A 42 year old male came into my office, reluctantly. He thought he was fine. He only came in to mollify an insistent spouse, a spouse familiar with a disease she herself has suffered with.
Ok - He had a tick bite a year ago - attached for a short time; he never became ill.
When I took a history symptoms began to emerge. He had been a little tired recently but thought this normal. He had had some depression and irritability and fragmented sleep. He had had some generalized body stiffness, especially involving his hands and knees. Maybe his memory was not as good as it was a year ago, chalked up to "old age."
His physical exam was unremarkable.
A Lyme Western Blot was sent to Stony Brook University Medical Center. Here are the (IgM) Lyme Western Blot results: The report says indeterminate. An IgM 41 band is reported.
Other "nonspecific IgM" were also found: 18, 37, 72, and 93.
Before you get too excited, let's discus why the IgM report is called indeterminate. In this case, the WB bands are interpreted based on the assumption the patient has already had a positive ELISA test for Lyme. This designation indeterminate assumes the blot is the second -confirmational part of the two tier test endorsed by the CDC surveillance case definition test. Of course the ELISA was never done - so the designation, indeterminate has no significance.(I think).
Based on the same CDC test, the 18 and 93 bands are considered specific only if IgG bands, those included in the second leg of the (IgG) CDC surveillance test. IgM bands are reported specific, by the same logic, only if they are bands 23, 39 and 41.
Of interest to me is the report of a 37 and 72 band.
Stony Brook reports these bands because they manufacture their own Western Blot kits which show many more bands than the other labs. The 37 band is considered specific for Lyme (based on my reading). The 72 band is a cross-reacting spirochete band. When the 37 band is combined with the 41 and 93 bands the evidence for exposure to Bb seems compelling.
The treatment for this disease is discussed elsewhere (somewhere) in this blog.
Tuesday, October 4, 2011
Tuesday, September 20, 2011
Babesia, re-visited
Those in the chronic Lyme community have a narrative for explaining the chronicity of Lyme disease or at least the persistence of Borrelia despite the onslaught of immune responses and antimicrobiobials, including such things as: genetic switching - up and down regulating of key surface proteins at key times, protection of the bacteria within a niche, polymorphic switching from spirochetes to cysts and then back again, biofims, and other proven effective stratagies for survival. Despite this evidence, we are still convincing the few.
With chronic Babesiosi we lack such a narrative. Patients are frequently treated for months or longer without clinical resolution. Patients have repeatedly shown me positive FISH(RNA)results for Babesia after extensive therapy, still sick with the disease. As one of my patients recently described in a YouTube video, two ID specialists at Johns Hopkins dismissed this evidence claiming that IgeneX is not a trustworthy lab and suggested the patient seek psychiatric care.
Although there is a great deal of overlap between the symptoms of Lyme and Babesia, certain symptoms are quite specific for babesiosis, inlcuding: recurrent flu like symptoms with low grade fevers, air hunger and night sweats.
Frequently the diagnosis of babesiosis is made on clinical grounds. There are over 100 known species of Babesia but only a few are though to cause human disease. In the US we look for B. microti and B. duncani. Another, yet unnamed species, MO1 has been shown to cause human disease in the US. Others are likely.
Babesia in humans is an infection of red blood cells. The protozoa invade and reproduces within red blood cells. When the cells rupture Babesia forms quickly attach to other red blood cells. Babesia has two hosts: mouse and tick, both of which are required for the parasite's normal life cycle. The tick is considered the definitive host because this is where sexual reproduction of the organism occurs. Humans are considered an unintended, bystander host, unlucky enough to have been bitten by the wrong tick. In humans Babesia is seen as any of three forms: sporozoites which microscopically have a spherical form, trophozoites which have a ring appearance and merozoites which may have the "Maltese cross" (tetrad) appearance.
Unfortunately, Babesia sp infect only a small percent of circulating red blood cells and direct evidence of its presence via microscopy is rarely evident.
Standard, and largely unchallenged dictum states that the microbe lives only within red blood cells, it does not hide in tissues, all of the forms are killed by the same antimicrobials/antiparasitics. The narrative to support the parasite's longevity seems lacking. Well, lets look at some recent medical literature: Clinical Infectious Diseases, 2008, Florescu, highlighted as important by the IDSA.
Two cases of Spenic Infarct are discussed. Both patients were critically ill, one succumbed. At autopsy Babesia-infected red blood cells were noted with the spleen, liver and lymph nodes. One then wonders, is the parasite seeking safe harbor within the microvasculature of these organs?
Of interest, the authors observed that the first patient who survived was co-infected with anaplasmosis "which may have contributed to the prolonged course of the illness." The implication is obvious to chronic TBD believers. The authors report that Babesia has been associated with retinal damage, ostensibly as a consequence of "microobstruction" of tiny blood vessels (by the parasites).
The authors report that multifocal coagulative necrosis has been shown to occur with B. duncani at least in Syrian hamsters. This means that Babesial infection within narrow blood vessels likely caused blood clotting associated with multi-organ damage.
