi internalization and intracellular innate immune signaling. Frontiers in Cellular and Infection Microbiology. 2014;4:175. doi:10.3389/fcimb.2014.00175.
In recent years it has been shown that localization to different cellular compartments plays a significant role in coordinating the activation of innate immune pathways. The broad classification of cell surface being distinct from intracellular receptors is no longer sufficient when describing the complexity of signaling pathways. Although “intracellular” is used to broadly imply endosomal localization it is now known that immune signaling can be orchestrated from intracellular vesicles and organelles (Kagan, 2012). In addition, some immune signaling complexes previously thought to be strictly cytoplasmic may in fact be recruited to specific compartments containing ligands. In support of this hypothesis, recent data has shown that caspase-1 can accumulate at the phagosome, suggesting that molecules of the inflammasome are also recruited to phagosomal compartments.
4. Toxins (which Bb doesn’t produce)

Toxins are more complicated and remain highly debatable and controversial even within the Lyme community. Borrelia burgdorferi have actually never been scientifically proven to 'produce neurotoxins'. A reasonably intelligent and scientifically debated forum thread on this topic is available. While some of the comments are not really relevant, most are and it is important to look at the entire thread from end to end to understand the controversy.
Borrelia neurotoxin circulation ... f=6&t=1698

For more information about the issue, readers might want to look at the following:

Neurotoxin - Wikipedia, the free encyclopedia


(Shaikh S, Dubey R, Joshi YM and Kadam VJ: Excitotoxicity and Cell Damage - A Review. In: Int J Pharm Sci Res 2013; 4(6); 2062-2066. ... aper-5.pdf

Because this avenue of Bb "neurotoxin" research was never really pursued further, I personally sincerely doubt that there is indeed a toxin that is produced by Borrelia and think it is far more likely (since one has not been isolated from the bacteria), that neurotoxicity or neuro excitotoxicity may be produced by human immune system macrophages themselves when stimulated by Borrelia lipoproteins. The end result for genesis of neurological symptoms and pain of course would be the same either way. But, the actual cause would be completely different, as would any potential treatment for the pain generated as a result of the cause.

Macrophage-induced neurotoxicity is mediated by glutamate and attenuated by glutaminase inhibitors and gap junction inhibitors. Life Sci. 2008 May 23;82(21-22):1111-6. doi: 10.1016/j.lfs.2008.03.010. Epub 2008 Apr 1. ... 0508001343

Gadani SP, Walsh JT, Lukens JR, Kipnis J. Dealing with Danger in the CNS: The Response of the Immune System to Injury. Neuron. 2015;87(1):47-62. doi:10.1016/j.neuron.2015.05.019.
Beneficial versus Destructive Roles of Macrophages in CNS Injury
After entering the CNS injury site macrophages have several functions, some of them shown to be beneficial and others detrimental (Figure 3). A well-known neurotoxic product of activated microglia and macrophages is glutamate, a primary CNS excitatory neurotransmitter, which is released in large quantities after injury and contributes to both neuronal excitotoxicity and secondary degeneration (Bullock et al., 1995; Doble, 1999; Yawata et al., 2008). Moreover, TNF—a cytokine robustly produced after injury—is a major stimulator of microglial production of glutamate and can further potentiate glutamate-induced killing of neurons (Leonoudakis et al., 2008; Olmos and Llado, 2014). Macrophages also contribute to secondary death through the production of nitric oxide synthase (iNOS) and free radicals.
5. Morphological changes (i.e., round bodies)


6. Antigenic variation of surface proteins


7. Antibiotic resistance (not seen in Bb)

I would change this one to "Antibiotic tolerance" which is seen in Bb and eliminate "resistance".

8. Immunosuppression by Bb products

Yup! But, you likely should also be adding immune dysfunction to this entry.

9. Biofilms


10. Persister cells following antibiotic treatment


In addition, I think you do need to add one more.........

