2 2009 Final Report's Proposed Changes to IDSA Lyme Disease Guidelines

I decided to take a break from discussing The Lancet antiscience letter and highlight a few items of note about proposed upcoming changes to the Infectious Disease Society of America's 2006 guidelines for the treatment of Lyme disease.

Below is a list of some Lyme disease guideline items and recommendations for their revision taken from the 2009 Final Report [.pdf] that the Infectious Disease Society of America (IDSA) review panel wrote in response to Senator Blumenthal's antitrust investigation of the IDSA a few years ago.

In this report, an independent review panel came to the conclusion that several changes needed to be made to the 2006 guidelines which would be included in the next version of the guidelines (which has yet to be published).

I have provided a table from the original final report which outlines what the quality of the evidence is which supports each recommendation and the strength of each recommendation, based on the IDSA review panel's judgment.

Following that table, I have provided a more detailed table which takes portions of the original 2006 Lyme disease diagnosis and treatment guidelines (which are more or less identical to the IDSA's 2000 treatment guidelines for Lyme disease with few exceptions) alongside the recommendations of the 2009 panel for the next version of the IDSA guidelines.

I provide this information, along with a few questions for readers:

1. The state of the science in Lyme disease has been moving along at a fair clip, and with more cases, more doctors are also getting a fair amount of clinical experience in treating Lyme disease (as well as other tickborne infections which are on the rise). Why is it that now, in 2013, doctors are referring to guidelines based on data from 2000 and not recommendations made from 2009? Is it the view of most doctors that they won't change their practice concerning Lyme disease until the IDSA's official guidelines are updated to include the changes in this 2009 report? Why wait?
   
   
2. A number of proposed changes which the panel highlighted - such as measuring elevated liver enzymes and looking for signs of disseminated disease - are old news to patients who were treated by LLMDs during the past decade. If LLMDs found these tests and diagnoses of value in helping patients earlier, couldn't their clinical experience have been incorporated into changes to guidelines sooner? Or, is the case that because there are some LLMDs who are viewed with suspicion by mainstream medical professionals that all of their experience is of no value and cannot be validated - therefore their clinical approach would not be considered in new guidelines? Or, is it the case that LLMDs were doing something some infectious disease doctors already had been doing - but none of their clinical ideas were being integrated into new guidelines anyway? What happened?
   
   
3. If one were to write out a table such as the one below with the strength of the recommendation and quality of evidence for each of the ILADS'guidelines, how would they compare to the revised guidelines with the included changes below?
   
   

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Table 1 - Infectious Diseases Society of America-US Public Health Service Grading System for ranking recommendations in clinical guidelines:

Category, grade
Strength of Recommendation:

A - Strongly in favor
B - Moderately in favor
C - Optional
D - Moderately against
E - Strongly against

Ranking of Quality of the Evidence:

I - Evidence from >1 properly randomized, controlled trial
II - Evidence from >1 well-designed clinical trial, without randomization; from cohort or case-controlled analytic studies (preferably from >1 center); from multiple time series studies; or from dramatic results from uncontrolled experiments
III - Evidence from opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

Please take note of the category AND quality of the evidence ranking for each item below. In particular, note items marked with a Level III evidence ranking, and those of Level I ranking which were considered by panel members to be too high.

Table 2 - Old 2006 Guidelines Versus Recommended Changes For New Guidelines:

Item - Tick Bite Prophylaxis Judgment	Recommendation
(p. 6) A single dose of doxycycline may be offered to adult patients (200 mg dose) and to children >8 years of age (4 mg/kg up to a maximum dose of 200 mg) (B-I) when all of the following circumstances exist: (a) the attached tick can be reliably identified as an adult or nymphal I. scapularis tick that is estimated to have been attached for >36 h on the basis of the degree of engorgement of the tick with blood or of certainty about the time of exposure to the tick; (b) prophylaxis can be started within 72 h of the time that the tick was removed; (c) ecologic information indicates that the local rate of infection of these ticks with B. burgdorferi is >20%; and (d) doxycycline treatment is not contraindicated. The time limit of 72 h is suggested because of the absence of data on the efficacy of chemoprophylaxis for tick bites following tick removal after longer time intervals. Infection of  >20% of ticks with B. burgdorferi generally occurs in parts of New England, in parts of the mid-Atlantic States, and in parts of Minnesota and Wisconsin, but not in most other locations in the United States. Whether use of antibiotic prophylaxis after a tick bite will reduce the incidence of HGA or babesiosis is unknown.	When the 2006 Lyme Guidelines are next updated, the Review Panel recommends the careful consideration of the grading for quality of evidence. One panel member thought the quality of evidence assigned to the recommendation (I) might be too high.
Item - Doxycycline Use, Pregnant Women and Young Children	Recommendation
(p. 7) Doxycycline is relatively contraindicated in pregnant women and children less than 8 years old. The panel does not believe that amoxicillin should be substituted for doxycycline in persons for whom doxycycline prophylaxis is contraindicated because of the absence of data on an effective short-course regimen for prophylaxis, the likely need for a multiday regimen (and its associated adverse effects), the excellent efficacy of antibiotic treatment of Lyme disease if infection were to develop, and the extremely low risk that a person with a recognized bite will develop a serious complication of Lyme disease (D-III).	When the 2006 Lyme Guidelines are next updated, the Review Panel recommends removal of the modifiers “relatively” contraindicated and “excellent” efficacy.
Item - Need For Doctors To Identify Tick & Engorgement Degree	Recommendation
(p. 7) To prescribe antibiotic prophylaxis selectively to prevent Lyme disease, health care practitioners in areas of endemicity should learn to identify I. scapularis ticks, including its stages (figure 1), and to differentiate ticks that are at least partially engorged with blood (figure 2A and 2B) (A-III).	When the 2006 Lyme Guidelines are next updated, the Review Panel recommends the careful consideration of the strength of recommendation. Although a subjective measure, two Review Panel members thought that the strength assigned to this recommendation (A) might be too high.
Item - Specifics On Monitoring Tickborne Coinfections & Disseminated Lyme Disease	Recommendation
(p. 8) Health care practitioners, particularly those in areas of endemicity, should become familiar with the clinical manifestations and recommended practices for diagnosing and treating Lyme disease, HGA, and babesiosis (A-III). Persons who have removed attached ticks from themselves (including those who have received antibiotic prophylaxis) should be monitored closely for signs and symptoms of tickborne diseases for up to 30 days; in particular, they should be monitored for the development of an expanding skin lesion at the site of the tick bite (erythema migrans) that may suggest Lyme disease. Persons who develop a skin lesion or viral infection–like illness within 1 month after removing an attached tick should promptly seek medical attention to assess the possibility of having acquired a tickborne infection.	The Review Panel determined that this recommendation is medically/scientifically justified in light of all of the evidence and information provided (8-0). When the 2006 Lyme Guidelines are next updated, the Review Panel recommends that consideration be given to specifying what constitutes “monitoring” and to providing anticipatory guidance for patients about possible manifestations of disseminated Lyme disease (e.g., arthritis, meningitis).
Item - Treatment of Early Lyme Disease	Recommendation
(p. 9) Doxycycline (100 mg twice per day), amoxicillin (500 mg 3 times per day), or cefuroxime axetil (500 mg twice per day) for 14 days (range, 10–21 days for doxycycline and 14–21 days for amoxicillin or cefuroxime axetil) is recommended for the treatment of adult patients with early localized or early disseminated Lyme disease associated with erythema migrans, in the absence of specific neurologic manifestations (see Lyme meningitis, below) or advanced atrioventricular heart block (A-I). Ten days of therapy is sufficient if doxycycline is used; however, given the much shorter half-life of ß-lactam drugs, such as amoxicillin or cefuroxime axetil, it is unclear whether a 10-day course of these drugs would be as effective. Therefore, for uniformity, a 14-day course of therapy is recommended for all of the first-line oral agents. Each of these antimicrobial agents has been shown to be highly effective for the treatment of erythema migrans and associated symptoms in prospective studies. Doxycycline has the advantage of being effective for treatment of HGA (but not for babesiosis), which may occur simultaneously with early Lyme disease. Doxycycline is relatively contraindicated during pregnancy or lactation and in children less than 8 years of age.	When the 2006 Lyme Guidelines are next updated, the Review Panel suggests removal of the modifiers “highly” and “relatively.”
Item - Choice of Treatment Modality	Recommendation
(p. 10) Because of a lack of biologic plausibility, lack of efficacy, absence of supporting data, or the potential for harm to the patient, the following are not recommended for treatment of patients with any manifestation of Lyme disease: first-generation cephalosporins, fluoroquinolones, carbapenems, vancomycin, metronidazole, tinidazole, amantadine, ketolides, isoniazid, trimethoprim- sulfamethoxazole, fluconazole, benzathine penicillin G, combinations of antimicrobials, pulsed- dosing (i.e., dosing on some days but not others), long-term antibiotic therapy, anti-Bartonella therapies, hyperbaric oxygen, ozone, fever therapy, intravenous immunoglobulin, cholestyramine, intravenous hydrogen peroxide, specific nutritional supplements, and others (see table 4) (E-III).	When the 2006 Lyme Guidelines are next updated, the Review Panel suggests that “lack of biological plausibility, lack of efficacy” be replaced with “lack of demonstrated efficacy in controlled studies.” There are data demonstrating that the following are ineffective in the treatment of Lyme disease: first-generation cephalosporins, fluoroquinolones, carbapenems, vancomycin, metronidazole, tinidazole, ketolides, isoniazid, trimethoprim-sulfamethoxazole, fluconazole, benzathine penicillin G and combinations of antimicrobials. There are also data demonstrating that the following are potentially harmful: combinations of antimicrobials, pulsed-dosing (i.e., dosing on some days but not others), and long-term antibiotic therapy (e.g., more than 4 weeks). There is a paucity of data regarding the safety and effectiveness of the use of the following in the treatments for Lyme disease: hyperbaric oxygen, ozone, fever therapy, intravenous immunoglobulin, cholestyramine, intravenous hydrogen peroxide, and specific nutritional supplements, but some of these are likely to be harmful to the patient. Many of these examples, such as fever therapy and hydrogen peroxide, carry considerable risk of harm to the patient.
Item - Diagnosing Tickborne Coinfections	Recommendation
Coinfection with B. microti or A. phagocytophilum or both may occur in patients with early Lyme disease (usually in patients with erythema migrans) in geographic areas where these pathogens are endemic. Coinfection should be considered in patients who present with more- severe initial symptoms than are commonly observed with Lyme disease alone, especially in those who have high-grade fever for >48 h, despite receiving antibiotic therapy appropriate for Lyme disease, or who have unexplained leukopenia, thrombocytopenia, or anemia (A-III).	When the 2006 Lyme Guidelines are next updated, the Review Panel recommends that abnormal hepatic transaminases (AST and ALT), lactate dehydrogenase, or bilirubin should also prompt evaluation for coinfection with B. microti or A. phagocytophilum.
(p. 11) Coinfection might also be considered in the situation in which there has been resolution of the erythema migrans skin lesion, but either no improvement or worsening of viral infection like symptoms (B-III).	When the 2006 Lyme Guidelines are next updated, the Review Panel recommends that consideration be given to changing “might” to “should.”
Item - Early Acute Neuroborreliosis Treatment	Recommendation
For adult patients with early Lyme disease and the acute neurologic manifestations of meningitis or radiculopathy, the use of ceftriaxone (2 g once per day intravenously for 14 days; range, 10–28 days) in early Lyme disease is recommended for adult patients with acute neurologic disease manifested by meningitis or radiculopathy (B-I).	When the 2006 Lyme Guidelines are next updated, the Review Panel recommends that consideration be given to the emerging data supporting the use of oral doxycyline as first line therapy in selected patients with neurologic manifestations of Lyme disease, such as those with hypersensitivity to beta lactam antibiotics.
Item - Lyme Arthritis Without Neurological Disease	Recommendation
(p. 14) Lyme arthritis can usually be treated successfully with antimicrobial agents administered orally. Doxycycline (100 mg twice per day) (B-I), amoxicillin (500 mg 3 times per day) (B-I), or cefuroxime axetil (500 mg twice per day) (B-III) for 28 days is recommended for adult patients without clinical evidence of neurologic disease.	When the 2006 Lyme Guidelines are next updated, the Review Panel suggests that careful consideration be given to the current quality of evidence for amoxicillin. Two Review Panel members thought that the quality of evidence assigned to doxycycline in this recommendation (I) might be too high based on the available evidence.
Item - Lyme Arthritis in Children	Recommendation
For children amoxicillin (50 mg/kg per day in 3 divided doses [maximum of 500 mg per dose]) (B-I), cefuroxime axetil (30 mg/kg per day in 2 divided doses [maximum of 500 mg per dose]) (B-III), or, if the patient is >8 years of age, doxycycline (4 mg/kg per day in 2 divided doses [maximum of 100 mg per dose]) (B-I) is recommended. Oral antibiotics are easier to administer than intravenous antibiotics, are associated with fewer serious complications, and are considerably less expensive. However, it is important to recognize that a small number of patients treated with oral agents have subsequently manifested overt neuroborreliosis, which may require intravenous therapy with a ß-lactam antibiotic for successful resolution. Further controlled trials are needed to compare the safety and efficacy of oral versus intravenous therapy for Lyme arthritis.	When the 2006 Lyme Guidelines are next updated, the Review Panel suggests that careful consideration be given to the current quality of evidence for amoxicillin. Two Review Panel members thought that the quality of evidence assigned to this recommendation (I) might be too high based on the available evidence.
Item - Diagnosis and Treatment of Neurological Disease	Recommendation
Neurologic evaluation that may include lumbar puncture should be performed for patients in whom there is a clinical suspicion of neurologic involvement. Adult patients with arthritis and objective evidence of neurologic disease should receive: parenteral therapy with ceftriaxone (A-II) for 2-4 weeks. Cefotaxime or penicillin G administered parenterally is an acceptable alternative (B-II).	When the 2006 Lyme Guidelines are next updated, the Review Panel suggests consideration of specifying neurological issues that should be included/excluded. In addition, the Review Panel suggests that “evidence of neurologic disease” be defined and that the adjective “objective” be deleted. Clarifying the language to indicate that penicillin is inferior to cefotaxime in this clinical setting should also be considered when the guideline is next updated.
For children intravenous ceftriaxone or intravenous cefotaxime is recommended (B-III); penicillin G administered intravenously is an alternative (B-III).	When the 2006 Lyme Guidelines are next updated, the Review Panel suggests that consideration be given to clarifying the language to indicate that penicillin is inferior to cefotaxime.
Adult patients with late neurologic disease affecting the central or peripheral nervous system should be treated with intravenous ceftriaxone for 2 to 4 weeks (B-II). Cefotaxime or penicillin G administered intravenously is an alternative (B-II). Response to treatment is usually slow and may be incomplete. Re-treatment is not recommended unless relapse is shown by reliable objective measures.	When the 2006 Lyme Guidelines are next updated, the Review Panel suggests that consideration be given to adding a rating for strength of recommendation and level of evidence to the last part of this recommendation. Consideration should also be given to providing examples of reliable “objective measures.”
Item - Post (-Treatment) Lyme Disease Syndrome	Recommendation
There is no well-accepted definition of post–Lyme disease syndrome. This has contributed to confusion and controversy and to a lack of firm data on its incidence, prevalence, and pathogenesis. In an attempt to provide a framework for future research on this subject and to reduce diagnostic ambiguity in study populations, a definition for post–Lyme disease syndrome is proposed in these guidelines. Whatever definition is eventually adopted, having once had objective evidence of B. burgdorferi infection must be a condition sine qua non. Furthermore, when laboratory testing is done to support the original diagnosis of Lyme disease, it is essential that it be performed by well-qualified and reputable laboratories that use recommended and appropriately validated testing methods and interpretive criteria. Unvalidated test methods (such as urine antigen tests or blood microscopy for Borrelia species) should not be used.	When the 2006 Lyme Guidelines are next updated, the Review Panel suggests that the sentence that begins with “Whatever definition” be modified as follows: “Whatever definition is eventually adopted, having once had objective clinical or laboratory evidence of B. burgdorferi infection must be a condition sine qua non until a syndrome is formally defined.”
To date, there is no convincing biologic evidence for the existence of symptomatic chronic B. burgdorferi infection among patients after receipt of recommended treatment regimens for Lyme disease.	When the 2006 Lyme Guidelines are next updated, the Review Panel suggests that consideration be given to changing the phrase “no convincing biologic evidence” to something more specific, such as “Reports purporting to show the persistence of viable B. burgdorferi organisms after treatment with recommended regimens for Lyme disease have not been conclusive or corroborated by controlled studies.” It has been proposed by some that there are hardy, drug-tolerant reservoirs of B. burgdorferi, including intracellular cystic forms. To date, this has not been shown to correlate with symptom persistence, nor has eradication of these forms been shown to correlate with symptom improvement.
Antibiotic therapy has not proven to be useful and is not recommended for patients with chronic (>6 months) subjective symptoms after recommended treatment regimens for Lyme disease (E-I).	Panel determination summary: [...] in the case of Lyme disease, there has yet to be a single high quality clinical study that demonstrates comparable benefit to prolonging antibiotic therapy beyond one month. Therefore, the Review Panel concluded that in the case of Lyme disease inherent risks of long-term antibiotic therapy were not justified by clinical benefit. [...] This conclusion was reached despite the large volume of case reports, case series, anecdotes, and patient testimonials reviewed that attested to perceived clinical improvement during antibiotic therapy. In the end, such sources of evidence were felt to be fertile material for hypothesis- generation, but intrinsically incapable of hypothesis-testing. By contrast, the prospective, randomized, controlled trials were formal hypothesis tests with strict recruitment criteria, prospectively defined outcome measures, and independent oversight. The Panel’s conclusions, which are consistent with those reached by guidelines panels from the IDSA as well as other societies, represent the state of medical science at the time of writing. Only high-quality, prospective, controlled clinical trial data demonstrating both benefit and safety will be sufficient to change the current recommendations.