In May 2011, The CDC reports a study of Babesia sp. EU1 (of reindeer) which found hemosiderin laden macrophages in multiple tissues, meaning that infected red blood cells were ingested by macrophages. Babesia DNA was found in: bone marrow, brain, heart, kidney, liver, lung, lymph nodes, small intestinal wall and spleen. Perhaps Babesia can sequester itself with organs.
In summary: Babesia can likely cause blood clotting with localized tissue damage. It may persist only within tiny blood vessels or it may be able to exist within tissues. There are many species of Babesia. They may exhibit different biological behavior. Little is known here.
The evolving science may help us uncover a better narrative by which we may describe patho-anatomic-physiological mechanisms supporting the notion of chronic Babesiosis.
In the meantime, our clinical experience and our supporting laboratory data cannot and should not be ignored.
With chronic Babesiosi we lack such a narrative. Patients are frequently treated for months or longer without clinical resolution. Patients have repeatedly shown me positive FISH(RNA)results for Babesia after extensive therapy, still sick with the disease. As one of my patients recently described in a YouTube video, two ID specialists at Johns Hopkins dismissed this evidence claiming that IgeneX is not a trustworthy lab and suggested the patient seek psychiatric care.
Although there is a great deal of overlap between the symptoms of Lyme and Babesia, certain symptoms are quite specific for babesiosis, inlcuding: recurrent flu like symptoms with low grade fevers, air hunger and night sweats.
Frequently the diagnosis of babesiosis is made on clinical grounds. There are over 100 known species of Babesia but only a few are though to cause human disease. In the US we look for B. microti and B. duncani. Another, yet unnamed species, MO1 has been shown to cause human disease in the US. Others are likely.
Babesia in humans is an infection of red blood cells. The protozoa invade and reproduces within red blood cells. When the cells rupture Babesia forms quickly attach to other red blood cells. Babesia has two hosts: mouse and tick, both of which are required for the parasite's normal life cycle. The tick is considered the definitive host because this is where sexual reproduction of the organism occurs. Humans are considered an unintended, bystander host, unlucky enough to have been bitten by the wrong tick. In humans Babesia is seen as any of three forms: sporozoites which microscopically have a spherical form, trophozoites which have a ring appearance and merozoites which may have the "Maltese cross" (tetrad) appearance.
Unfortunately, Babesia sp infect only a small percent of circulating red blood cells and direct evidence of its presence via microscopy is rarely evident.
Standard, and largely unchallenged dictum states that the microbe lives only within red blood cells, it does not hide in tissues, all of the forms are killed by the same antimicrobials/antiparasitics. The narrative to support the parasite's longevity seems lacking. Well, lets look at some recent medical literature: Clinical Infectious Diseases, 2008, Florescu, highlighted as important by the IDSA.
Two cases of Spenic Infarct are discussed. Both patients were critically ill, one succumbed. At autopsy Babesia-infected red blood cells were noted with the spleen, liver and lymph nodes. One then wonders, is the parasite seeking safe harbor within the microvasculature of these organs?
Of interest, the authors observed that the first patient who survived was co-infected with anaplasmosis "which may have contributed to the prolonged course of the illness." The implication is obvious to chronic TBD believers. The authors report that Babesia has been associated with retinal damage, ostensibly as a consequence of "microobstruction" of tiny blood vessels (by the parasites).
The authors report that multifocal coagulative necrosis has been shown to occur with B. duncani at least in Syrian hamsters. This means that Babesial infection within narrow blood vessels likely caused blood clotting associated with multi-organ damage.
In May 2011, The CDC reports a study of Babesia sp. EU1 (of reindeer) which found hemosiderin laden macrophages in multiple tissues, meaning that infected red blood cells were ingested by macrophages. Babesia DNA was found in: bone marrow, brain, heart, kidney, liver, lung, lymph nodes, small intestinal wall and spleen. Perhaps Babesia can sequester itself with organs.
In summary: Babesia can likely cause blood clotting with localized tissue damage. It may persist only within tiny blood vessels or it may be able to exist within tissues. There are many species of Babesia. They may exhibit different biological behavior. Little is known here.
The evolving science may help us uncover a better narrative by which we may describe patho-anatomic-physiological mechanisms supporting the notion of chronic Babesiosis.
In the meantime, our clinical experience and our supporting laboratory data cannot and should not be ignored.
Thursday, September 1, 2011
Fear
Every once in a while a patient surprises me and makes it all worthwhile. This is such a story. A 17 year-old female presented in my office in a wheelchair this past spring. She was holding her head, her neck flexed, her face invisible to me. Severe unrelenting daily headaches were unbearable and driving her mad.(in the British sense). She was disoriented - cognitive impairments were profound. For me the most frightening aspect of her presentation was profound weakness. When I asked her to get out of the wheel chair her thighs muscles appeared to contract in a floppy, asynchronous fashion. The analogy that came to my mind was a fish hopelessly flopping on the deck of my boat. I quickly asked her to sit back down. After examining her I thought she was suffering with a severe motor neuropathy.
