Wednesday, November 19, 2014

Why your doctor does not believe in Lyme disease

In his new book, Dr. Horowitz gently discusses the issue. He talks about a paradigm change. This doesn’t answer the question for patients on a visceral level.

I surveyed some physician friend colleagues asked them if they can think of another disease that has been as divisive as Lyme disease.  They always come up empty-handed.  

Your doctor is being bashed by medical boards, ridiculed by other medical professionals, even shunned and ostracized and generally not having a good time (in some arenas, not globally).

You are angry, infuriated, incensed, bellicose or just pissed off. 

Patients new to this world all ask same question .Why?

There is a war going on. Years ago, I had a conversation with an infectious diseases specialist I thought it was collegial; at the end of the discussion I said “I guess we’ll just have to agree to disagree.” She said no we won’t and proceeded to report me to the Medical Board. Doctors don’t usually report their colleagues to Medical Boards. Most follow the rule, “people who live in glass houses shouldn’t throw stones”

Phenomenologically, Dr. Steere and is infectious diseases specialist saw a Lyme as a vectorborne illness causing joint pain or rash: something straightforward. Something easy to treat.

Phenomenologically, Dr. Burrascano and primary care colleagues, saw patients in Lyme endemic areas as poly-symptomatic; patients had every symptom in the book.

Dr. Steere, Dr. Burrascano, myself and likely all the physicians I can think of were taught that there is no disease that causes so many disparate symptoms. These has a “positive review of systems,” meaning they has a psychiatric disorder. Easy one.  

Lyme breaks the mold.

Dr. Burrascano and others thought all these patients cannot be crazy; something else is going on. The cohort of sick patients lived in rural areas known to have a lot of Lyme, they enjoyed outdoor activities, they had a history of previously treated Lyme disease, they had a history of tick bites, the had a history of rashes and summer flus, or they just had an insidious, progressive disease. 

First impressions are important. Dr. Steere’s first impression was that Lyme causes joint pain and is easy to treat.

Dr. Burrascano’s first impression was that these were very sick patients, commonly referred to a “train wrecks.” These patients got better when given antibiotics; symptoms returned when antibiotics were stopped; symptoms got better again antibiotics were restarted. The first impression was that Lyme is a complex multi-system disease which is hard to treat.

These two groups were describing something entirely different, something universes apart. Both were called Lyme disease. 

The war began. Steere  was reported to a Medical Board. Burrascano was doomed. Once the war broke out the truth didn’t matter. Since Steere and his colleagues are associated with Ivy League institutions they won the battle. They have created educational programs for doctors espousing their point of view point and ridiculing the views of the other camp.

I hop the answer to the big question is contained in the above narrative. 

In this war I see the IDSA crowd is calling lymies and their doctors crazy and “antiscience.”  Lymies believe the IDSA crowd is involved in some vast conspiracy. Get a grip.

It comes down to stubbornness, hubris and ego. They call me “antiscience.” A friend once told me: “watch what they call you; that is what they are.”

Wednesday, November 12, 2014

Biofilms and Quorum Sensing

There is a lot of confusion about biofilms and Lyme disease.  I have frequently heard from patients that a “biofilm-buster” is needed. Biofilms consistent of colonies of microorganisms who live within the confines of a protective membrane made of mucopolysaccharides with odd pieces of DNA. These molecules are long chain sugars. We know that biofilms provide a protective niche permitting the survival of Lyme spirochetes and many other bacteria. Most of what we know about biofilms is derived from in-vitro, test tube studies which focus on surface infections, for example, diabetic wounds and cytstic fibrosis. Most of this research has focused on Pseudomonas, a notoriously stubborn pathogen associated with these diseases. We have precious little information about Lyme biofilms.

Biofilms comprised of Pseudmonas aeruginosa have experimentally been treated with a number of topical agents, like xylitol, with some success. Ammons found that lactoferrin has biofilm activity for surface Pseudomonas. How well does this translate? One mechanism of action is the chelation of iron. While this may work with Pseudomonas it may not work with Lyme (even topically), because these spirochetes use manganese in lieu of iron. Other agents, like stevia, have had some success treating Lyme biofilm-like colonies but these finding are from test tube studies and likely do not apply to systemic infection.

