There is confusion about FDA approval of Lyme testing. It has been stated (by IDSA experts) that ILADS associated physicians have essentially created their own laboratories which are not FDA approved. And furthermore, these laboratories and physicians use non-peer-reviewed methods to interpret the results.
This is very misleading at the very least.
Laboratories are licensed by state regulatory agencies. Certified laboratories meet strict standards, including proficiency testing.
The FDA is charged with regulating drugs and medical devices. Test kits, commercially prepared for mass distribution are considered medical devices. This is why the FDA licenses these Lyme Western Blot tests. The FDA has licensed more than 70Lyme Western Blot kits made by varying manufactures. There exists no published data validating any one of these kits let alone all 70 or more.
Standard kits report the 13 Western Blot bands specified by the 1994 Dearborn criteria. This standard was created so that various doctors and scientists could communicate with one another reading from the same sheet of music. This surveillance test, never approved for diagnosis, has no peer-reviewed literature supporting its use - especially in light of FDA approval of so many test kits. In fact, a review of the literature shows investigators have used various Band criteria.
Laboratories producing their own testing kits (not for mass distribution) like Stony Brook and IgeneX do not require FDA approval. In fact, these tests cannot be regulated by the FDA. These laboratories must comply with the same regulations and proficiency tests required by all state licensed facilities.
Specialty laboratories likely do a better Lyme Western blot. For example, Stony Brook Lyme lab only does Lyme Western Blots. IgenX has decades of experience. Clongen and MDL are meticulous.
While mass produced Lyme Western Blot kits report 13 bands. Other maligned specialty labs report 28 or even 52 bands.
As stated in the 1994 report the diagnosis of Lyme is(was) largely clinical.
The question then is: How can more be less?
Thursday, December 29, 2011
Friday, December 23, 2011
Heart Block
I first saw this patient 10 months ago. She had been ill with a disabling multi-system illness for 12 years.
She suffered with many symptoms, including but not limited to: profound fatigue global cognitive dysfunction, joint pains, swelling with effusions, weakness and numerous neurological manifestations. Lyme was suggested. She had a positive Western Blot (10 years ago) an IDSA doctor prescribed two weeks of doxycyline.
An LLMD subsequently prescribed over a year of antibiotics including mincycline and Ceftin. Many symptoms improved, except the over-powering fatigue.
She stumbled along for years off antibiotics, symptoms waxing an waning. Still, she managed to functioned as a high level executive.
As of late she was not doing well at all. When I met her she had been sidelined with disability for more than two years. She had no energy or stamina. She was unable to grocery shop or attend to the most basic activities of daily living. She had perpetual flu-like symptoms - a loss of sensation in her fingers and toes. She was stumbling and falling. Joint pain with swelling had returned. She had global cognitive dysfunction with episodes of syncope, confusion and disorientation. She could not speak well, think clearly or read and write. She was a shell of her former self.
Two months before an IDSA doctor refused to treat her because she had a negative Lyme test.
Despite the fact that she nearly died of complete heart block now treated with a permanent pacemaker. And - despite the fact the attending cardiologist suspected Lyme as the culprit.
I became her doctor.
After months of fits and starts with oral therapy she has no been on IV Rocephin for 3 months and tells me she is getting her life back. She is contemplating starting a new business after two years of complete disability.
Now she gets out of the house and can read. Now she can do many things unthinkable a few months before. She is still very sick with many persisting constitutional and neurological symptoms. Her stamina is poor. After brief activites she requires extensive rest for recuperation. But she tells me she getting better almost on a daily basis. Most of the improvement seen after 2 and 1/2 months of therapy.
Lets look at some labs. These are IgM Western Blot results from three different labs. Labcorp found a 23 band. Clongen reported a 41 band and a weak, 23% of control 23 band reaction. Stony Brook found: Bands, 18,37,58,66,72,93.
The 37 and 93 bands either one alone might be enough to make the diagnosis according to some sources. I do not know why there was no 41 or 23 band found. Different strains of Lyme may be used in different kits lending bias to which bands react.
I do not understand not treating heart block with a documented history of Lyme disease. The CDC test is a surveillance test. It has never been validated as a diagnostic test. And the notion that IgG bands show up in late Lyme is not substantiated in any literature I can find.
The highly vaunted NIH/IDSA studies of long-term therapy never included Rocephin use for longer than 10 weeks.
Happy Holidays
She suffered with many symptoms, including but not limited to: profound fatigue global cognitive dysfunction, joint pains, swelling with effusions, weakness and numerous neurological manifestations. Lyme was suggested. She had a positive Western Blot (10 years ago) an IDSA doctor prescribed two weeks of doxycyline.
An LLMD subsequently prescribed over a year of antibiotics including mincycline and Ceftin. Many symptoms improved, except the over-powering fatigue.
She stumbled along for years off antibiotics, symptoms waxing an waning. Still, she managed to functioned as a high level executive.
As of late she was not doing well at all. When I met her she had been sidelined with disability for more than two years. She had no energy or stamina. She was unable to grocery shop or attend to the most basic activities of daily living. She had perpetual flu-like symptoms - a loss of sensation in her fingers and toes. She was stumbling and falling. Joint pain with swelling had returned. She had global cognitive dysfunction with episodes of syncope, confusion and disorientation. She could not speak well, think clearly or read and write. She was a shell of her former self.
Two months before an IDSA doctor refused to treat her because she had a negative Lyme test.
Despite the fact that she nearly died of complete heart block now treated with a permanent pacemaker. And - despite the fact the attending cardiologist suspected Lyme as the culprit.
I became her doctor.
After months of fits and starts with oral therapy she has no been on IV Rocephin for 3 months and tells me she is getting her life back. She is contemplating starting a new business after two years of complete disability.
Now she gets out of the house and can read. Now she can do many things unthinkable a few months before. She is still very sick with many persisting constitutional and neurological symptoms. Her stamina is poor. After brief activites she requires extensive rest for recuperation. But she tells me she getting better almost on a daily basis. Most of the improvement seen after 2 and 1/2 months of therapy.
Lets look at some labs. These are IgM Western Blot results from three different labs. Labcorp found a 23 band. Clongen reported a 41 band and a weak, 23% of control 23 band reaction. Stony Brook found: Bands, 18,37,58,66,72,93.
The 37 and 93 bands either one alone might be enough to make the diagnosis according to some sources. I do not know why there was no 41 or 23 band found. Different strains of Lyme may be used in different kits lending bias to which bands react.
I do not understand not treating heart block with a documented history of Lyme disease. The CDC test is a surveillance test. It has never been validated as a diagnostic test. And the notion that IgG bands show up in late Lyme is not substantiated in any literature I can find.