These proposed changes to some of the guidelines look like a case of updating them to reflect a reality those of us who have been ill already knew years ago based on testing and experience. In particular:

• It appears antibiotics used to treat Lyme disease in its early acute stage are not as effective as they were originally thought to be. 
• It appears that objective evidence of neurological involvement isn't the only reason to consider more intense antibiotic treatment - subjective neurological symptoms may be considered, too - provided they are well-characterized and defined.
• Abnormal liver panels can be used to indicate the presence of coinfections.
• Coinfections should always be considered when symptoms are severe and/or persist after initial antibiotic treatment for Lyme disease.
• A single 200 mg dose of doxycycline as prophylaxis may not have the originally stated quality of evidence to back its use. 

The IDSA has stated repeatedly that its current 2006 guidelines are evidence-based and are the best science has to offer. But it seems that the current guidelines are already outdated and have been, and do not reflect the state of the science nor clinical experience. They need to be updated, even within the most conservative perspective of how Lyme disease should be viewed and treated.

It should be noted that in a number of cases, items with Level I evidence ratings were considered to be rated too high according to some members of the review panel.

One thing I question is what the state of the science is and level of transparency on any recommendation which is labeled with an evidence level of "III". Those who wrote the guidelines used their expertise and unpublished information to determine that recommendation, with no external validation as to which data they relied upon and how they drew their conclusions about that recommendation based on that data. Level III recommendations are about opinion - not double blind, random controlled trials or observational studies on patients, which are a higher level of evidence.

If anyone is an investigative reporter or researcher on Lyme disease - let alone a patient suffering from it - wouldn't you like to know more about how the experts came to their conclusions about such recommendations in the first place?