Proteolytic enzymes have been widely touted as ‘biofilm-busters.” This has never made sense to me since biofilms do not contain protein.  

Yeast have biofilms. Cremer et al, current Antimicrobial Agents Chemotherapy, screened 1600 drugs/agents and found that Artemisinins were synergistic with miconazole for the treatment of Candida albicans biofilm related infection. This synergy did not occur with several other anti-fungal drugs studied. I am sure many readers have personal experience with stubborn Candida biofilms on their tongues. This highlights the fact that drugs used for a single purpose (artemisinin for Babesia) may help in unexpected ways (Candida).  

The recent study from Hopkins about Lyme persisters and the original studies of Sapi are at odds with one another. The Hopkins study lumps cysts or round bodied forms together with biofilm-like colonies calling them stationary phase bacteria. Sapi considers cyst or round body forms and biofilm forms to be two separate entities. Hopkins reports that doxycycline, amoxicillin and Flagyl have no effect on stationary forms. Sapi found amoxicillin and Flagyl have anti-cyst effects and that Tindamax works well against cysts and also kills spirochetes within biofilms. More study is needed.
An explanation of Tindamax’s greater effect against biofilms may be due to disruption of quorum sensing: a process by which bacteria within the biofilm communicate with each other by molecular signaling (very complicated stuff). In Pseudomonas models a number of antibiotics have been shown to interfere with quorum sensing and associated virulence factors.

Experimentally, these have included: Zithromax, Flagyl, Tindamax and Cipro. 

The take-away point is that the best biofilm-buster might be a specific antibiotic or combination of antibiotics.

Cyst forms, round body forms, L-forms, biofilms forms: now we have a new buzz word to add to the list, quorum sensing (QS).

I think parsing ‘Lyme” into these parts and trying to tailor therapy for each one is generally not helpful. These notions are helpful in a general sense only; patients respond differently, unpredictably. Experience remains our best teacher. Theory is no substitute for that which is tried and true.

Tuesday, September 23, 2014

Correction to below

After asking Labcorp rep, they still perform Lyme WB, at least upon my request, without ELISA or EIA.  Please note.

Tuesday, August 26, 2014

Labcorp and the Lyme Western Blot

As many are aware, Labcorp will no longer allow physicians to order Western Blots for Lyme disease. The only test available is the ELISA with reflex to Western Blot if positive.

They have also taken away the C6 peptide.  The results are presented as only negative if less than 0.91.

These changes are not going to get Labcorp any more business.  What motivated the change?

One can only guess that someone affiliated with the IDSA influenced the policy change. In the past, when the Western Blot was ordered, the laboratory informed us the ELISA test should be ordered as well. Should be? According to whom?

Some ID doctors are inappropriately applying the HIV testing paradigm in the case of Lyme testing. When testing for HIV it is crucial to do the ELISA first because it is possible to have a positive Western Blot and a negative ELISA rendering a negative test.  Luckily with HIV there are other, better,  confirmatory tests available.

There is no evidence the same applies with Lyme testing.  The IDSA has claimed there are a lot of false positive Lyme Western Blots because of cross reactivity.  This claim remains largely unreferenced.  I recently saw a patient with a history of syphilis, RPR positive. The Lyme Western Blot was entirely negative. Many patients test positive for rheumatoid arthritis and Epstein Barr Virus and have negative Western Blots. (these are the common scenarios said to cause false positive tests). The ELISA is known to have many false negatives. Skipping this test and going to the Western Blot increases the sensitivity of the test.  If there is some decrease in specificity it would seem to be minimal at best.  In other words, patients are more likely to get an accurate result when the physician orders the Western Blot directly and skips the ELISA.

The CDC still states that Western Blot testing should only be done when the ELISA is first positive. The Website states that IgM results found after the first 4-6 weeks are likely false positive unless 5/10 IgG bands appears at that time. These facts are referenced back to findings from 1994-95. As you may recall this finding was based on an assay using the discarded N40 strain of Lyme and B31 has become the standard strain.