The highly vaunted NIH/IDSA studies of long-term therapy never included Rocephin use for longer than 10 weeks.
Happy Holidays
Thursday, December 22, 2011
Brown powder
There is always the patient you dread seeing. When I see this particular patient in the waiting room an uneasiness wells up from my gut. Don't misunderstand. She is a lovely person. Maybe it would be easier if she wasn't so nice. It is her disease I take issue with. Progress has been excruciatingly slow with regression the rule. After two years treating her I am frustrated. She knows I can help people. Her son and mother responded beautifully.
She was a park ranger. Now she is disabled, unable to work: Fatigue with a capital F, pain and scrambled brain. She experiences confusion and disorientation at times. She suffers with numerous areas of neurocognitive dysfunction. She has been troubled by severe mood swings with sudden uncontrollable tears.
She has been treated aggressively for co-infections and with intravenous antibiotics.
Finally I insisted again that we go down a different path(having suggested this many times in the past). I referred her to a practitioner of traditional Chinese medicine. She was skeptical given a background in science. Spiritual healing, cupping and acupuncture she felt were of little or no help. But herbs. Herbs were a different story. She was provided with strange bottles containing brown powder and hand written labels. The labels made various claims: anti-Lyme, anti-Bartonella, detoxifying, anti-inflammatory, anti-biofilm and others. Neither she nor I have a clue what is in these foul tasting mixtures to be taken several times daily with water. But they Work. The combination of herbs and antibiotics has been particularly effective.
Unfortunately she regresses if she stops either the herbs or the antibiotics. Herbs, like antibiotics may be required as maintenance therapy.
Take her off the list.
She was a park ranger. Now she is disabled, unable to work: Fatigue with a capital F, pain and scrambled brain. She experiences confusion and disorientation at times. She suffers with numerous areas of neurocognitive dysfunction. She has been troubled by severe mood swings with sudden uncontrollable tears.
She has been treated aggressively for co-infections and with intravenous antibiotics.
Finally I insisted again that we go down a different path(having suggested this many times in the past). I referred her to a practitioner of traditional Chinese medicine. She was skeptical given a background in science. Spiritual healing, cupping and acupuncture she felt were of little or no help. But herbs. Herbs were a different story. She was provided with strange bottles containing brown powder and hand written labels. The labels made various claims: anti-Lyme, anti-Bartonella, detoxifying, anti-inflammatory, anti-biofilm and others. Neither she nor I have a clue what is in these foul tasting mixtures to be taken several times daily with water. But they Work. The combination of herbs and antibiotics has been particularly effective.
Unfortunately she regresses if she stops either the herbs or the antibiotics. Herbs, like antibiotics may be required as maintenance therapy.
Take her off the list.
Thursday, December 15, 2011
Primay care: Lyme endemic
Follow up visit. I have known this 50 year old male for a long time. He is a chronic depressive type. Divorced poorly. Working two jobs. Antidepressants help and he needs a refill. He mentions as a side bar he had red bumps on his leg 8 weeks ago, thought it was bug bites and went to a walk in clinic. Told - nothing to worry about. he suffers with anxiety and is disease phobic too. Just updating my files. Great. Thanks for the info. This was three visits ago.
No symptoms except the usual fatigue and depressed mood.
I order a few tests, perhaps the wrong test, including a tick borne disease panel. I have Lyme on my brain. Gotta stop that. Surprise(or not). Labcorp CDC positive for Lyme, ELISA and IgM WB. Babesia duncani titer 1:512 cinches the deal.
I carefully query: " Change in fatigue, Headaches, neck pain, change in vision, night sweats, any sweats, air hunger, joint pain, muscle pain, muscle pain, twitching muscles, Numbness and tingling, brain fog, cognitive issues, anything?"
He pauses to think: Maybe a few night sweats, over the last 6 months. Perhaps the heat was up too high, wearing heavy night clothes, not sure. Nothing else.
I treat him with antibiotics and Mepron for a month.
Now the current follow up visit.
Feels the same, except anxiety has increased; now he is worried about these new exotic sounding and frightening diseases.
It would be a lot easier if he was sick. Then I would know what to do.
There are the perils of a primary care practice - seeing patients on the front line. I suspect most patients infected with Lyme are asymptomatic. It is impossible to test this theory. I know many patients infected with Babesia are asymptomatic.
In a specialty Lyme referral practice you don't have to wrestle with these problems. I spent more time thinking about his case than I did the sick patients I saw that day.
Now I know a lot of readers are thinking: Treat him, treat him! Here's the problem. With Lyme you treat until symptoms are gone. What end point do you suggest I use?
I am still scratching my chin.
"
No symptoms except the usual fatigue and depressed mood.
I order a few tests, perhaps the wrong test, including a tick borne disease panel. I have Lyme on my brain. Gotta stop that. Surprise(or not). Labcorp CDC positive for Lyme, ELISA and IgM WB. Babesia duncani titer 1:512 cinches the deal.
I carefully query: " Change in fatigue, Headaches, neck pain, change in vision, night sweats, any sweats, air hunger, joint pain, muscle pain, muscle pain, twitching muscles, Numbness and tingling, brain fog, cognitive issues, anything?"
He pauses to think: Maybe a few night sweats, over the last 6 months. Perhaps the heat was up too high, wearing heavy night clothes, not sure. Nothing else.
I treat him with antibiotics and Mepron for a month.
Now the current follow up visit.
Feels the same, except anxiety has increased; now he is worried about these new exotic sounding and frightening diseases.
It would be a lot easier if he was sick. Then I would know what to do.
There are the perils of a primary care practice - seeing patients on the front line. I suspect most patients infected with Lyme are asymptomatic. It is impossible to test this theory. I know many patients infected with Babesia are asymptomatic.
In a specialty Lyme referral practice you don't have to wrestle with these problems. I spent more time thinking about his case than I did the sick patients I saw that day.
Now I know a lot of readers are thinking: Treat him, treat him! Here's the problem. With Lyme you treat until symptoms are gone. What end point do you suggest I use?
I am still scratching my chin.
"
Monday, December 12, 2011
Lyme Western Blots: another look
In October 1994 at a weekend conference, a group of experts developed criteria for the the definition of Lyme surveillance testing. The outcome of this conference led to a maelstrom of controversy which continues.
The test has never been re-evelated even though two key bands: 34 OspB and 31 OspA were ommitted.