She had a well documented diagnosis of Lyme disease. She had been treated by another physician in a nearby state with oral antibiotics for an entire year. Despite this, her condition had steadily deteriorated.
I knew that the only treatment that might be effective was IV antibiotics. I ordered a PICC and started Rocephin. I saw her back in two weeks, as is my practice. She was no better. At that point I decided she should be evaluated in a tertiary care center. I sent her to Georgetown. I have found Georgetown more Lyme friendly than hospitals in my own state.
My experience had been with adult side. She was 17, so she was admitted to the pediatric ward. A neurologist barely peaked at her. No EMG/NCV test was performed as I requested. The ID doctor stopped in for a moment I was told. The attending pediatrition diagnosed fibromyagia and a somatoform disorder - a psychiatric condition. The good doctor wanted to stop the IV antibiotics. The youg lady's father insisted otherwise (with some vehemence I suspect) and won the day.
After a few days she was sent to the National Rehabilitation Hospital. This was helpful and she got stronger. The doctors there also reluctantly agreed to continue the Rocephin. Two weeks later she was back in my office.
She looked better. A little better. I felt encouraged and continued the treatment. The brain fog lifted a bit. She asked me if she would be able to attend an important camp activity three months hence. I looked at her in the wheel chair and said: "we'll see."
And then something magical happened. She started getting better - fast. I used the regimen which has served me best. Rocephin layered with Zithromax and the Flagyl IV. I also prescribed Mepron for Babesia symptoms.
After two more months it looked like she might actually be able to go to the activity. A positive thing for her is that she forgot how sick she had been as she improved. Not only was she out of the chair, she was running and dancing.
All of her symptoms gradually began to peel away. She had missed a whole year of school and was now reading and catching up on her studies.
After 3 and 1/2 months, she was looking good. Essentially back to normal. She did no get to go to the camp activity, but she did go to her family beach vaccation, sans PICC line.
Doctors are afraid. They are afraid to prescribe IV antibiotics. To do so you need to be on staff at a local hospital. You have to face the scrutiny of the Infectious disease doctors, the neurologists, the hospital board and various attendant committies - And possibly - the State licensing board. It is safer to prescribe oral antibiotics, to keep plugging away with all the oral medicines in your arsenal. Harder. More. Something will work if you keep trying. It is safer.
Fear.
What else is there to do.
She had a well documented diagnosis of Lyme disease. She had been treated by another physician in a nearby state with oral antibiotics for an entire year. Despite this, her condition had steadily deteriorated.
I knew that the only treatment that might be effective was IV antibiotics. I ordered a PICC and started Rocephin. I saw her back in two weeks, as is my practice. She was no better. At that point I decided she should be evaluated in a tertiary care center. I sent her to Georgetown. I have found Georgetown more Lyme friendly than hospitals in my own state.
My experience had been with adult side. She was 17, so she was admitted to the pediatric ward. A neurologist barely peaked at her. No EMG/NCV test was performed as I requested. The ID doctor stopped in for a moment I was told. The attending pediatrition diagnosed fibromyagia and a somatoform disorder - a psychiatric condition. The good doctor wanted to stop the IV antibiotics. The youg lady's father insisted otherwise (with some vehemence I suspect) and won the day.
After a few days she was sent to the National Rehabilitation Hospital. This was helpful and she got stronger. The doctors there also reluctantly agreed to continue the Rocephin. Two weeks later she was back in my office.
She looked better. A little better. I felt encouraged and continued the treatment. The brain fog lifted a bit. She asked me if she would be able to attend an important camp activity three months hence. I looked at her in the wheel chair and said: "we'll see."
And then something magical happened. She started getting better - fast. I used the regimen which has served me best. Rocephin layered with Zithromax and the Flagyl IV. I also prescribed Mepron for Babesia symptoms.
After two more months it looked like she might actually be able to go to the activity. A positive thing for her is that she forgot how sick she had been as she improved. Not only was she out of the chair, she was running and dancing.
All of her symptoms gradually began to peel away. She had missed a whole year of school and was now reading and catching up on her studies.
After 3 and 1/2 months, she was looking good. Essentially back to normal. She did no get to go to the camp activity, but she did go to her family beach vaccation, sans PICC line.
Doctors are afraid. They are afraid to prescribe IV antibiotics. To do so you need to be on staff at a local hospital. You have to face the scrutiny of the Infectious disease doctors, the neurologists, the hospital board and various attendant committies - And possibly - the State licensing board. It is safer to prescribe oral antibiotics, to keep plugging away with all the oral medicines in your arsenal. Harder. More. Something will work if you keep trying. It is safer.
Fear.
What else is there to do.
Tuesday, August 30, 2011
c diff
C diff - (clostridia difficile) infection is the bane of the existence for patients(and their doctors) who take long term antibiotics for Lyme disease. The infection occurs when normal gut flora are destroyed by antibiotics clearing the way for the opportunistic bacteria to take hold.