1) These results are based on a meeting which occurred 20 years ago. When the testing remains so controversial why hasn't there been a more recent reassessment?

2) At best this is revisionist history. The test was developed for surveillance (an epidemiology or research tool) not for diagnosis.  How a test developed for an entirely different purpose (monitoring the relative number of cases in different locations over time) morphed into a bullet proof test for diagnosis of Lyme disease is far beyond my ability to comprehend. 

Why are we going backwards. Why is there a problem with giving physicians and their patients more information?

The CDC stubbornly says on their website that there are no borderline positive tests. There is an absolute requirement to have 5/10 bands because at least this many always shows up.  According to the logic presented by the CDC the finding of a positive ELISA followed by the appearance of 4 IgG Western Blot bands is absolutely, 100% negative for Lyme.

One would like to know who wrote this tripe.

The long arm of the IDSA has managed to promote its agenda by manipulating the CDC and now Labcorp.

I caught Ben Beard, the chief of the bacteria section (Lyme included)  of vector borne diseases for CDC off balance when I had the opportunity to meet with him along with members of Nat Cap Lyme some years ago. Dr. Beard was flustered when I pointed out the contradictions in the CDC pronouncements especially about the appropriate use of the two tiered Lyme test.

When I asked him if the CDC wasn't speaking out of both sides of its mouth on the topic he hemmed and hawed and then ultimately responded "well, that's the party line."

What party was he referring to? Democrats? Republicans? Perhaps the IDSA vs ILADS. Dr. Beard's s comment to me was an admission that politics have trumped reason, logic and science. The IDSA has extended its mandate. They are no longer a professional society for infectious disease physicians. They are in fact a political party. Triumphantly they can say, Labcorp: Welcome to the party!  As with all political parties, the truth is frequently abandoned when its application leads to undesired results.

In the wake of emerging science and changes in the very nature of the pathogens responsible for Lyme disease this discussion is becoming more and more a moot point.

Its a win for:  Quest, Clongen, IgeneX, Stony Brook and a few others.  Lyme patients who are insured by health insurance companies that insist Labcorp be used should complain and lobby for a change to another lab.  As they say: vote with your feet.

Monday, August 4, 2014

Are staunch supporters of the IDSA admitting they might have been wrong all along?

A paper from the Department of Molecular Biology and Immunology from Johns Hopkins is quite remarkable, especially since Paul Auwaerter is one of the authors.  The paper presents ideas which are a complete turnaround from the previous orthodoxy promoted by this institution and this author in particular.  The entity in question is called PTLSD, post-treatment Lyme disease syndrome by the authors. The authors state they do not know the cause of the syndrome. They concede that up to 1/5 of the patients treated for Lyme disease by IDSA standards have persisting or lingering symptoms.
The authors state recruitment for clinical trials has been difficult. Why?  The only patients accepted into the studies were treated for early, classic Lyme and subsequently developed the famous 5/10 CDC IgG bands. Findings these patients is like finding a needle in a haystack.  Recent peer-reviewed literature suggests that patients with chronic symptoms tend to have poor IgM responses and never develop IgG responses. The patients we see in our clinical practices rarely have CDC positive IgG responses. Chronic Lyme studies recruit a small cohort of patients likely to be healthier than the vast majority of chronic patients.

Let me digress.  The IDSA and CDC keep insisting that patients with chronic Lyme develop 5/10 IgG bands in virtually every case. Repeating something over and over again does not make it true.

The 5/10 come from a paper written by Dressler in 1993, one year before the ill-fated Dearborn conference. This is the same Dressler that suggested IgM criteria should be 2/8 bands (sounds an awful lot like IgeneX criteria). The criteria was dismissed because Dressler’s research was based on the N40 strain of B. burgdorferi, not the B31 which has become the standard. Therefore, the “flawed” IgM standard was dismissed. Somehow, the “flawed” IgG criteria based on the same discarded strain of Lyme was allowed to become the standard and this has never changed.