It was decided that a two tier protocol should be followed. The criteria for the IgM Western Blot came from the work of Engstrom et al. Three strains of Lyme were found to perform equally well. The 23 band, identified as the OspC band, the 39 band, and the Fla (41) band were chosen for the assay. A positive result was 2/3 of these bands. It was noted that the 37 band could be added and that 2/4 of these bands would increase the accuracy of the test. (not accurate)
Dressler et al proposed a different criteria for IgM scoring. A different strain of Lyme was used which did not express the 39 band well. A positive result was the presence of 2/8 bands: 18,21,28,37,45,58 and 93. This test performed about as well as the above test.
Two radically different test and test criteria were found to produce almost the same results!
Padula et al found the 23 band to be of diagnostic significance, especially in early Lyme - and that "this protein may be poorly expressed in a number of North American strains of Borrelia burgdoreri." Weinstein and Johnsone report: "Despite these limitations, the proposed criteria for a positive immunoblot in late Lyme disease - at least 5 or the 10 specified IgG bands - seemed to stand up reasonably well in other laboratories...The criteria (will) be used..pending further studies."
What studies?
Where did the 37 band go?
Stony Brook reports it.
Ah, the missing band that would have made the CDC test more accurate by its own admission.
Two labs prepare their own Lyme Western Blot kits: IgeneX and Stony Brook. IgeneX has developed criteria for a positive result (IgG and IgM) - sounds like the Dressler criteria. They report a positive result if there is a reaction with two highly specific bands, inclding: 23,31,41,34,39,and 93.
Different assays have produced different bands. Dressler reported a 21 band. Stony Brook only reports a 20 band.
Are you as confused as I am?
In addition, in my experience I have found reported Western Blot results differ amongst commonly used "LLMD" laboratories.
In 1994 Gubler reports the two tier test is not the gold standard. (culture is). He states that "in the not too distant future, the development of new tests that use a cocktail of recombinant antigens or chimeric antigens(will increase)the sensitivity and specificity of serological tests for B. burdorferi."
Its been more that 17 years. We are still waiting.
The test has never been re-evelated even though two key bands: 34 OspB and 31 OspA were ommitted.
It was decided that a two tier protocol should be followed. The criteria for the IgM Western Blot came from the work of Engstrom et al. Three strains of Lyme were found to perform equally well. The 23 band, identified as the OspC band, the 39 band, and the Fla (41) band were chosen for the assay. A positive result was 2/3 of these bands. It was noted that the 37 band could be added and that 2/4 of these bands would increase the accuracy of the test. (not accurate)
Dressler et al proposed a different criteria for IgM scoring. A different strain of Lyme was used which did not express the 39 band well. A positive result was the presence of 2/8 bands: 18,21,28,37,45,58 and 93. This test performed about as well as the above test.
Two radically different test and test criteria were found to produce almost the same results!
Padula et al found the 23 band to be of diagnostic significance, especially in early Lyme - and that "this protein may be poorly expressed in a number of North American strains of Borrelia burgdoreri." Weinstein and Johnsone report: "Despite these limitations, the proposed criteria for a positive immunoblot in late Lyme disease - at least 5 or the 10 specified IgG bands - seemed to stand up reasonably well in other laboratories...The criteria (will) be used..pending further studies."
What studies?
Where did the 37 band go?
Stony Brook reports it.
Ah, the missing band that would have made the CDC test more accurate by its own admission.
Two labs prepare their own Lyme Western Blot kits: IgeneX and Stony Brook. IgeneX has developed criteria for a positive result (IgG and IgM) - sounds like the Dressler criteria. They report a positive result if there is a reaction with two highly specific bands, inclding: 23,31,41,34,39,and 93.
Different assays have produced different bands. Dressler reported a 21 band. Stony Brook only reports a 20 band.
Are you as confused as I am?
In addition, in my experience I have found reported Western Blot results differ amongst commonly used "LLMD" laboratories.
In 1994 Gubler reports the two tier test is not the gold standard. (culture is). He states that "in the not too distant future, the development of new tests that use a cocktail of recombinant antigens or chimeric antigens(will increase)the sensitivity and specificity of serological tests for B. burdorferi."
Its been more that 17 years. We are still waiting.
Thursday, December 1, 2011
Chasing the sweats
Let me clarify this confusing post: It is based on a true clinical scenario. I was drawn into a hole chasing Babesia; the symptoms were classic, especially the profound night sweats. The "Babesia" stubbornly wouldn't go away, with everything thrown its way: Mepron, malarone, Artemesia, Coartem and Larium.
I was willing to treat Babesia as a clinical diagnosis with aggressive, long term therapy; positive lab confirmation is rare. I convinced myself that resolution was just around the corner.
I was reluctant to treat Lyme with intravenous therapy(I had been treating Lyme with oral antibiotics) If the clinical picture had been more "Lyme flavored," I may have pulled the trigger for IV therapy more quickly.
The patient had clear symptoms of neuroborreliosis including hallucinations at one point. Still, the clinician could rationalize the marked neuropsychiatric manifestations were the product of cerebral babesiosis.
Over a period of several months the patient requested (stridently) that she needed a PICC and IV therapy.
The diagnosis of tick borne disease is still made clinically. Still, in borderline situations the clinician sometimes turns to laboratory results, as I did here, to help justify the more dangerous step up in therapy.
The patient's mantra for some time was: I need a PICC.
I acquiesced after 9 months of oral therapies.
Incredible improvements with resoltion of both cognitive and physical symptoms were seen within the first month. The so-called classic Babesia symptoms also melted away.
This raises many interesting clinical questions.
I am not offering any clinical advise here. Please do not misinterpret. Every case is different.
In this case, the patient had insights about her care which turned out to be true.
I was willing to treat Babesia as a clinical diagnosis with aggressive, long term therapy; positive lab confirmation is rare. I convinced myself that resolution was just around the corner.
I was reluctant to treat Lyme with intravenous therapy(I had been treating Lyme with oral antibiotics) If the clinical picture had been more "Lyme flavored," I may have pulled the trigger for IV therapy more quickly.
The patient had clear symptoms of neuroborreliosis including hallucinations at one point. Still, the clinician could rationalize the marked neuropsychiatric manifestations were the product of cerebral babesiosis.
Over a period of several months the patient requested (stridently) that she needed a PICC and IV therapy.
The diagnosis of tick borne disease is still made clinically. Still, in borderline situations the clinician sometimes turns to laboratory results, as I did here, to help justify the more dangerous step up in therapy.
The patient's mantra for some time was: I need a PICC.
I acquiesced after 9 months of oral therapies.
Incredible improvements with resoltion of both cognitive and physical symptoms were seen within the first month. The so-called classic Babesia symptoms also melted away.