While the debate rages on about chronic Lyme disease or Post-treatment Lyme Disease Syndrome, and the reviewers of these guidelines stated that there isn't evidence to support the use of long term antibiotics for patients with persisting symptoms - the reviewers do not offer any alternative treatment methods or recommendations, either. This is a long outstanding issue which strongly needs to be addressed.

Either doctors who are using long term treatments and having success with their patients will be asked to produce evidence of that success outside of testimonials and case studies - or longer clinical trials using antibiotic regimens other than those already used in double blind clinical trials will need to be conducted.

But even before one gets there, one has to ask this question: How adequately have early stage Lyme disease cases been treated based on some of the above proposed changes to the guidelines? 

And whether patients agree or not with the proposed changes to guideline recommendations, why is anyone still waiting for these proposed changes to be included and published 3 YEARS after the 2009 report?

Has any research been completed in the past 3 years which challenges the content in these guidelines?

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0 Mitt Romney, Lyme Disease, And The Media

Well, I guess I had to come out of the woodwork to comment on this recent turn of events... If life wasn't so hectic lately, I could have blogged sooner, and written about David Suzuki's observations on how changes in the environment have led to increased incidence of Lyme disease, or Senator Blumenthal's request for personal stories of patients who have been affected by Lyme disease, or the discovery of a new, serious  tickborne phlebovirus in Missouri.

But no, that didn't happen...

The first opportunity I really have to sit down and write here, the news that is crossing my desk and getting a lot of airtime is about Presidential candidate Mitt Romney and the media's commentary on how his support for greater awareness of chronic Lyme disease has been used to ignite interest in Virginia voters who have been struggling with the disease.

And the media has not stopped there, with its opinion pieces focused on how any candidate for office can and will try to influence the vote of certain subgroups of people affected by issue x or issue y... No, after initial criticism was volleyed at Romney, a number of journalists posted articles on chronic Lyme disease and how it is not a real medical condition.

Well, here we go again. It is the same story told by some newspapers and writers, over and over again, about how chronic Lyme disease doesn't exist and how doctors who treat it are taking unfair advantage of patients who are suffering and how patients are naive dupes for a disease based on pseudoscience.

I honestly think at this point that many of you who are writing these pieces for publication have a template for about five boilerplate articles on chronic Lyme disease that you have slight variations on, and publish each article just far apart from each other that the busy, overworked, and exhausted public won't notice that you essentially wrote the same damn thing again - but perhaps with a little twist.

When I first began this blog, it was because of an article written in the Chicago Tribune which was supposed to be about how chronic Lyme disease is a dubious diagnosis - when the content of the article itself had no relationship to the title, and did not examine the issue of whether or not Borrelia burgdorferi - the bacteria which causes Lyme disease - could potentially cause a persistent infection in some people.

What the article in the Chicago Tribune did was look at two doctors who were said to have treated chronic Lyme disease who were reported for disciplinary action to their medical boards for various reasons unrelated to Lyme disease and one charlatan who - like many who promise to offer a cure for cancer - has no cure and no credentials whatsoever.

What a brave and insightful piece of literature it was, to move beyond the carefully crafted soundbites of a puffed-up opinion piece, by closely examining all the issues behind why some doctors, researchers, and patients may think that Lyme disease could persist - and why and why that isn't supported by existing evidence.

Not.

The article did not in any way, shape, or form discuss the scientific complexity involved in Borrelia infections, and the difficulty that doctors can have in properly diagnosing it as its symptoms mimic other conditions. It did not look at the state of the science on Borrelia burgdorferi sensu latu, and how a broad range of strains have different effects and disseminate at different rates.

Anyone reading it would have walked away not with the message that Lyme disease and other tickborne infections can produce a complex symptom presentation. Anyone reading it would not have learned how to prevent such illnesses or to even learn if there are differential diagnoses which one should look at which may be confused with chronic Lyme disease. It wasn't a helpful article that way. What they would have walked away with is the message that there are some doctors out there who have been disciplined for various reasons who happen to treat people with persisting symptoms related to Lyme disease, and some misinformation online about what Lyme disease is and is not.

The recent spate of articles which spend time criticizing Mitt Romney's move to spread awareness of Lyme disease as part of his future goals if elected have also had pretty much the same kind of content, and as opinion pieces are intended to persuade the audience and win them over to the writer's view. However, it should be noted that in no way should these opinion pieces be taken as the final word or even current word in science on what Lyme disease is all about - because as opinion pieces, they are neglecting mention of the scientific evidence needed to support their assertions.

The New Yorker's  recent article, "Mitt Romney Versus Lyme Disease And Science", states that:

"...If left untreated, Lyme disease can be crippling, yet it is a difficult illness to contract: a tick needs to attach itself to your body for at least twenty-four hours. Even then, two weeks worth of commonly prescribed antibiotics will kill the bacterium."

Yes, indeed, if left untreated Lyme disease can be crippling. This much is true: late stage, untreated Lyme disease can lead to cardiac, neurological, and arthritic complications. However, there is more to the rest of the story when it comes to the remainder of this passage: If a tick is on your body for fewer than twenty-four hours, there are circumstances under which transmission of Lyme disease (as well as other tickborne infections) may occur - including if the tick is improperly removed. Also, even the most conservative reading of the IDSA's 2006 guidelines for the treatment of Lyme disease would state that given certain objective and clinical signs, some patients may need retreatment or more than two weeks' worth of antibiotics - particularly if there are certain cardiac, neurological, and arthritic symptoms present.

The New Yorker article simplifies the nature of Lyme disease and makes sweeping statements here. What it could have said - and still be true to mainstream infectious disease canon - could have been this:

"...If left untreated, Lyme disease can be crippling. In American scientific research to date, it has been shown that in most cases, an Ixodes scapularis or pacificus tick needs to attach itself to your body for at least twenty-four hours before Lyme disease can be contracted. Improper tick removal and other factors may, however, contribute to earlier contraction of disease. One might note that there is some evidence that in Europe, Ixodes ricinus ticks have a shorter transmission time for passing on Lyme disease bacteria than American ticks. But even then, in acute cases, the immediate treatment of two weeks' worth of commonly prescribed antibiotics will kill the bacterium in most cases. If symptoms continue, further evaluation for more severe infection and tickborne coinfections is needed."

I think some more qualifiers are needed there. And I know - this is, perhaps, a less targeted passage in that it steps outside of American research and points at what's happening in Europe. But the point is, Lyme disease is a global issue and a global problem, due to global warming and climate change. It's not just Virginia's. Or even the eastern seaboard's problem.

People travel. People get sick overseas. Lyme disease is overseas. And perhaps it helps to raise the question of how much scientific research on Borrelia may be applicable in different locations the more that is learned about the bacteria as a whole... More research here is really the key to better understanding this bug.