The biosphere of the GI tract is composed of trillions of micro-organisms including a wide variety of bacteria, fungi and parasites. Destruction of these "good bacteria" clears the way for c diff, previously contained within a narrow niche of the overall ecosystem of the gut flora, to disseminate and cause disease. The infection can be mild or severe, at times even life threatening.
Although c diff may be a naturally occurring part of the gut flora, infection may be introduced externally through spores or infected individuals. Even in these cases an intact gut flora helps to prevent the development of clinical disease.
So what are these good bacteria? Our bodies are colonized with massive quantities of micro-organisms. These bacteria/organisms may be parasitic or symbiotic. Parasites live off the land, offering nothing in return. Symbionts on the other hand can be either commensal (neutral) or mutualistic: something positive is provided to both the bacteria and the host.
One hears a lot about the beneficial effects of "good" bacteria. It turns out that some bacteria are good and beneficial to our immune systems
Good bacteria may: synthesize and excrete vitamins, prevent the colonization of pathogenic (disease causing) bacteria, provide natural antibiotic effects and aid in the production of natural antibodies (amongst others).
There are two take home points (yet to be made).
Some antibiotics are more commonly associated with c diff and some probiotics may help prevent the disease.
Quinolones such as Levaquin are highly associated with development of c diff. In addition, because of resistance, these agents appear to be associated with more virulent strains of c diff. Cephalosporins are more highly implicated. For example: Ceftin and Omnicef are more frequently associated with c diff then drugs from the penicillin family like amoxicillin. Clindamycin is also highly associated with c diff. This knowledge can help direct the prescription of the safest antibiotics.
In a published clinical study a proprietary mix(yogurt drink)of bacterial probiotics: L casei, L bulgaricus and S thermophilus has been shown to decrease the frequency of c diff. In addtion, the probiotic S boulardii, yeast based, may form a barrier which protects the gut.
Please take your probiotics. C diff can lead to sepsis, emergency surgery and even death. Treatments are available (Flagyl/Vancomycin), but they are not always effective. And, more virulent strains of c diff are starting to appear. More importantly, c diff tends to recur. This can make ongoing treatment very challenging to say the least.
The biosphere of the GI tract is composed of trillions of micro-organisms including a wide variety of bacteria, fungi and parasites. Destruction of these "good bacteria" clears the way for c diff, previously contained within a narrow niche of the overall ecosystem of the gut flora, to disseminate and cause disease. The infection can be mild or severe, at times even life threatening.
Although c diff may be a naturally occurring part of the gut flora, infection may be introduced externally through spores or infected individuals. Even in these cases an intact gut flora helps to prevent the development of clinical disease.
So what are these good bacteria? Our bodies are colonized with massive quantities of micro-organisms. These bacteria/organisms may be parasitic or symbiotic. Parasites live off the land, offering nothing in return. Symbionts on the other hand can be either commensal (neutral) or mutualistic: something positive is provided to both the bacteria and the host.
One hears a lot about the beneficial effects of "good" bacteria. It turns out that some bacteria are good and beneficial to our immune systems
Good bacteria may: synthesize and excrete vitamins, prevent the colonization of pathogenic (disease causing) bacteria, provide natural antibiotic effects and aid in the production of natural antibodies (amongst others).
There are two take home points (yet to be made).
Some antibiotics are more commonly associated with c diff and some probiotics may help prevent the disease.
Quinolones such as Levaquin are highly associated with development of c diff. In addition, because of resistance, these agents appear to be associated with more virulent strains of c diff. Cephalosporins are more highly implicated. For example: Ceftin and Omnicef are more frequently associated with c diff then drugs from the penicillin family like amoxicillin. Clindamycin is also highly associated with c diff. This knowledge can help direct the prescription of the safest antibiotics.
In a published clinical study a proprietary mix(yogurt drink)of bacterial probiotics: L casei, L bulgaricus and S thermophilus has been shown to decrease the frequency of c diff. In addtion, the probiotic S boulardii, yeast based, may form a barrier which protects the gut.
Please take your probiotics. C diff can lead to sepsis, emergency surgery and even death. Treatments are available (Flagyl/Vancomycin), but they are not always effective. And, more virulent strains of c diff are starting to appear. More importantly, c diff tends to recur. This can make ongoing treatment very challenging to say the least.
Thursday, August 4, 2011
Biofilms
Biofilms are ubiquitous. Their role in chronic infections in mainstream. Biofims have been found in chronic sinusitis, chronic ear infections, chronic skin and bone infections, kidney stones and many other clinical scenarios.In these other diseases biofilms can be readily identified because the occur on surfaces. The existence of biofilms in Lyme disease is more difficut to establish because of infection within deeper, inaccessible tissues. It is commonly cited that biofilms may play a role in up to 80%of human infections.