The authors list possible causes of the syndrome:  autoimmune, persisting debris (dead germs) or persisting infection. Only the persistent infection hypothesis is called “controversial,” even though this is the only hypothesis backed by fact.

It is silly to have a discussion about whether animals have chronic Lyme symptoms. The authors state: “a number of prospective, randomized clinical studies demonstrated no significant beneficial effect of additional antibiotic therapy… and no evidence of presence of B. burgdorferi in patients with long-term symptoms.” 

How do they define “significant?”  Patients showed improvements in fatigue, pain and quality of life issues and Dr. Fallon the last author of the famous NIH sponsored studies believes that additional antibiotic therapy helps because there is persisting infection.  The authors claim there is no evidence of presence of B. Burdorferi. There certainly is no evidence that the spirochete is gone. The authors also note that some studies showed a decrease in fatigue. The authors seem to be arguing amongst themselves.

The authors are intrigued by the fact that one patient who had been treated for Lyme gave the germ to a tick allowed to feed on his blood.  This test seem just wrong to me.  Why wasn’t a PCR done of the patient’s blood at the same time? This procedure makes a lot more sense to me. Anyway, I am glad the authors are intrigued.

The authors concede that recent literature demonstrates the persistence of infection in mice.

This is where it gets weird. The authors talk about 3 morphological forms: spirochete, L-form, and cyst. I am I reading this right? This sounds like the ILADS’ pabulum which the same sources have spent a lot of resources on, even in recent months, discrediting.

Without this apparent change of face there would be reason to do this research or publish this paper.

These authors discuss two stages in the life cycle of Lyme: the rapid growth phase and the stationary phase. These authors commit blasphemy. The cross one more line and talk about “biofilm-like aggregates.”

In the test tube, the researchers found there are always persisters.

The purpose of the study was to show the researchers had developed a tool to help identify antimicrobials which may better able to eliminate persisters.

“Our findings may have implications for the development of a more effective treatment for Lyme disease and for the relief of long-term symptoms that afflict some Lyme disease patients.”

I am getting confused.  Was this study written by IDSA proponents or backers of the ILADS’ way of thinking?

Even in a test tube. No antimicrobial was found that could kill all the persisters.  That should be like “shooting fish in a barrel.”

In a real human being things are a bit more complex. The germs hide on the inside and outside of cells. The germs penetrate deep tissues like cartilage with minimal blood flow. The spirochetes invade a panoply of host tissues, all with different characteristics:  brain, nerves, joints, cartilage, tendon, heart, colon and numerous others.

Based on these few facts it seems outlandish to believe that a short course of IDSA sanctioned therapy is likely to eradicate all of the spirochetes.

Novel drugs like: clofazimine, daptomycin, cefoperazone, carbomycin are the best drugs for killing cysts.

Let’s not rush in – please.  Flagyl is said to have no anti-cyst activity, contradicting other work which proves the opposite. Most of these drugs are highly specialized, too potent and should likely not be used.

It seems that the science is catching up with ILADS, leaving the IDSA in it's wake.

Tuesday, July 29, 2014

The Lyme World On Its Head: Rapidly Emerging New Paradigms

The Lyme world is being turned upside down.

A recent study, as many are aware, performed PCR testing on stored sera of 52 patient samples from patients diagnosed with Lyme disease. Four were PCR positive. This underscores the problem with PCR. It has a low yield. If it were feasible to do 5-10 tests on every patient we would probably have a pretty good test. The finding are intriguing. Two of four, 50% were positive for Lyme as we know it, Borrelia burgdorderi. One was positive for B. Miyamotoi and one a "novel" species of Borrelia.  The paradigm is changing. "Lyme disease" more often than not may be caused by species other than the one over which there has been so much fuss:  B. burgdorferi.  This is just where the story begins. A recent survey of a nearby park (Montgomery County, Maryland)  was performed by Clongen (Dr. Kilani). His team collected 45 ticks. Two were dog tick and the rest were lone star ticks. Not one dear tick in the sampling. Why? Lone star ticks are known to be much more aggressive than deer ticks and appear to be taking over the ecological niche. Do these ticks cause Lyme disease? I think we can answer that question.  One quarter of the lone star ticks were infected with  B. lonestari. About 15% had anaplasmosis and one half showed infection with Babesia species. I do not think the Babesia species PCR is all inclusive, so it is possible that even a higher percentage of these more relevant ticks are laden with Babesia.