This raises many interesting clinical questions.
I am not offering any clinical advise here. Please do not misinterpret. Every case is different.
In this case, the patient had insights about her care which turned out to be true.
Saturday, November 26, 2011
Lyme labs and babs
A 22 year old female had a tick bite with at rash at age 5 (recalled by mother). Her pediatrician treated her for 3 weeks. No symptoms recalled. At age 10 she had another bite, treated the same way, no problems. At age 12 she found herself not feeling quite right. It started with vague aches and pains, loss of energy. Her pediatrician diagnosed growing pains. She still did not feel well. Her concentration at school lessened, straight As were replaced with Bs. Her pediatrician diagnosed pre-teen hormones and prescribed reassurance. An avid athlete and enthusiastic basketball player, she collapsed on the court at age 13. The cardiologist and neurologist gave her a clean bill of health.
Her state of well being fluctuated. She had good and bad days, good and bad months. High school was a struggle. She had little time for friends or extracurricular activities. She started going to sleep at 7:30 and having a hard time waking up. She maintained her grades, B+: memory, concentration and focus were poor.
At 16 her pediatrician referred her to a psychiatrist. A diagnosed of depression made she was started on Zoloft. Maybe it helped; maybe not.
She finished one year of college but had to drop out. She had more memory problems, fatigue, joint pains, headaches and other symptoms.
Her mother asked her doctor to do a Lyme test. The test showed a negative ELISA and a positive Western Blot with a 41 IgG band and 41 and 23 IgM bands. The ah ha moment. She was treated with doxy for a month. Didn't help. The infectious disease specialist had nothing to offer. A friend referred her to me.
A repeat Lyme Western Blot 6 months later showed now only a 41 IgG band. The co-infection panel was negative.(I later noted that the B duncani test had not been done).
Her symptoms were typical in my experience for chronic Lyme: fatigue, brain fog, cognitive problems, numbness and tingling in the extremities, headaches, neck pain, muscle pains, migratory joint pain of both large and small joints and prominent depression.
She was treated with an aggressive anti-Lyme regimen. She felt worse over the next two months. Two months later a new symptoms emerged: profound night sweats, air hunger, flu-like symptoms with low grade fevers. A repeat round of lab tests showed a positive titer to B. duncani at the lowest cut-off point. Anti-babesia therapy was started. She had prominent nausea and Mepron intolerance. Zofran was needed to manage the nausea. Over time she began to feel better.
A new Lyme Western Blot from a different laboratory showed 58 and 41 IgG bands and a 41 IgM band. There was a partial reaction at the 23 band.
She continued to improve over the next six months. However cognitive problems were slow to respond. Intravenous treatment was discussed. There was an insurance snag. PICC never placed. Two months later she seemed to be better nonetheless.
A year into treatment she is doing pretty well. After a year at home she is back in college doing fairly well. Symptoms, especially night sweats quickly relapse off Malarone. Still a problem.
Follow up LabCorp testing, including B. ducani was negative. We were specifically looking for a positive Lyme test for insurance, not clinical reasons.
An additional Lyme Western Blot was sent to Stony Brook. This test showed: 41 and 60IgG bands and 18,35,41,72 and 93 IgM bands. I thought this was a definite positive.
Clinical note: The odd Babesia scenario has been relatively common in my practice. Initially the patient denies any symptoms suggestive of Babesia. Babesia symptoms only become prominent after Lyme therapy has been started, as if the Lyme Herx somehow awakens the sleeping dog of asymptomatic chronic babesiosis. The two players seem to act together.
Lab comments:
My confidence in Western Blots is waning. Different laboratories frequently come up with divergent results - not even close.
I am sure this patient has a form of babesiosis. Still, one laboratory I use frequently turns up positive results for B dunani at the lowest cut off point, frequently in patients who would otherwise show a negative Lyme/co-infection panel.
Could the reported "WA1" IgG antibody actually cross react with a different organism. Or, are there a lot of false positives? Dr. Fry suggested this may be a cross-reaction to a non-Babesia protozoan which he has identified.
In truth, sometimes I order a lot of Lyme related tests searching for the positive that might justify IV therapy if anyone is looking.
Another lab's Western Blots would have undoubtedly showed different results. Maybe its best to look at Lyme Western Blots from several labs if it doesn't break the bank.
Her state of well being fluctuated. She had good and bad days, good and bad months. High school was a struggle. She had little time for friends or extracurricular activities. She started going to sleep at 7:30 and having a hard time waking up. She maintained her grades, B+: memory, concentration and focus were poor.
At 16 her pediatrician referred her to a psychiatrist. A diagnosed of depression made she was started on Zoloft. Maybe it helped; maybe not.
She finished one year of college but had to drop out. She had more memory problems, fatigue, joint pains, headaches and other symptoms.
Her mother asked her doctor to do a Lyme test. The test showed a negative ELISA and a positive Western Blot with a 41 IgG band and 41 and 23 IgM bands. The ah ha moment. She was treated with doxy for a month. Didn't help. The infectious disease specialist had nothing to offer. A friend referred her to me.
A repeat Lyme Western Blot 6 months later showed now only a 41 IgG band. The co-infection panel was negative.(I later noted that the B duncani test had not been done).
Her symptoms were typical in my experience for chronic Lyme: fatigue, brain fog, cognitive problems, numbness and tingling in the extremities, headaches, neck pain, muscle pains, migratory joint pain of both large and small joints and prominent depression.
She was treated with an aggressive anti-Lyme regimen. She felt worse over the next two months. Two months later a new symptoms emerged: profound night sweats, air hunger, flu-like symptoms with low grade fevers. A repeat round of lab tests showed a positive titer to B. duncani at the lowest cut-off point. Anti-babesia therapy was started. She had prominent nausea and Mepron intolerance. Zofran was needed to manage the nausea. Over time she began to feel better.
A new Lyme Western Blot from a different laboratory showed 58 and 41 IgG bands and a 41 IgM band. There was a partial reaction at the 23 band.
She continued to improve over the next six months. However cognitive problems were slow to respond. Intravenous treatment was discussed. There was an insurance snag. PICC never placed. Two months later she seemed to be better nonetheless.
A year into treatment she is doing pretty well. After a year at home she is back in college doing fairly well. Symptoms, especially night sweats quickly relapse off Malarone. Still a problem.
Follow up LabCorp testing, including B. ducani was negative. We were specifically looking for a positive Lyme test for insurance, not clinical reasons.
An additional Lyme Western Blot was sent to Stony Brook. This test showed: 41 and 60IgG bands and 18,35,41,72 and 93 IgM bands. I thought this was a definite positive.