I will, however, give The New Yorker's Michael Specter credit for this mention:

"In fact, there is a clear scientific issue that can only make Lyme disease worse—but it is a problem that Romney and the Republicans have ignored. The Intergovernmental Panel on Climate Change has noted that increasing temperature helps keep ticks alive. More ticks means more Lyme disease. This is a connection, as Mother Jones first noted, that Romney has failed to consider. Instead, he has said that spending huge sums trying to reduce CO2 emissions is “not the right course for us."

Climate change is a huge player in the tickborne illness game, and I don't need Al Gore or the IPCC or even David Suzuki to point this out for me. Look outside every year, and tell me what I don't see with my own eyes: The ticks are out there earlier, and out there for longer periods of time than they've been in the past. Ask the epidemiologists and entomologists, too, if you need confirmation... Sure populations will wax and wane to a degree - but what's the trend over time?

The Business Insider's article, "Why Romney's Statements About Chronic Lyme Disease Are Dangerous", does tend to give the topic a somewhat more balanced approach by acknowledging that there is a debate within the medical and scientific community by stating, "Many doctors and researchers don't believe in this syndrome, which lasts much longer than your run-of-the-mill Lyme disease infection. The CDC, NIAID, and leading medical professionals agree that the syndrome doesn't exist. There are others within the scientific community, and especially outside of it, that debate these experts."

This, at least, is an opening gambit which sets the tone for the rest of the article by acknowledging there is a debate - with the primary focus being that politicians such as Mitt Romney should steer clear of medical debates and leave such debates to science, where they belong. Politicians are not qualified to participate in such debates.

One notable passage for me was this one:

"The symptoms of chronic Lyme disease could also be caused by an auto-immune reaction to the infection, or lasting damage from the bacterial invasion. Either way, these symptoms aren't helped by additional long-term antibiotic treatment, which has side effects and dangers of its own."

This is perhaps the first and only statement in the entire article which focuses on what some potential causes are of chronic Lyme disease, giving it some acknowledgement that yes, in fact, this condition does exist - even if its cause has been greatly debated. But there are no citations and there is no supporting evidence given to back this passage - nor a good percentage of other statements made in the article. There is no mention, either, of Dr. Monica Embers' "Persistence of Borrelia burgdorferi in Rhesus Macaques" study or other research which present the possibility that Borrelia burgdorferi might persist after antibiotic treatment.

In Slate magazine, Laura Helmuth reports this personal story:

"A friend of one of my brothers had been suffering for years from headaches, fatigue, a sense of despair, a belief that she wasn’t worthy of her job or her boyfriend. She was diagnosed with chronic Lyme disease and was treated with antibiotics, which were ineffective. What she wasn’t treated for, and could have been, was severe depression. She killed herself."

While I am very saddened to hear of this woman's death, there isn't enough information here to know exactly what happened. She may have had severe depression, she may have had Lyme disease, and/or she may have had a completely different medical issue. I simply don't know - there's no way to verify this story - it is also possible the woman in question had both Lyme disease and depression, because it happens to a number of people. It happened to me, too... I was in so much pain in the past, I was begging for God to take me.

If you are depressed, I hope you will seek treatment for it, and see a qualified licensed therapist for help. But it has been said by many in the medical profession to seek alternative causes for depression and fatigue, as hypothyroidism and other conditions may give rise to these symptoms. There can be underlying medical reasons for one's depression, and it may be that antidepressants are not the primary tool for healing.

In any piece of writing, it is important to consider the following questions:

• What is the expertise and education of the person writing?
• What is the agenda of the writer? Are they trying to promote an idea, sell a product, evoke a strong emotional response to gain readership, present different sides of a contested issue, or educate the public on an important matter?
• What is the outcome that can be achieved by publishing this specific piece in this particular publication?
• What references and citations has the writer given to support their assertions and statements?
• Does a thorough survey of the information provided and research completed from different sources provide evidence which support the writer's position? 
• Is there information and research which supports an alternative position? What is the strength of the evidence supporting these positions?

I encourage anyone reading these articles about Mitt Romney and chronic Lyme disease to ask themselves the same questions above, and to do your own research on whether or not Lyme disease can lead to persisting symptoms after initial (especially delayed) treatment with antibiotics.

The entire Internet is out there at your disposal to use, and scientific journals, books, PubMed, and other reliable sources from which to get your information on Lyme disease - all free of spin.

Of course, you yourself will end up walking away from all the research required to even begin to understand Borrelia burgdorferi with your own personal spin - but at least you will know more than you can learn from reading a random article which gets published in an online newspaper or magazine.

And write to researchers if you want to better understand their research. It's the honest way to understand what their position is on their own work, rather than assume their position based on others' interpretations of their work. They will likely be touched that you made the effort to ask questions than assume someone else's interpretation (which may or may not be correct), and be pleased that you took the attitude that no question is a stupid question.

As for your vote: vote with your conscience. I can't tell anyone how to vote and it's not my job to tell you how to vote. I can only tell you that after seeing George W. Bush in office and how little attention and assistance he gave the Lyme disease patient community after his own battle with the disease that I have little faith in any politician delivering the much needed funds for translational medicine and treatment research that will help me and my fellow patients.

I feel pretty much the same about anyone else running for office, and anyone trying to stay in office: Show me you can make my life better, either directly or indirectly through concrete and substantial action - or hire someone working for you who will.

I don't want someone to discuss synergy (some vague assertion with no concrete plan), creating another task force or Lyme disease committee, or official state day in observance of Lyme disease. No. What I want to see is money going directly towards treatment and testing research - towards something tangible that has clear actionable goals and benchmarks to be met. What I want to see is concerted effort towards directly supporting those who are ill, with access to a wider range of treatment options, home health care aides, transportation, and supportive services (therapy to help patients physically and emotionally) during the darkest times of our lives.

I also am not a "single issue voter", either. If you are running for office and you make campaign promises that are about promoting awareness of Lyme disease - but slash support for medicare and disability, and make it harder for those of us who are ill and dysfunctional to get the help we need on a broad scale - I can't in my good conscience vote for you. I have to vote for someone who supports all of us who are dealing with disabilities - my fellow humans who are suffering - and those who are currently well who, unfortunately, may one day join our ranks.

In closing, I leave you with one passage from The Business Insider:

"Romney should pledge to funnel money into research organizations that could find the actual cause of this disease, and he could help stop its spread by addressing the causes of global climate change, the main reason the disease has reached so far and wide and continues to spread."

I wouldn't stop there. EVERYONE should pledge to funnel money into research organizations that could find the actual cause of this disease - and more importantly, effective treatment and testing for it.