Biofilms are indeed complex structures. Previously freely motile bacteria become frozen in a gel-like matrix due to the result of complex molecular and genetic swiching. The organisms within these films are able to communicate and establish a social network. Frequently these bacteria go into a starvation mode and exhibit a very low metabolic rate. Biofilms may release motile bacteria when enviromental factors become favorable. Biofilms may be polymicrobial or consist of a single organism. Biofilms have been cited as a mechanism by which opportunistic germs, eg Pseudomonas, can become pathogenic. Bacteria turn out to be very clever little fellows, after all, they have been on the earth for 3.5 billion years. Biofilm fossils have been uncovered evincing their antiquity.
Bacteria within these biofilms are difficult to kill. They exist in a highly protected niche. They frequently become extremely resistant to antibiotics and destruction through normal immune responses.
Antibiotics such as Beta-lactams (penicillins and cephalosporins) are generally ineffective because these cell wall inhibitors work only when bacteria are rapidly dividing or remodelling their cell walls. Biofilm bacteria are frequently in a state of suspended animation.
The biological characteristics of biofilm contained bacteria quickly begin to resemble those attributed to cystic forms of Borrelia burdorferi (Lyme). Both have a slow metabolic rate and are not typically killed by Beta-lactams, except for the amoxicillin paradox described in my last blog.
One could postulate that antibiotics which are effective against cyst forms of Lyme could also be effective against biofilm forms.
Some have been very critical of Dr. Sapi's work. She has developed "biofilm like" colonies which she does not define. These are not the same thing as actual biofilms which develop within infected tissues.
There are no published studies (in peer reviewed journals) documenting the existence of Lyme biofilms let alone which treatments might be effective.
When you Google the words Lyme and Biofilm it inevitably leads you to MacDonald and Sapi. MacDonald's work is fascinating but unpublsihed or vallidated by other investigators. It also is unhelpful from a clinical perspective.
In the meantime, my patients tell about earthworm extracts, mushroom extracts and a variety of other enzymes. I have found no compelling reasons to believe that any of these treatments would be effective.
At this point we are left at the same place we were two years ago. Lyme may persist because of many mechanisms. The contribution of biofilms remains unknown. Treatments (from the perspective of my allopathic mind) should be rational and based on what we do know from the the science at hand and what we have garnered from clinical experience.
It appears that Lyme infection within the brain is frequently manifested through biofilms and atypical cystic, granular/pleomorphic forms of the organism.
I only discus patient cases after I have recieved their consent. (Some have questioned this)
I have continued to treat patients with severe encephlopathic neuroborreliosis including some diagnosed with premature Alzheimer's disease.
My clinical experiences have been consistent. The addition of IV Flagyl has been very effective for such patients. Perhaps this relates to mechanisms alluded to above.
Biofilms are indeed complex structures. Previously freely motile bacteria become frozen in a gel-like matrix due to the result of complex molecular and genetic swiching. The organisms within these films are able to communicate and establish a social network. Frequently these bacteria go into a starvation mode and exhibit a very low metabolic rate. Biofilms may release motile bacteria when enviromental factors become favorable. Biofilms may be polymicrobial or consist of a single organism. Biofilms have been cited as a mechanism by which opportunistic germs, eg Pseudomonas, can become pathogenic. Bacteria turn out to be very clever little fellows, after all, they have been on the earth for 3.5 billion years. Biofilm fossils have been uncovered evincing their antiquity.
Bacteria within these biofilms are difficult to kill. They exist in a highly protected niche. They frequently become extremely resistant to antibiotics and destruction through normal immune responses.
Antibiotics such as Beta-lactams (penicillins and cephalosporins) are generally ineffective because these cell wall inhibitors work only when bacteria are rapidly dividing or remodelling their cell walls. Biofilm bacteria are frequently in a state of suspended animation.
The biological characteristics of biofilm contained bacteria quickly begin to resemble those attributed to cystic forms of Borrelia burdorferi (Lyme). Both have a slow metabolic rate and are not typically killed by Beta-lactams, except for the amoxicillin paradox described in my last blog.
One could postulate that antibiotics which are effective against cyst forms of Lyme could also be effective against biofilm forms.
Some have been very critical of Dr. Sapi's work. She has developed "biofilm like" colonies which she does not define. These are not the same thing as actual biofilms which develop within infected tissues.
There are no published studies (in peer reviewed journals) documenting the existence of Lyme biofilms let alone which treatments might be effective.
When you Google the words Lyme and Biofilm it inevitably leads you to MacDonald and Sapi. MacDonald's work is fascinating but unpublsihed or vallidated by other investigators. It also is unhelpful from a clinical perspective.
In the meantime, my patients tell about earthworm extracts, mushroom extracts and a variety of other enzymes. I have found no compelling reasons to believe that any of these treatments would be effective.
At this point we are left at the same place we were two years ago. Lyme may persist because of many mechanisms. The contribution of biofilms remains unknown. Treatments (from the perspective of my allopathic mind) should be rational and based on what we do know from the the science at hand and what we have garnered from clinical experience.
It appears that Lyme infection within the brain is frequently manifested through biofilms and atypical cystic, granular/pleomorphic forms of the organism.