Clinical note: The odd Babesia scenario has been relatively common in my practice. Initially the patient denies any symptoms suggestive of Babesia. Babesia symptoms only become prominent after Lyme therapy has been started, as if the Lyme Herx somehow awakens the sleeping dog of asymptomatic chronic babesiosis. The two players seem to act together.
Lab comments:
My confidence in Western Blots is waning. Different laboratories frequently come up with divergent results - not even close.
I am sure this patient has a form of babesiosis. Still, one laboratory I use frequently turns up positive results for B dunani at the lowest cut off point, frequently in patients who would otherwise show a negative Lyme/co-infection panel.
Could the reported "WA1" IgG antibody actually cross react with a different organism. Or, are there a lot of false positives? Dr. Fry suggested this may be a cross-reaction to a non-Babesia protozoan which he has identified.
In truth, sometimes I order a lot of Lyme related tests searching for the positive that might justify IV therapy if anyone is looking.
Another lab's Western Blots would have undoubtedly showed different results. Maybe its best to look at Lyme Western Blots from several labs if it doesn't break the bank.
History
History instructs us, oft the best predictor of the future.
Infectious plagues, epidemics and endemic, have molded the course of human history. The Black plaque, or black death - Bubonic/pneumonic plague of the 14th century has been called the greatest European catastrophe in history. Houses were emptied, villages abandoned, fields were littered with dead. The mysterious disease syphilis followed soon after, infecting many prominent world leaders, forever altering the course of human history. Henry V111, Francis 1 of France, Pope Alexander Borgia, Ivan the Terrible, and many more. Napoleon's madness was perhaps molded by Typhus. Epidemics of malaria, yellow fever, tuberculosis, influenza and AIDS were yet to come. The Spanish flu of 1918-1919 killed more people than WW1. Woodrow Wilson, the American president, contracted the flu while in Paris working out the details of the Treaty of Versailles. One could ponder: would things have worked out differently if he had been well?
Syphilis is perhaps the most pertinent to our story. A painless frequently unseen chancre is followed by a benign secondary stage a long latent stage and then a tertiary disease with protean manifestations. This "great imitator" can attack almost any organ in the body, frequently with central nervous system involvement. End stage disease,"general paresis," manifests itself with various symptoms: headache, "lightening pains," impotence, epilepsy, joint pains, progressive personality and cognitive changes, frank dementia and many more. Some infected have no symptoms and still transmit the disease to the unborn.
Every point in history, has to some extent, been intertwined with and perhaps influenced by its own epidemic(s).
Perhaps epidemics can be less obvious and still alter the history of mankind: no putrid cough and waisting of consumption/tuberculosis.
Perhaps there can exist a silent epidemic: an insidious creeping crawling yet quiet plague.
I know someone. An acquaintance let's say. A fifty something, suffering with fatigue, depression, joint pains and cognitive problems. He believes his family doctor and believes in the "system." The Lyme test was negative. Not Lyme. "Please see 'Under Our Skin.'" Not interested. The person, as of this writing continues to see a panoply of specialists and even non-traditional herbalists. Not Lyme.
I cannot raise the topic of Lyme, now a touchy subject. "You think everything is Lyme."
Arthritis. Fibromyalgia. Chronic fatigue. MS. Early dementia. POTS. "not feeling as well as 80 year old parents." All on the rise - and others.
A quiet epidemic. Denial. "Aches and pains of daily living." "Anti-science. Unseen.
True story: Tall sailing ships, those of Christopher Columbus were sailing to the Island of Hispanola. The natives scanning the horizon could see nothing. Perhaps a perturbation of the waters. After all, such things could not exist in their universe. They called the Shaman. He saw the ships. Only then could the people see them too. (to their detriment, but that's another story)
The 19th century European obstetrician. Semmelweise literally lost his mind trying to convince the experts that puerperal fever (child bed fever). a lethal epidemic, was caused by germs and that hand washing was the cure. He gave up everything to fight the battle against prevailing world opinion. Not living to see the paradigm change - slowly, he died pitifully in a mental hospital.
What can we see in the calm - no turbulent waters?
Infectious plagues, epidemics and endemic, have molded the course of human history. The Black plaque, or black death - Bubonic/pneumonic plague of the 14th century has been called the greatest European catastrophe in history. Houses were emptied, villages abandoned, fields were littered with dead. The mysterious disease syphilis followed soon after, infecting many prominent world leaders, forever altering the course of human history. Henry V111, Francis 1 of France, Pope Alexander Borgia, Ivan the Terrible, and many more. Napoleon's madness was perhaps molded by Typhus. Epidemics of malaria, yellow fever, tuberculosis, influenza and AIDS were yet to come. The Spanish flu of 1918-1919 killed more people than WW1. Woodrow Wilson, the American president, contracted the flu while in Paris working out the details of the Treaty of Versailles. One could ponder: would things have worked out differently if he had been well?
Syphilis is perhaps the most pertinent to our story. A painless frequently unseen chancre is followed by a benign secondary stage a long latent stage and then a tertiary disease with protean manifestations. This "great imitator" can attack almost any organ in the body, frequently with central nervous system involvement. End stage disease,"general paresis," manifests itself with various symptoms: headache, "lightening pains," impotence, epilepsy, joint pains, progressive personality and cognitive changes, frank dementia and many more. Some infected have no symptoms and still transmit the disease to the unborn.
Every point in history, has to some extent, been intertwined with and perhaps influenced by its own epidemic(s).
Perhaps epidemics can be less obvious and still alter the history of mankind: no putrid cough and waisting of consumption/tuberculosis.
Perhaps there can exist a silent epidemic: an insidious creeping crawling yet quiet plague.
I know someone. An acquaintance let's say. A fifty something, suffering with fatigue, depression, joint pains and cognitive problems. He believes his family doctor and believes in the "system." The Lyme test was negative. Not Lyme. "Please see 'Under Our Skin.'" Not interested. The person, as of this writing continues to see a panoply of specialists and even non-traditional herbalists. Not Lyme.
I cannot raise the topic of Lyme, now a touchy subject. "You think everything is Lyme."
Arthritis. Fibromyalgia. Chronic fatigue. MS. Early dementia. POTS. "not feeling as well as 80 year old parents." All on the rise - and others.
A quiet epidemic. Denial. "Aches and pains of daily living." "Anti-science. Unseen.