Image Credit: Former Governor Mitt Romney giving an interview at a supporters rally in Paradise Valley, Arizona. December 6, 2011. Source: http://www.flickr.com/photos/gageskidmore/6468744615/. Taken by Gage Skidmore. This image is licensed under the Creative Commons Attribution-Share Alike 2.0 Generic license.

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2 Microarray Analyses of Inflammation Response of Human Dermal Fibroblasts to Different Strains of B. burgdorferi S.S.

This interesting abstract just got posted on PubMed and is in PLoSONE:

Microarray Analyses of Inflammation Response of Human Dermal Fibroblasts to Different Strains of Borrelia burgdorferi Sensu Stricto

Schramm F, Kern A, Barthel C, Nadaud S, Meyer N, Jaulhac B, Boulanger N.

Abstract

In Lyme borreliosis, the skin is the key site of bacterial inoculation by the infected tick, and of cutaneous manifestations, erythema migrans and acrodermatitis chronica atrophicans. We explored the role of fibroblasts, the resident cells of the dermis, in the development of the disease.

Using microarray experiments, we compared the inflammation of fibroblasts induced by three strains of Borrelia burgdorferi sensu stricto isolated from different environments and stages of Lyme disease: N40 (tick), Pbre (erythema migrans) and 1408 (acrodermatitis chronica atrophicans).

The three strains exhibited a similar profile of inflammation with strong induction of chemokines (CXCL1 and IL-8) and IL-6 cytokine mainly involved in the chemoattraction of immune cells. Molecules such as TNF-alpha and NF-κB factors, metalloproteinases (MMP-1, -3 and -12) and superoxide dismutase (SOD2), also described in inflammatory and cellular events, were up-regulated.

In addition, we showed that tick salivary gland extracts induce a cytotoxic effect on fibroblasts and that OspC, essential in the transmission of Borrelia to the vertebrate host, was not responsible for the secretion of inflammatory molecules by fibroblasts.

Tick saliva components could facilitate the early transmission of the disease to the site of injury creating a feeding pit. Later in the development of the disease, Borrelia would intensively multiply in the skin and further disseminate to distant organs.

Link: http://www.ncbi.nlm.nih.gov/pubmed/22768217

Comments:

Take note of that last paragraph:

"Tick saliva components could facilitate the early transmission of the disease to the site of injury creating a feeding pit. Later in the development of the disease, Borrelia would intensively multiply in the skin and further disseminate to distant organs."

Do you think the implications of the above fit in nicely with the mathematical modeling of Borrelia burgdorferi infection cycles mentioned in an earlier entry?

Why or why not?

See:

Abstract: Population Dynamics Of Borrelia burgdorferi In Lyme Disease
http://campother.blogspot.com/2012/04/abstract-population-dynamics-of.html

The implications - for me at least - seem to fit a model where the first wave of infection dies off but then a bigger, immune-resistant subpopulation explodes onto the scene (the site of infection).

Awaiting PLoSONE to publish the full text so I can give a more thorough analysis...

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23 Let's Not Be Rash About Erythema Migrans

On May 21, Skidmore College in New York conducted the Lyme Next Forum in which various doctors, researchers, patient advocates, and Lyme disease organization leaders gave presentations on various topics related to Lyme disease and its coinfections. (All presentations in four parts can be viewed as streaming videos on Joanne's Looking at Lyme blog.)

While different presentations may have grabbed the attention of other patients, one presentation which stood out for me early on was Holly Ahern's presentation.

Holly is an associate professor at SUNY Adirondack who teaches microbiology and was recipient of a 2008-2009 Research Residency award from the American Society for Microbiology (ASM). So she knows a little something about Lyme disease from a microbiological perspective. But she also has more direct experience of what it is like because her daughter developed a chronic form of the disease.

Holly's presentation was about the potential impact of Lyme disease in New York State in terms of projected undiagnosed cases and unreported cases. But what grabbed my attention in particular was the portion of her presentation focused on research related to the well-known "bull's eye" rash - also known as erythema migrans (EM).

Prior to this, I've read different reports of how many patients who are diagnosed with Lyme disease initially present with an EM rash and how to identify one, so some of this information was not new to me.

While everyone thinks about a Lyme disease rash as being a bull's eye with central clearing (it looks like a target) a 2007 paper published in the Journal of Emergency Medicine, 'An update on the diagnosis and treatment of early Lyme disease: "focusing on the bull's eye, you may miss the mark"', states the following in its abstract:

"To confidently diagnose and treat Lyme disease, the clinician must first understand the natural history of this disease, especially its protean early manifestations. Emergency physicians, primary care physicians, and other providers need to be vigilant in terms of the timely recognition of erythema migrans (EM), the unique marker of early localized stage 1 disease. The classic EM, originally described as a slowly expanding bull's eye lesion, is now recognized to be present in only the minority of cases (9%); the dominant morphologic lesion of EM is now recognized to be the diffusely homogenous red plaque or patch, which occurs in over 50% of cases. This update will define the current morphologic features of early Lyme disease, the indication for serologic studies, and the most recent treatment guidelines, including therapeutic pitfalls."

Based on this, a more evenly colored rash is typical with Lyme disease - whereas a target-like presentation is actually in the minority.

And there are other reports of just how wide the variety of rashes and skin manifestations of EM there can be.

In his testimony to the FDA in preparation for discussion of the approval of the Lymerix vaccine, Dr. Vijay Sikand shared his experience with rashes related to Lyme disease:

"In terms of the variability of Lyme disease, it is indeed a very variable infection, if not a very complex infection. In its very simplest form, it is erythema migrans, well localized, which we can all recognize and which we can all easily treat and from which most patients can get better. However, erythema migrans is not a single beast. Certainly this is the one which we easily recognize and which I just referred to. Before I continue with further slides, let me point out that the erythema migrans lesions you are about to see are all biopsy lesions which were laboratory proven to be caused by Borrelia burgdorferi.

Sometimes erythema migrans can present as a pustular lesion as is this one in the popliteal fossa inviting the scalpel of a surgeon. Sometimes the lesions are vesicular in nature, inviting a diagnosis perhaps of herpes simplex infection. Sometimes our round lesion is actually triangular. Sometimes it doesn't even look round or red at all and invites a diagnosis of an intertriginous fungal infection in the groin of this patient who was biopsied and proven to have Lyme disease. Sometimes the lesion is more plaque-like, inviting diagnosis of nummular eczema, psoriasis, or other similar lesions. Sometimes it is in unusual locations. Sometimes it is large like this one. Sometimes it is small with satellite areas. Sometimes it is multiple, appearing almost like urticaria or erythema multiform. Sometimes, as in this individual who was a placebo recipient in the Lyme 008 SmithKline Beecham trial, it presents with other manifestations of early dissemination. This individual came in mainly because he was concerned about his face and it felt kind of funny and it was weak on one side. When I asked him whether he had had any unusual rashes, he said oh do you mean this one, and he showed me his arm with that EM. This is simply to illustrate the infranuclar 7th nerve palsy with which he presented. This patient, by the way, had no history of a tick bite or any unusual antecedent illness which he could remember."