I only discus patient cases after I have recieved their consent. (Some have questioned this)
I have continued to treat patients with severe encephlopathic neuroborreliosis including some diagnosed with premature Alzheimer's disease.
My clinical experiences have been consistent. The addition of IV Flagyl has been very effective for such patients. Perhaps this relates to mechanisms alluded to above.
Monday, July 25, 2011
Lyme tests old and new
My recommendations for Lyme testing have not changed.
Some new tests have been introduced, unfortunately there are no published studies demonstating their validity. One test is called an immune tolerance test. It measures T cell proliferation after exposure to select Lyme antigens. There exist very few studies regarding such lymphocyte proliferation tests for diagnosing Lyme. Oddly, the background paper published by the manufacturer, describing the underpinnings of this technology, cites an old Wormser study in the foot notes. The Wormser study using somewhat different methods concluded the test was insensitive but specific.
A second test measures an array of cytokines levels in response to antigenic stimulation. This test is also offered without any validation.
I suspect the problem may relate to the way the immune system responds to Lyme infection. The early immune response to Lyme infection, the cell mediated response, is measured here. Lyme bacteria are known to be very immungenic. Early Lyme infections are associated with dramatic immune responses. This is why for example, early EM rashes frequently show marked inflammation. It is also why early Lyme may be associated with fever and a flu like illness(mini-cytokine storm).
I think the concept of a cell mediated immune assay for the diagnosis of Lyme is right.
Such a test has been developed for tuberculosis. It measures a direct cytokine response to antigen presentation.
A new test for Lyme is sorely needed. Current tests remain clearly inadequate.
When I test my patients I continue to skip the ELISA and go right to the Western Blot. Although there are some patient who are ELISA positive and WB negative, these patients generally show some reactivity on WB assays.
Various labs seem to offer complete Lyme Western Blots. These include: IgeneX, Clongen, MDL, and SUNY. The SUNY Lyme lab presents some bands not seen from the other laboratories. Western Blot testing may also be available through the Mayo Clinic I have been informed. (I only have direct experience with IgeneX and Clongen although I have seen reports from other labs)
I like the C6 peptide test. This is a very specific ELISA test. It has a lot of false negatives because the antigen tested can easily change its epitope. Any value greater than 0.1 needs to be considered. With values of 0.4 and greater, I am fairly comfortable suggesting the patient has had prior exposure to Bb even in the face of a negative WB.
Co-infection testing is indispensible. Any positive results significantly increase the likelihood that a co-infection (here Borrelia) is also present.
The best test still remains a careful history and physical examination of the patient.
Some new tests have been introduced, unfortunately there are no published studies demonstating their validity. One test is called an immune tolerance test. It measures T cell proliferation after exposure to select Lyme antigens. There exist very few studies regarding such lymphocyte proliferation tests for diagnosing Lyme. Oddly, the background paper published by the manufacturer, describing the underpinnings of this technology, cites an old Wormser study in the foot notes. The Wormser study using somewhat different methods concluded the test was insensitive but specific.
A second test measures an array of cytokines levels in response to antigenic stimulation. This test is also offered without any validation.
I suspect the problem may relate to the way the immune system responds to Lyme infection. The early immune response to Lyme infection, the cell mediated response, is measured here. Lyme bacteria are known to be very immungenic. Early Lyme infections are associated with dramatic immune responses. This is why for example, early EM rashes frequently show marked inflammation. It is also why early Lyme may be associated with fever and a flu like illness(mini-cytokine storm).
I think the concept of a cell mediated immune assay for the diagnosis of Lyme is right.
Such a test has been developed for tuberculosis. It measures a direct cytokine response to antigen presentation.
A new test for Lyme is sorely needed. Current tests remain clearly inadequate.
When I test my patients I continue to skip the ELISA and go right to the Western Blot. Although there are some patient who are ELISA positive and WB negative, these patients generally show some reactivity on WB assays.
Various labs seem to offer complete Lyme Western Blots. These include: IgeneX, Clongen, MDL, and SUNY. The SUNY Lyme lab presents some bands not seen from the other laboratories. Western Blot testing may also be available through the Mayo Clinic I have been informed. (I only have direct experience with IgeneX and Clongen although I have seen reports from other labs)
I like the C6 peptide test. This is a very specific ELISA test. It has a lot of false negatives because the antigen tested can easily change its epitope. Any value greater than 0.1 needs to be considered. With values of 0.4 and greater, I am fairly comfortable suggesting the patient has had prior exposure to Bb even in the face of a negative WB.
Co-infection testing is indispensible. Any positive results significantly increase the likelihood that a co-infection (here Borrelia) is also present.
The best test still remains a careful history and physical examination of the patient.
Sunday, July 24, 2011
Everything you thought you knew about cyst busters is wrong
Eva Sapi's recent research calls into question everything we thought we knew about Lyme "cysts." In fact it destroys the old thinking.
We have heard about cell wall antibiotics, intracellular antibiotics and cyst-busters. Think again.