True story: Tall sailing ships, those of Christopher Columbus were sailing to the Island of Hispanola. The natives scanning the horizon could see nothing. Perhaps a perturbation of the waters. After all, such things could not exist in their universe. They called the Shaman. He saw the ships. Only then could the people see them too. (to their detriment, but that's another story)
The 19th century European obstetrician. Semmelweise literally lost his mind trying to convince the experts that puerperal fever (child bed fever). a lethal epidemic, was caused by germs and that hand washing was the cure. He gave up everything to fight the battle against prevailing world opinion. Not living to see the paradigm change - slowly, he died pitifully in a mental hospital.
What can we see in the calm - no turbulent waters?
Thursday, November 10, 2011
Iceman
Readers know - the suffering of Lyme is so great that contemplation of suicide is common. And then to make matters worse - so often, the degree of misery is unseen by those closest.
Many suffering with Lyme have heard from others: "I had Lyme: it was no big deal."
"He should only be in my body for one day!"
Maybe these unsympathetic individuals actually had a different version of the disease.
It turns out "Lyme" may a wide diversity of clinical presentations because patients are frequently infected with different strains of the organism.
Maybe we can begin to answer the question: why do some patients infected with Lyme with the tell tale EM rash never become sick without treatment, while others infected with Lyme disease treated early with recommended doses of antibiotics go on to develop full-blown chronic Lyme disease?
Research has shown that some strains of Borrelia burgdorgeri are more virulent, quickly causing dissemination into tissues, while others strains are relatively benign and may be associated with little or no disease. Borrelia bacteria show a surprising amount of genetic diversity.
Lyme bacteria have been here for thousands of years providing a long time frame for evolution and differentiation. The famous iceman dug up from the permafrost in the Italian alps in 1991 has now had an autopsy. The DNA from a fragment of hip bone showed an unexpected finding: Borrelia burgdorferi. Likely, persisting DNA from cystic forms. Still, I am surprised not only that Bb was found, but that it was found in bone.
The Lyme epidemic is world wide and has been found in all the continents with the possible exception of Australia.
It is confusing that bacteria with names like: B. afzeli, B. bissette, B. miyamotoi all cause "Lyme disease."
The international organization with classifies bacteria calls all species of Borrelia which cause human Lyme-like disease, (12 or more species) "Borrelia burdorgferi sensu latu." These associated illnesses have varying degrees of similarity and dissimilarity to our Lyme disease. Some of these species have crossed borders into other regions.
The Lyme disease bacteria we usually think of(in the US)is called Borrelia burdorferi sensu strictu. Even within this narrower sub-species of the Lyme community the genetic diversity is mind boggling and mostly unknown.
A recent scientific publication from the American Journal of Pathology studied three sub-strains of a sub-strain of Bb sensu stricto and found one sub-sub type to be more pathogenic than the others two.
To illustrate how diverse the Lyme zoo is: The study examined the pathogenicity of three strains of Borrelia burdorferi sensu strictu, Osp C (type A) known as RTST 1,2 and 3.
The Lyme Osp C (outer surface protein) is associated with the 23 band on a Western Blot. Its molecular weight can actually vary from 20-25 Kds. The OsP C protein is quite variable. Twenty-one types have been identified. One of these Osp C types, type A, was subdivided in this study into three more sub-variations based on " ribosomic RNA intragenic spacers." One was nastier than the others.
In other words, there are a gabillion versions of Lyme, some making us sicker than others.
Treatment may be difficult because of this unknown variety of strains. It is well documented that a single host can be simultaneously infected with multiple strains.
Of note: Dr. Allen Steere is one of the authors of the above described study.
Many suffering with Lyme have heard from others: "I had Lyme: it was no big deal."
"He should only be in my body for one day!"
Maybe these unsympathetic individuals actually had a different version of the disease.
It turns out "Lyme" may a wide diversity of clinical presentations because patients are frequently infected with different strains of the organism.
Maybe we can begin to answer the question: why do some patients infected with Lyme with the tell tale EM rash never become sick without treatment, while others infected with Lyme disease treated early with recommended doses of antibiotics go on to develop full-blown chronic Lyme disease?
Research has shown that some strains of Borrelia burgdorgeri are more virulent, quickly causing dissemination into tissues, while others strains are relatively benign and may be associated with little or no disease. Borrelia bacteria show a surprising amount of genetic diversity.
Lyme bacteria have been here for thousands of years providing a long time frame for evolution and differentiation. The famous iceman dug up from the permafrost in the Italian alps in 1991 has now had an autopsy. The DNA from a fragment of hip bone showed an unexpected finding: Borrelia burgdorferi. Likely, persisting DNA from cystic forms. Still, I am surprised not only that Bb was found, but that it was found in bone.
The Lyme epidemic is world wide and has been found in all the continents with the possible exception of Australia.
It is confusing that bacteria with names like: B. afzeli, B. bissette, B. miyamotoi all cause "Lyme disease."
The international organization with classifies bacteria calls all species of Borrelia which cause human Lyme-like disease, (12 or more species) "Borrelia burdorgferi sensu latu." These associated illnesses have varying degrees of similarity and dissimilarity to our Lyme disease. Some of these species have crossed borders into other regions.
The Lyme disease bacteria we usually think of(in the US)is called Borrelia burdorferi sensu strictu. Even within this narrower sub-species of the Lyme community the genetic diversity is mind boggling and mostly unknown.
A recent scientific publication from the American Journal of Pathology studied three sub-strains of a sub-strain of Bb sensu stricto and found one sub-sub type to be more pathogenic than the others two.
To illustrate how diverse the Lyme zoo is: The study examined the pathogenicity of three strains of Borrelia burdorferi sensu strictu, Osp C (type A) known as RTST 1,2 and 3.
The Lyme Osp C (outer surface protein) is associated with the 23 band on a Western Blot. Its molecular weight can actually vary from 20-25 Kds. The OsP C protein is quite variable. Twenty-one types have been identified. One of these Osp C types, type A, was subdivided in this study into three more sub-variations based on " ribosomic RNA intragenic spacers." One was nastier than the others.
In other words, there are a gabillion versions of Lyme, some making us sicker than others.
Treatment may be difficult because of this unknown variety of strains. It is well documented that a single host can be simultaneously infected with multiple strains.
Of note: Dr. Allen Steere is one of the authors of the above described study.
Sunday, November 6, 2011
Lyme: the tissue pathogen
It has long perplexed me why Borrelia bacteria appear to be so abundant in the blood of other mammals but so sparse in human blood. An Ixodes tick, generally the poppy seed size nymph form has a blood meal, typically from a mouse, becoming infected with Lyme along with an assorted host of other co-infecting germs. Even though the tick takes many such meals - (how much blood can the tick eat)? - it would appear that spirochetes must exist in fairly high numbers in circulating blood in these other mammalian hosts.