Based on Dr. Sikand's reports and laboratory testing, it would appear that a typical red rash is not the only manifestation of Lyme disease rashes and there can be much variation.

Having these kinds of reports - and that of the Journal of Emergency Medicine - leads to questions about the reliability of having a uniform description of a rash that doctors would need to look for as part of the definition of the disease. It also raises questions about the utility of using a uniformly described rash in the CDC surveillance case definition for determining where confirmed and probable cases of Lyme disease are reported.

When is a rash an EM rash and when isn't it an EM rash - if one is found at all?

It's clear that if a patient with Lyme disease has a rash which does not match the description of the bull's eye rash that they may be diagnosed with some condition other than Lyme disease.

One way to confirm the diagnosis in this situation would be to look at a patient's history of exposure to ticks, overall symptom presentation for symptoms which suggest Lyme disease, and to get a culture from an odd looking rash and test it for Borrelia burgdorferi even if it takes weeks to receive results.

But what if the patient does not present with an EM rash at all? Perhaps the rash is small and in the hairline where it is not easily seen. And taking it a step further: What if it never even happened?

Ahern pointed to a paper that I had cited on the blog before: "Prophylaxis with single-dose doxycycline for the prevention of Lyme disease after an Ixodes scapularis tick bite". (You may be more familiar with this paper in reference to a recent discussion on prophylactic treatment of tick bites on this blog.)

Ahern made two statements during her presentation which I hadn't recalled reading in this publication:

1. Only tick bites from nymphal ticks produced an EM rash in the host.
   
   
2. When an adult tick (assessed by entomologist in lab for age) had bitten the host, there was NO EM rash.

In addition to these two bits of data, the authors also mentioned that a prophylactic dose of antibiotics prevented the development of an EM rash.

While I had read about antibiotics preventing the development of an EM rash before, the other two pieces of data were new to me. 

So I immediately called up the paper for review to see what had been written about these two statements, and found this information:

"In untreated subjects, bites from nymphal ticks were significantly more likely than bites from adult ticks to be associated with erythema migrans (8 of 142 [5.6 percent] vs. 0 of 97 [0 percent], P=0.02)." 

"In the two groups combined, nymphal ticks were nearly twice as likely as adult ticks to be partially engorged (159 of 266 ticks [59.8 percent] vs. 64 of 197 ticks [32.5 percent], P < 0.001)."

"Untreated bites from nymphal ticks that had been attached to subjects for an estimated 72 hours or longer were more likely to result in erythema migrans than were untreated bites from nymphal ticks that had been feeding for less than 72 hours (3 of 12 bites [25 percent; 95 percent confidence interval, 7 to 57 percent] vs. 0 of 48, P=0.006)." 

"... In addition, our findings support those of previous epidemiologic studies that have shown a temporal association between the development of erythema migrans and exposure to nymphal rather than adult ticks.13 One possible explanation for this is that adult ticks (which are considerably larger than nymphal ticks) are detected and removed earlier in the feeding process than nymphal ticks [...]"

So it seems that at this point, it was already well established that nymphal ticks were already far more likely to cause an EM rash than adult ticks - and because of their small size, nymphal ticks would be less likely to be removed by someone due to not being noticed. They could more easily transmit infection due to the duration of their feeding and missed detection. That sounds logical.

However, what about the adult ticks?

Has there been verification beyond this publication that those who are bitten by adult ticks do not develop an EM rash? Does the lack of an EM rash - not even in the hairline - indicate one is not infected with Borrelia burgdorferi? Or can a host still be infected by an adult tick without the presence of an EM rash?


Further discussion of these questions and this phenomenon will be found in the next installment of "Let's Not Be Rash About Erythema Migrans"...

Image Credit:
"Bulls-eye" Lyme Disease rash by Mangojuice's father

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0 Female Pheromones and Infection May Affect Tick Behavior

Image: Researcher drags white
flannel to collect questing ticks. 

Recently I came across an abstract for the paper, "The correlation between tick (Ixodes persulcatus Sch.) questing behaviour and synganglion neuronal responses to odours".

I'm looking forward to reading the full text, as the abstract demonstrates two findings on tick behavior which may reveal who is more likely to be bitten by ticks.

In this experiment, the taiga tick or Ixodes persulcatus is used - a tick common in parts of Russia. It is unknown if other Ixodes ticks would respond to the same odors the same way, and I think the same experiment should be conducted in Western Europe and North America with local Ixodes ticks to see if there would be a similar outcome.

The researchers experimented with seeing which odors would attract and repel ticks, focusing on seeing how ticks respond to synthetic hormones and insecticides/acaricides. Osmopherone®, Osmopherine®, DEET®, ethanol, and water were placed in a simple maze, and changes in their synganglia - basically their entire central nervous system, as ticks do not have a brain as we think of one - were measured to reflect whether they were attracted, repelled, or neutral to the specific odor tested.

Also, researchers tested which odors were most likely to encourage the maximum height ticks could reach during questing behavior by placing ticks on glass rods which were held at a 75 degree angle.

Two notable findings came from these experiments:

1. Ticks were, as expected, repelled by DEET® and ethanol. It's good to have further confirmation that DEET® works as a repellent. But what was interesting is that ticks were totally neutral to Osmopherone® and water - and attracted to Osmopherine® .
   
   
2. Questing ticks were studied not only for their attraction to certain odors but were tested for whether or not they were infected with Borrelia burgdorferi sensu lato and tickborne encephalitis virus. It was found that not only did those ticks which were most attracted to Osmopherine® reach the highest questing height - but also those ticks which were infected with Borrelia burgdorferi sensu lato were more likely to reach the highest questing height.
   

What is the difference between Osmopherone® and Osmopherine®? Osmopherone® is a synthetic sex pheromone that is meant to mirror the scent human males give off. Osmopherine® is a synthetic sex pheromone that is meant to mirror the scent human females give off. Each of these pheromones are found in their natural form on people and are not an obvious smell people give off - they are registered on a subconscious level and may act as an attractant to the opposite sex.

In these experiments, it appears the female sex pheromone, Osmopherine®, attracts ticks, and ticks infected with Borrelia burgdorferi sensu lato are more likely to have the highest questing height in a laboratory.

What is not known is whether or not the same behavior occurs in the wild, outside a lab - and how much other factors may play into ticks' behavior when questing. Different ticks have different behavior in the wild to begin with, such as Amblyomma americanum tends to be more aggressive in searching out a blood meal and Ixodes scapularis is a more passive questing tick.