She investigated the effect of various antibiotics on Lyme spirochetes and round body forms - also know as cystic forms.
Doxycycline worked according to plan. Doxy inhibits protein synthesis - it kills bacteria, including Lyme, by action within the cytoplasm, inhibiting the manufacture of proteins required for the bacteria's survival. Doxy and others are commonly referred to as intracellular antibiotics.
Spirochete loads decreased by about 90% while cyst levels increased by 200% - just as expected.
Then amoxicillin data was presented. Amoxicillin inhibits the formation of bacterial cell walls. Amox and similar drugs should then only be effective in killing spirochetes with an intact cell wall. This is where the results start deviating from the plotted course.
Amoxicillin killed 90% of spirochete forms - OK, but -- it also killed 68% of the cystic forms! Amoxicillin and other cell wall drugs are not cyst busters - only specific anti-parasite drugs kill cysts - or so we thought.
Well lets think again for a second: what are cysts? Are they balled up forms of spirochetes with a different kind of membrane - or blebs (also described) expressed through the spirochete membrane? Maybe the former retain much of the cell wall from the original spirochete - maybe that is why amoxicillin works here.
This would seem to clear up a nagging question raised by others. Are cysts and L-forms really the same thing? These results show that cysts cannot represent a version of L-forms or spheroplasts which result when gram negatives shed their cell walls. If this were the case a cell wall drug would be ineffective. Cysts and L-forms are distinct and different forms. (There may be a hole in this reasoning. I will explain later).
OK So we have learned something new: cell wall antibiotics can also kill some cyst forms which are not L-forms.
Let's look at some more data. Tigecyline is a not a cyst drug either. Wrong. Tigecycline kills 90% of spirochetes, good so far, but it also kills 90% of cysts! Tigecycline is an intracellular antibiotic similar to doxycycline! Another fly in the ointment.
OK. Cysts with their lower metabolic rate, still need ribosomal proteins to survive, just not at the levels of intact spirochetes. Tigecyline is a more powerful drug, higher levels are delivered into the cytoplasm of the cysts. This makes sense. Cyst forms are still essentially a pleomorphic version of Lyme bacteria with somewhat different features. In this scenario, cysts could be L-forms. But we have already shown that this is not true because amoxicillin can kill them. Right?
Amoxil is a cell wall drug. I thought so. Kersten, (antimicrobial agents and chemotherapy, May 1995, p. 1127-1133) states that Beta-lactam antibiotics, which include amox, penicillin and Rocephin, have been shown to cause a specific loss of total intracellular RNA in the absence of cell wall hydrolysis. In other words, amoxil could possibly work in part as an intracellular agent. If this is right cyst forms of Lyme could still be L-forms. So perhaps we have not shown that L-forms and cyst forms are different after all.
The question remains unanswered.
Let's get to the Cyst-busters. It takes antiparasitic drugs, so we thought, to kill the cysts. Cyst-busters, anti-parasite drugs, kill parasites (and Lyme cysts) not bacteria. The so called cyst-busters were heretofore used in combination or cycled with other antibiotics. Previous thinking was that typical antibiotics would kill spirochetes and/or L-forms and that cyst busters would disrupt only the cystic forms.
Cyst-busters do not kill intact spirochetes - so we are told. Very wrong this time.
I cannot cover the whole Sapi study. The most exciting finding is that Tindamax (tinidazole) - our premier Cyst-buster, is the most effective drug overall. This "cyst-buster" kills 90% of cysts and spirochetes: by far the best drug. We don't know it's effect on L-forms, but we can guess. Tindamax probably works by an intracellular mechanism. If this is true it should be equally effective against L-forms.
It gets even better. Tindamax is the only drug which does a great job on biofilm colonies as well!
(not to be discussed now). More on biofilms later.
Tindamax passes the blood brain barrier and penetrates well into most tissues. It has been effective in my patients with neurocognitive deficits - neuroborreliosis.
Recently I tried it on another sort of patient. This patient has had intractable Lyme arthritis of his knees. This young athlete had been extensively treated with IV Rocephin followed by a year of typical oral antibiotics. Knee effusions have persisted - until I prescribed Tindamax. Now, after two months, the fluid in his knees has evaporated. His knees are dry and painless for the first time in over one year.
This raises the question: should Tindamax be used as mono-therapy? Well, I cannot endorse blanket use at this time. Tindamax has a black box warning. It has been associated with cancer in some laboratory animals. Perhaps there are more compelling reasons to use Tindamax, but this will have to wait for another post.
My nagging question:
Why does penicillin kill Lyme? It shouldn't. Lyme is a gram negative bacteria. While certain Beta-lactam antibiotics can kill gram negative bacteria, penicillin cannot. Penicillin is only active against gram positive bacteria.
Maybe this other mechanism alluded to above, the alternative intracellular RNA mechanism is significant and explains why penicillin kills Lyme spirochetes. Maybe not.
We need to continually reevaluate things which we have assumed to be true, because many of them are not.
We have heard about cell wall antibiotics, intracellular antibiotics and cyst-busters. Think again.