In humans the paradigm/narrative states: the spirochetes stick to the extracellular matrix, become intracellular, convert to cyst forms, avoid immune defenses and antibiotics by avoiding blood and body fluids and finds safe harbor within biofilm communities.
"It is a tissue bacteria, not one to be found in the blood."
Now thinking about these statements they do seem wrong. Textbooks have instructed me the bacteria is spread via the blood stream. I conveniently discarded this explanation along other textbook things Lyme. But - Lyme bacteria cannot spread to many disparate tissues including the central nervous system unless carried by circulating blood. Of course I knew this. Right.
We have looked for the bacteria in blood of infected humans by PCR testing, a direct assay for detection of Lyme DNA. This is what has mislead me. The results have been almost always negative. Getting a positive PCR for Lyme has been like hitting the jackpot.
With improved culture techniques Lyme bacteria have now successfully been cultured from human blood consistently.
Culture is the absolute gold standard for proving the presence of the bacteria and chronic Lyme disease (not post Lyme syndrome).
Why the negative PCRs?. PCR technology uses primer pieces of DNA which target sub-regions of the organism's complete genome. These reactions are amplified and read by a machine. The primers target specific regions of DNA known to be conserved within different strains of the organism.
Sample size may be an issue. The PCR machine may be sampling a small amount of DNA taken from a small sample of blood. PCR testing may not be sensitive enough to detect the most minute traces of DNA. There are also various technical glitches which may occur with the technology.
With culture techniques a larger amount of blood/DNA may be tested. Perhaps this is why culturing has been more successful.
Bottom line: new staining and culturing techniques may be shattering another part of the paradigm. Lyme is not just a tissue pathogen in humans but can usually be found in blood if you just know how to look for it.
In humans the paradigm/narrative states: the spirochetes stick to the extracellular matrix, become intracellular, convert to cyst forms, avoid immune defenses and antibiotics by avoiding blood and body fluids and finds safe harbor within biofilm communities.
"It is a tissue bacteria, not one to be found in the blood."
Now thinking about these statements they do seem wrong. Textbooks have instructed me the bacteria is spread via the blood stream. I conveniently discarded this explanation along other textbook things Lyme. But - Lyme bacteria cannot spread to many disparate tissues including the central nervous system unless carried by circulating blood. Of course I knew this. Right.
We have looked for the bacteria in blood of infected humans by PCR testing, a direct assay for detection of Lyme DNA. This is what has mislead me. The results have been almost always negative. Getting a positive PCR for Lyme has been like hitting the jackpot.
With improved culture techniques Lyme bacteria have now successfully been cultured from human blood consistently.
Culture is the absolute gold standard for proving the presence of the bacteria and chronic Lyme disease (not post Lyme syndrome).
Why the negative PCRs?. PCR technology uses primer pieces of DNA which target sub-regions of the organism's complete genome. These reactions are amplified and read by a machine. The primers target specific regions of DNA known to be conserved within different strains of the organism.
Sample size may be an issue. The PCR machine may be sampling a small amount of DNA taken from a small sample of blood. PCR testing may not be sensitive enough to detect the most minute traces of DNA. There are also various technical glitches which may occur with the technology.
With culture techniques a larger amount of blood/DNA may be tested. Perhaps this is why culturing has been more successful.
Bottom line: new staining and culturing techniques may be shattering another part of the paradigm. Lyme is not just a tissue pathogen in humans but can usually be found in blood if you just know how to look for it.
Tuesday, October 4, 2011
More bands
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.
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, 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.
Saturday, April 30, 2011
Immune dysfunction and antibiotics
Clongen reports many unusual organisms seen swimming around in a drop of blood taken from many of the most ill, chronically afflicted patients. Why? I believe these patients are immunologically compromised. People of the ILADS/chronic Lyme disease community, have long claimed that Lyme disease infection (Borrelia spirochetes) is immunosupressive: this, it is argued, why co-infections, erstwhile opportunists, are able to easily grab a foothold. As one of my patients pointed out to me, there exists research showing a mechanism by which this might occur. Wooten and others have shown that Borrelia infection can lower a specific cytokine ( a mediator of normal immune function), IL 10. This weakens the ability of the immune system to fight or contain certain infections. If one microbe can do this, it is plausible that many others can do so as well, through various mechanisms. For example, XRMV, has been linked to Chronic Fatigue Syndrome. Not CFS. The proper nomenclature is CFIDS (Chronic Fatigue Immunodeficiency Syndrome) because the syndrome is believed to be associated with a yet understood, dysfunction within the immune system
The epidemic of CFS started suddenly in the mid 1980s. The Medical community at first thought it might be caused by Epstein Barr Virus, but ultimately decided the cause was unknown. The CDC was concerned about this new epidemic because they developed a case definition for the disorder, first in 1988, then revised in 1994.
Please visit the CDC website and print out their Case definition of CFS. Compare this to the ILADS published expanded definition of chronic Lyme disease. They match, nearly to a T.
Fibromyalgia arrived on the scene around the same time. For the longest time, most physicians refused to consider it a "real disease." Ultimately, The American Academy of Rheumatology published a case definition, in essence, pronouncing Fibromyalgia a genuine disease.
Fibromyalgia shares many features with chronic Lyme disease and CFS. Even the terminology sounds familiar. Instead of having Brain fog - Patients have "fibro-fog."
Let me turn the table a bit more. Pain - and I will introduce a new variable, Migraines: why does it hurt. Pain occurs when sensory fibers are stimulated, carrying a message to the brain/pain center causing the subjective feeling of pain.
Why Migraines? At first doctors thought it was a vascular disorder caused by constriction and dilation of blood vessels. Then, it was understood to be a brain disorder. Abnormal brain function can be imaged associated with migraines. Now - Botox injections can treat migraines. What is going on here?
Botox paralyzes nerves, relaxes muscles. This decompresses some nerves.
Inflamed, architecturally changed muscle tissue, impinges on nerves which too may be damaged and inflamed, perhaps exacerbated by autoimmune damage of tissues.
A lot of patients with migraines also have fibromyalgia, associated with tight muscles in the back of the neck. It is now understood that pressure applied to tiny nerve fibers, compressed by local abnormal muscles initiates the cascade. Messages are sent to the brain leading to abnormal brain function and then changes in blood vessels. The vessels constrict and then dilate, pressing on nerves. This is why migraines have a pounding quality. The vessels dilate more when the heart contracts. Fibro muscles irritate nerves but in a different way. The same can be said for Lyme patients.