Fast forward to a patient I recently saw. This patient had a classic bull's eye rash on his foot in April. A doctor prescribed 3 weeks of doxycycline. When he complained of persisting symptoms another three weeks was prescribed. Symptoms continued. He was prescribed a course of Zithromax which provided little further relief. This patient has suffered with fatigue; night sweats; numbness and tingling; severe anxiety; memory problems and cognitive dysfunction; severe joint pain with swelling; palpitations, air hunger and shortness of breath, weight loss of 15 pounds and other symptoms. These symptoms persisted in the face of more than double the IDSA recommended course of therapy. Post treatment Lyme syndrome, right?  He had a Lyme Western blot through Labcorp: 41 IgG band only. He had PCR testing through Clongen: Positive for large numbers of Borrelia lonestari, not Lyme per se and negative for Babesia. 

Have we have a documented case of post-treatment B. lonstari showing persistence of the organism.  Maybe the first. The PCR test was not previously available. So the patient has STARI, Master's disease.

Wait a minute. Doesn't the IDSA/CDC crew say that STARI is no big deal? Oh yeah. They say the same about Lyme don't they.

Let's put this together. Lone star ticks are emerging as the dominant species of tiny hard body ticks which transmit tickborne disease and Lyme or its equivalent. They do not usually carry classic Lyme B. burdorferi, rather they carry a new germ about which we know very little; in half the cases of "old Lyme" transmitted by deer ticks, other species of Borrelia, rather than the expected B. Burdorferi may be the cause.  We have a paradigm which is being turned on its heels. Borrelia burdorferi as the causative agent of Lyme disease may soon be of historical importance.

Even with the conventional B. burdorferi, Lyme testing is known to be inaccurate (at least in Virginia). What now? We are bereft of any tests. I actually think there is some cross reactivity, so the appearance of CDC "nonspecific" bands may take on more importance in the short term. We are left with the idea that the diagnosis is a clinical one. This idea puts a real sour taste in the mouth of IDSAers who continue to promote an inaccurate, and now perhaps obsolete Lyme test as the basis for diagnosis as they discount the idea that the "subjective" (therefore untrustworthy)  history and physical exam can be used to make the diagnosis. When I went to medical school, a long time ago I know, we were taught that if you listened to the patient he would give you the diagnosis in the vast majority of cases.

How about Babesia? I have seen an epidemic on the rise. Babesia species. Which species? 

Back to the patient at hand. He was PCR negative for Babesia species and sero-negative for B. microti and B. duncani.  I did a blood smear and found a few, possible hemato-parasites. Test indeterminate.

The symptoms sounded classic for Babesia. And -- with anti-malaria therapy --  night sweats, air hunger and other symptoms have abated within only 2 weeks.

We don't have a dependable test for these largely unknown species of Babesia; but we have evidence that this tickborne disease may be playing a very major role in the exploding, frequently devastating (still invisible to many) epidemic.

How about resistance?  There is a lot of information about drug resistant versions of Malaria but none forthcoming about Babesia. Clinically we know this is a problem as we step up the ladder from Meporn to Malarone to Coartem and then to even Larium and Quinine with persisting symptoms.

In front of me is an abstract for J Parasitol 2014, Feb 28, Cao et al who state: "The resistance of Babesia parasites to current anti-babesiosis drugs is an issue of major concern." 

Thank you. Someone is taking notice.

None of this should be that surprising. We are dealing with a new and emerging disease. The tick vectors were barely known to exist before the 1970s. Borrelia are a very diverse genus as are Babesia of which more than 100 species are known to exist.