She investigated the effect of various antibiotics on Lyme spirochetes and round body forms - also know as cystic forms.
Doxycycline worked according to plan. Doxy inhibits protein synthesis - it kills bacteria, including Lyme, by action within the cytoplasm, inhibiting the manufacture of proteins required for the bacteria's survival. Doxy and others are commonly referred to as intracellular antibiotics.
Spirochete loads decreased by about 90% while cyst levels increased by 200% - just as expected.
Then amoxicillin data was presented. Amoxicillin inhibits the formation of bacterial cell walls. Amox and similar drugs should then only be effective in killing spirochetes with an intact cell wall. This is where the results start deviating from the plotted course.
Amoxicillin killed 90% of spirochete forms - OK, but -- it also killed 68% of the cystic forms! Amoxicillin and other cell wall drugs are not cyst busters - only specific anti-parasite drugs kill cysts - or so we thought.
Well lets think again for a second: what are cysts? Are they balled up forms of spirochetes with a different kind of membrane - or blebs (also described) expressed through the spirochete membrane? Maybe the former retain much of the cell wall from the original spirochete - maybe that is why amoxicillin works here.
This would seem to clear up a nagging question raised by others. Are cysts and L-forms really the same thing? These results show that cysts cannot represent a version of L-forms or spheroplasts which result when gram negatives shed their cell walls. If this were the case a cell wall drug would be ineffective. Cysts and L-forms are distinct and different forms. (There may be a hole in this reasoning. I will explain later).
OK So we have learned something new: cell wall antibiotics can also kill some cyst forms which are not L-forms.
Let's look at some more data. Tigecyline is a not a cyst drug either. Wrong. Tigecycline kills 90% of spirochetes, good so far, but it also kills 90% of cysts! Tigecycline is an intracellular antibiotic similar to doxycycline! Another fly in the ointment.
OK. Cysts with their lower metabolic rate, still need ribosomal proteins to survive, just not at the levels of intact spirochetes. Tigecyline is a more powerful drug, higher levels are delivered into the cytoplasm of the cysts. This makes sense. Cyst forms are still essentially a pleomorphic version of Lyme bacteria with somewhat different features. In this scenario, cysts could be L-forms. But we have already shown that this is not true because amoxicillin can kill them. Right?
Amoxil is a cell wall drug. I thought so. Kersten, (antimicrobial agents and chemotherapy, May 1995, p. 1127-1133) states that Beta-lactam antibiotics, which include amox, penicillin and Rocephin, have been shown to cause a specific loss of total intracellular RNA in the absence of cell wall hydrolysis. In other words, amoxil could possibly work in part as an intracellular agent. If this is right cyst forms of Lyme could still be L-forms. So perhaps we have not shown that L-forms and cyst forms are different after all.
The question remains unanswered.
Let's get to the Cyst-busters. It takes antiparasitic drugs, so we thought, to kill the cysts. Cyst-busters, anti-parasite drugs, kill parasites (and Lyme cysts) not bacteria. The so called cyst-busters were heretofore used in combination or cycled with other antibiotics. Previous thinking was that typical antibiotics would kill spirochetes and/or L-forms and that cyst busters would disrupt only the cystic forms.
Cyst-busters do not kill intact spirochetes - so we are told. Very wrong this time.
I cannot cover the whole Sapi study. The most exciting finding is that Tindamax (tinidazole) - our premier Cyst-buster, is the most effective drug overall. This "cyst-buster" kills 90% of cysts and spirochetes: by far the best drug. We don't know it's effect on L-forms, but we can guess. Tindamax probably works by an intracellular mechanism. If this is true it should be equally effective against L-forms.
It gets even better. Tindamax is the only drug which does a great job on biofilm colonies as well!
(not to be discussed now). More on biofilms later.
Tindamax passes the blood brain barrier and penetrates well into most tissues. It has been effective in my patients with neurocognitive deficits - neuroborreliosis.
Recently I tried it on another sort of patient. This patient has had intractable Lyme arthritis of his knees. This young athlete had been extensively treated with IV Rocephin followed by a year of typical oral antibiotics. Knee effusions have persisted - until I prescribed Tindamax. Now, after two months, the fluid in his knees has evaporated. His knees are dry and painless for the first time in over one year.
This raises the question: should Tindamax be used as mono-therapy? Well, I cannot endorse blanket use at this time. Tindamax has a black box warning. It has been associated with cancer in some laboratory animals. Perhaps there are more compelling reasons to use Tindamax, but this will have to wait for another post.
My nagging question:
Why does penicillin kill Lyme? It shouldn't. Lyme is a gram negative bacteria. While certain Beta-lactam antibiotics can kill gram negative bacteria, penicillin cannot. Penicillin is only active against gram positive bacteria.
Maybe this other mechanism alluded to above, the alternative intracellular RNA mechanism is significant and explains why penicillin kills Lyme spirochetes. Maybe not.
We need to continually reevaluate things which we have assumed to be true, because many of them are not.
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