Stardard medical thinking holds that painful conditions like fibro and irritable bowel syndrome are due to overly sensitive nerves. This thinking seems to have a psycho-somatic slant. These sorts of biases need to be replaced with a better understanding of the science and a respect for the suffering of the patients, rather than blaming the patient - as if in some way, the patient is responsible for the illness.
This thinking is fueled by observations that certain illnesses are more prevalent in women - the implication: women are prone to hysteria and psycho-somatic problems. In fact women have more robust immune responses than men and are twice as likely to experience autoimmune disease. This is where we need to look.
Let's go back to the first paragraph. Sick patient have germs in the blood; parasites bacteria, unknowns. The immune system is to some measure broken. These germs should be contained in a box, somewhere else, by a competent immune system.
Perhaps an initial infection: Lyme, Mycoplasm or something else, initiates the process seen in our: chronic Lyme, CFS, fibro, chronic pain syndromes, migraine, IBS, chronic pelvic pain, IC and other patients. The smart, offending germs are in some way programmed to disrupt normal immunological functions(as is known to be the case with Borrelia) causing a wide range of downstream sequelae.
Some antidepressants, Cymbalta, Elavil disrupt the neuronal messages sent to the pain center, or in some way alter the perception of pain in the brain. The same is true for anticonvulsants like Neurontin, Lyrica. They may help some. But they do not get at the root of the cause.
Sometimes - antimicrobials, of various sorts, (from doxycycline to Tindamax to Malarone) work much better for these patients.
Immune compromise, mediated by one infection ( not to discount the role of genetics, stress and other factors) can "activate" heretofore quiescent germs. This explains why patients relapsing with Lyme often experience a rip-roaring relapse of a previously controlled co-infections, like Babesia.
The process may be associated with multiple breakdowns of normal imune function. For example: cytokines become dysregulated, T cell and B cells malfunction, autoantibodies are made. Autoantibodies, the cause of autoimmune disorders, play a huge role in the disease complex.
Bottom line: sometimes it is best not to worry what it is: are bands present or not? Is it fibro or CFS. Not to say you should stop trying to figuring it out.
It comes down to this: either the illness responds to anti-microbial agent or it doesn't.
This begs the question: which antibiotics/anti-malarials or anti-parastic agents. If you don't pick the right ones you won't know if the illness is anti-microbial responsive.
That's the tricky part. That's what you pay us to figure out.
The epidemic of CFS started suddenly in the mid 1980s. The Medical community at first thought it might be caused by Epstein Barr Virus, but ultimately decided the cause was unknown. The CDC was concerned about this new epidemic because they developed a case definition for the disorder, first in 1988, then revised in 1994.
Please visit the CDC website and print out their Case definition of CFS. Compare this to the ILADS published expanded definition of chronic Lyme disease. They match, nearly to a T.
Fibromyalgia arrived on the scene around the same time. For the longest time, most physicians refused to consider it a "real disease." Ultimately, The American Academy of Rheumatology published a case definition, in essence, pronouncing Fibromyalgia a genuine disease.
Fibromyalgia shares many features with chronic Lyme disease and CFS. Even the terminology sounds familiar. Instead of having Brain fog - Patients have "fibro-fog."
Let me turn the table a bit more. Pain - and I will introduce a new variable, Migraines: why does it hurt. Pain occurs when sensory fibers are stimulated, carrying a message to the brain/pain center causing the subjective feeling of pain.
Why Migraines? At first doctors thought it was a vascular disorder caused by constriction and dilation of blood vessels. Then, it was understood to be a brain disorder. Abnormal brain function can be imaged associated with migraines. Now - Botox injections can treat migraines. What is going on here?
Botox paralyzes nerves, relaxes muscles. This decompresses some nerves.
Inflamed, architecturally changed muscle tissue, impinges on nerves which too may be damaged and inflamed, perhaps exacerbated by autoimmune damage of tissues.
A lot of patients with migraines also have fibromyalgia, associated with tight muscles in the back of the neck. It is now understood that pressure applied to tiny nerve fibers, compressed by local abnormal muscles initiates the cascade. Messages are sent to the brain leading to abnormal brain function and then changes in blood vessels. The vessels constrict and then dilate, pressing on nerves. This is why migraines have a pounding quality. The vessels dilate more when the heart contracts. Fibro muscles irritate nerves but in a different way. The same can be said for Lyme patients.
Stardard medical thinking holds that painful conditions like fibro and irritable bowel syndrome are due to overly sensitive nerves. This thinking seems to have a psycho-somatic slant. These sorts of biases need to be replaced with a better understanding of the science and a respect for the suffering of the patients, rather than blaming the patient - as if in some way, the patient is responsible for the illness.
This thinking is fueled by observations that certain illnesses are more prevalent in women - the implication: women are prone to hysteria and psycho-somatic problems. In fact women have more robust immune responses than men and are twice as likely to experience autoimmune disease. This is where we need to look.
Let's go back to the first paragraph. Sick patient have germs in the blood; parasites bacteria, unknowns. The immune system is to some measure broken. These germs should be contained in a box, somewhere else, by a competent immune system.
Perhaps an initial infection: Lyme, Mycoplasm or something else, initiates the process seen in our: chronic Lyme, CFS, fibro, chronic pain syndromes, migraine, IBS, chronic pelvic pain, IC and other patients. The smart, offending germs are in some way programmed to disrupt normal immunological functions(as is known to be the case with Borrelia) causing a wide range of downstream sequelae.
Some antidepressants, Cymbalta, Elavil disrupt the neuronal messages sent to the pain center, or in some way alter the perception of pain in the brain. The same is true for anticonvulsants like Neurontin, Lyrica. They may help some. But they do not get at the root of the cause.
Sometimes - antimicrobials, of various sorts, (from doxycycline to Tindamax to Malarone) work much better for these patients.
Immune compromise, mediated by one infection ( not to discount the role of genetics, stress and other factors) can "activate" heretofore quiescent germs. This explains why patients relapsing with Lyme often experience a rip-roaring relapse of a previously controlled co-infections, like Babesia.
The process may be associated with multiple breakdowns of normal imune function. For example: cytokines become dysregulated, T cell and B cells malfunction, autoantibodies are made. Autoantibodies, the cause of autoimmune disorders, play a huge role in the disease complex.
Bottom line: sometimes it is best not to worry what it is: are bands present or not? Is it fibro or CFS. Not to say you should stop trying to figuring it out.
It comes down to this: either the illness responds to anti-microbial agent or it doesn't.
This begs the question: which antibiotics/anti-malarials or anti-parastic agents. If you don't pick the right ones you won't know if the illness is anti-microbial responsive.
That's the tricky part. That's what you pay us to figure out.