11. Pyruvate Protects Pathogenic Spirochetes from H2O2 Killing

Bryan Troxell, Jun-Jie Zhang, Travis J. Bourret, Melody Yue Zeng, Janice Blum, Frank Gherardini, Hosni M. Hassan, X. Frank Yang ... ne.0084625

Pathogenic spirochetes cause clinically relevant diseases in humans and animals, such as Lyme disease and leptospirosis. The causative agent of Lyme disease, Borrelia burgdorferi, and the causative agent of leptospirosis, Leptospria interrogans, encounter reactive oxygen species (ROS) during their enzootic cycles. This report demonstrated that physiologically relevant concentrations of pyruvate, a potent H2O2 scavenger, and provided passive protection to B. burgdorferi and L. interrogans against H2O2. When extracellular pyruvate was absent, both spirochetes were sensitive to a low dose of H2O2 (≈0.6 µM per h) generated by glucose oxidase (GOX). Despite encoding a functional catalase, L. interrogans was more sensitive than B. burgdorferi to H2O2 generated by GOX, which may be due to the inherent resistance of B. burgdorferi because of the virtual absence of intracellular iron. In B. burgdorferi, the nucleotide excision repair (NER) and the DNA mismatch repair (MMR) pathways were important for survival during H2O2 challenge since deletion of the uvrB or the mutS genes enhanced its sensitivity to H2O2 killing; however, the presence of pyruvate fully protected ΔuvrB and ΔmutS from H2O2 killing further demonstrating the importance of pyruvate in protection. These findings demonstrated that pyruvate, in addition to its classical role in central carbon metabolism, serves as an important H2O2 scavenger for pathogenic spirochetes. Furthermore, pyruvate reduced ROS generated by human neutrophils in response to the Toll-like receptor 2 (TLR2) agonist zymosan. In addition, pyruvate reduced neutrophil-derived ROS in response to B. burgdorferi, which also activates host expression through TLR2 signaling. Thus, pathogenic spirochetes may exploit the metabolite pyruvate, present in blood and tissues, to survive H2O2 generated by the host antibacterial response generated during infection.
If I have missed any others, I would refer you to "Survival strategies of Borrelia burgdorferi,
the etiologic agent of Lyme disease" by Monica E. Embers, Ramesh Ramamoorthy and Mario T. Philipp. ... orferi.pdf

To fight, flee or hide are the imperatives of long-term survival by an infectious microbe. Active immune suppression, induction of immune tolerance, phase and antigenic variation, intracellular seclusion, and incursion into immune privileged sites are examples of survival strategies of persistent pathogens. Here we critically review the supporting evidence for possible stratagems utilized by Borrelia burgdorferi, the spirochete that causes Lyme disease, to persist in the mammalian host.
AND to:

Berndtson K. Review of evidence for immune evasion and persistent infection in Lyme disease. International Journal of General Medicine. 2013;6:291-306. doi:10.2147/IJGM.S44114.

Is chronic illness in patients with Lyme disease caused by persistent infection? Three decades of basic and clinical research have yet to produce a definitive answer to this question. This review describes known and suspected mechanisms by which spirochetes of the Borrelia genus evade host immune defenses and survive antibiotic challenge. Accumulating evidence indicates that Lyme disease spirochetes are adapted to persist in immune competent hosts, and that they are able to remain infective despite aggressive antibiotic challenge. Advancing understanding of the survival mechanisms of the Lyme disease spirochete carry noteworthy implications for ongoing research and clinical practice.

Re: Invincible borrelia?

Posted: Sun 31 Jul 2016 21:09
by Henry
I've answered your questions 1 & 2, Duncan. :bonk: Since the NIH sponsored clinical trials were RCTs, any patients that were culture or PCR positive obviously would have been excluded for ethical reasons for fear that they would have been randomized to the placebo group. Such patients would have been referred to their primary care physician for standard treatment. However, let me remind you that the issue was whether patients who participated in the NIH-sponsored studies were tested at all for active infection. They were.

Re: Invincible borrelia?

Posted: Sun 31 Jul 2016 21:32
by duncan
dlf, yes, silly appropriately sums it up.

Silly qualifies quite nicely many precarious positions advocated by Old Guard supporters these days.

Other qualifiers come to mind: Absurd, outrageous, grotesque, harmful, demeaning, disconnected, fantastical...

A tip of my hat to your well-thought out and detailed analysis of the core issues of the thread.