With incredulity I ask the rhetorical question: how can insurance companies, State Medical Boards, the CDC and the IDSA hold up guidelines written 8 years ago as the gold standard which defines the standard of care for the management of Lyme disease and other tickborne illnesses?

Thursday, May 15, 2014

Why do some patient develop chronic Lyme?

A new study may help us understand why some patients get better and other don’t.  This topical study: Serum Inflammatory Mediators as Markers of Human Lyme Disease Activity, was published in PLOS one-- the lead authors are from Johns Hopkins University. All published Lyme studies have had problems with patient selection. Patient groups are selected because they are supposed to have the same thing. IDSA criteria are generally used. The group in this study had early Lyme associated with EM rash.  As I have discussed previously, most patients with acute Lyme do not present with a rash; and more to the point, most patients with chronic Lyme are not diagnosed in a timely fashion. Nonetheless, this study conveys important information.  

This study demonstrates the exist of two distinct patient populations who have very different immunological responses to infection with Borrelia burgdorferi (Lyme) – one group has a robust response based on measurements of cytokines and markers of inflammation; the other group has a minimal immunological reaction using the same indicators. The two groups have very different clinical outcomes. 

I am pleased by a change in verbiage/terminology. In this study the authors use the words PTLDS, post-treatment Lyme disease syndrome, which replaces the old term PLDS, post-Lyme disease syndrome. This small change leaves the door open to the notion that Lyme organisms may persist after treatment. And here we are dealing with acute patients treated early in the course of the illness.
The study measures molecules which moderate immune responses.  The immune system is tasked with finding offending invaders, like germs, and eradicating them by a host of complex mechanisms and devices. (Seek out and destroy)  This study measures the messengers that help direct the traffic of the immune system – sending signals to an assortment of cells, telling them where to go and when.
The authors note the immune system alone is unable to eradicate Lyme infection and that late-stage arthritis develops in many patients. They describe a subset of patients who develop antibiotic refractory disease 12 months or more. The dogma that host immune responses is the major factor in such cases is discussed, but, from the mouse model -- another possibility is discussed.  “Delays in the generation of long-lived plasma cells (the cells that make antibodies) and a weak, largely IgM response (sound familiar) may be part of a Lyme (Borrelia burdorferi) strategy to avoid clearance.”(Yet another mechanism of survival).  The authors reflect that residual antigen or infection in some treated patient may explain the persistence of symptoms, in post-treatment Lyme disease, but state: “this is a very controversial area.” 

The scientists measures many molecules that traffic immune cells, with names like: CCL1 9, CXCL 19, CXCL 10, CRP, SAA, IL-1a, IL-18, IL33, IL6, TNF alpha, and others.
Two distinct responses were identified. On groups showed high levels of these markers of immune response while the other showed low levels of these markers.

One particular mediator of inflammation, IL-6 remained elevated in patients with late stage Lyme which the authors found surprising.  These patients with post-treatment, symptomatic Lyme disease showed immunological evidence of persistent inflammation – or infection. 

The group of patient with a high level of reaction (cytokines, chemokines) had lower WBC counts, increased liver function counts and higher levels of markers of inflammation such as CRP. This group produced Lyme antibodies, or seroconverted. This group showed clinical remission.  The group with low level reactions to the same molecules did not share these features: these patients had a tendency not to seroconvert. This group of patients was more likely to develop post treatment symptoms like chronic joint pain.  

This study has clearly identified a subset patient who are more likely to develop chronic Lyme disease even after IDSA recommended treatment for stage one disease. This study sheds light on why many patients are seronegative (do not make antibodies) or have weak IgM responses as we commonly see. This study lays the foundation for the development of a test which helps us predict which patients need more help early on -- those who are at higher risk for developing chronic disease.
On another note…

Another scientist’s face is displayed in a Johns Hopkins University magazine in an article which states he has beliefs contrary to the IDSA and that he believes in Lyme persiters which might respond to a drug for tuberculosis. The article say that while these ideas would not be controversial regarding tuberculosis they are very controversial when mentioned in the context of Lyme disease.