Ticks are already attracted to the source of their blood meal through detecting heat and carbon dioxide (CO₂) given off by exhalation. One thing I would hope the full text of this article would explain is how the presence of warm blooded, CO₂ exhaling researchers was shielded so they did not have any influence on these ticks. It may be that these indicators of the next potential dinner may play a bigger role than the gender of the potential host in front of them and whether or not the tick is currently infected with Borrelia burgdorferi s.l. 

Certainly more research is needed to determine what the case is in the wild, but in the meantime these findings provide one with more food for thought as to how a tick host's gender and the tick's state of infection might play a role in tick behavior.

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3 Abstract: Population Dynamics Of Borrelia burgdorferi In Lyme Disease.

Credit goes to Joanne, of the Looking at Lyme blog, for mentioning this abstract: It describes a response to Borrelia burgdorferi infection in mice where the first immune response almost clears the infection - but approximately 1 week post infection, the bacterial population recovers and reaches an even larger size before entering the chronic phase.

Front Microbiol. 2012;3:104. Epub 2012 Mar 22.
Population Dynamics of Borrelia burgdorferi in Lyme Disease.
Binder SC, Telschow A, Meyer-Hermann M.

Source
Department of Systems Immunology, Helmholtz Centre for Infection Research Braunschweig, Germany.

Abstract

Many chronic inflammatory diseases are known to be caused by persistent bacterial or viral infections. A well-studied example is the tick-borne infection by the gram-negative spirochaetes of the genus Borrelia in humans and other mammals, causing severe symptoms of chronic inflammation and subsequent tissue damage (Lyme Disease), particularly in large joints and the central nervous system, but also in the heart and other tissues of untreated patients.

Although killed efficiently by human phagocytic cells in vitro, Borrelia exhibits a remarkably high infectivity in mice and men. In experimentally infected mice, the first immune response almost clears the infection. However, approximately 1 week post infection, the bacterial population recovers and reaches an even larger size before entering the chronic phase.

We developed a mathematical model describing the bacterial growth and the immune response against Borrelia burgdorferi in the C3H mouse strain that has been established as an experimental model for Lyme disease.

The peculiar dynamics of the infection exclude two possible mechanistic explanations for the regrowth of the almost cleared bacteria.

Neither the hypothesis of bacterial dissemination to different tissues nor a limitation of phagocytic capacity were compatible with experiment.

The mathematical model predicts that Borrelia recovers from the strong initial immune response by the regrowth of an immune-resistant sub-population of the bacteria. The chronic phase appears as an equilibration of bacterial growth and adaptive immunity.

This result has major implications for the development of the chronic phase of Borrelia infections as well as on potential protective clinical interventions.

(Special thanks to Frontiers in Microbiology journal for having what appears to be a solid peer review process and Creative Commons license.)

Comments:


I can't wait to read the full text of this paper. This is an intriguing abstract and it leads to more questions.

How did these researchers come up with their mathematical model? Have other researchers previously observed this second wave of bacteria during infection? What about evidence of peaks in immune response in Borrelia burgdorferi infected animal models which have been documented?

In which way, precisely, is the regrowing immune-resistant sub-population actually immune-resistant? What is happening to B cells and T cells in relationship to this second phase of Borrelia?

From Fig. 3 of Tunev et al., 2011.  Day 8 of infection.  The arrows point to intact extracellular B. burgdorferi in the subcapsular sinus of the lymph node, which was culture positive beginning on day 1 of infection.   Source

Do these phases respond with plasma B cells containing low quality antibodies in germinal centers?

Is there typical somatic hypermutation and antigen affinity or not? What is happening to the T-cell independent response?

And does this model have any implication for antibiotic treatment? As in: Does this second immune-resistant sub-population also have a different response to antibiotics than the initial wave? This model is about infection without treatment, and it is not discussed what the implications could be.

Lots of questions here...


UPDATE: Joanne has informed me the free full text is available online. See: http://www.frontiersin.org/Microbial_Immunology/10.3389/fmicb.2012.00104/full

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0 The Wall Street Journal On The Increase Of Tickborne Diseases

Today, Laura Landro of the Wall Street Journal published an article in its Life & Culture section on "This Season's Ticking Time Bomb: Warm Weather Means Ticks Will Be Out Early; A 'Horrific' Season for Lyme and Other Diseases."

It sounds like a sensationalized piece from the title at first - but it's not. It's straightforward reporting on how this year the number of tickborne diseases will be on the rise due to earlier warm temperatures and how to protect your yourself and your family through interactive advice.

Laura's article outlines the typical topics around Lyme disease: symptoms, the difficulty of early diagnosis and treatment, the rising number of cases reported to the CDC over the past decade, and the steps one can take to prevent contracting Lyme disease.

There is also mention of a CDC study on the use of sprays to limit tick population and how a Connecticut scientist sets Japanese barberry on fire to remove it as a source of ticks' sheltering habitat.

For more information, check out Laura's article on the WSJ here:

http://online.wsj.com/article/SB10001424052702303404704577305630267988716.html?mod=WSJ_LifeStyle_Lifestyle_6

In addition to this article, Laura Landro also wrote a blog entry in the Health section, "Doctors Clash Over Best Treatments for Lyme Disease", which discusses the IDSA's treatment guidelines approach (short, and possibly not sweet) and ILADS treatment approach (in for the long haul) for patients with persisting symptoms.

In the blog, Paul Mead of the CDC, Leo J. Shea III of ILADS, and Kristin Schofield, founder of a central New York chapter of the Empire State Lyme Disease Association, are all interviewed.

Read and comment on her blog entry here, as I did:

http://blogs.wsj.com/health/2012/03/27/doctors-clash-over-best-treatments-for-lyme-disease/tab/comments/#comment-1553317

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0 Babesiosis Fatality In Australia

Earlier this week, the Australian television show Today Tonight aired a story about a 56 year old man from New South Wales who died from Babesiosis. There is some concern by others that the man contracted the infection within Australia and not overseas, though more evidence is needed this is the case.

Babesiosis is a tickborne illness caused by a protozoan parasite, Babesia, which infects red blood cells and produces symptoms which are similar to those found in malaria. It can be subclinical and cause no to mild symptoms - but it can also lead to moderate and severe symptoms. And sadly, as we've seen - even kill people.

People who are most likely to have severe symptoms are the elderly, those with compromised immune systems, and those who do not have a spleen.

I know firsthand what Babesiosis is like because several months after I was bitten by a tick, new symptoms showed up in me which were indicative of an infection with Babesia. I also was fortunate to get a positive blood smear - not something which is easily accomplished in the lab.

The most obvious symptoms I experienced were an ongoing shortness of breath with the sensation of a vice-like grip around my ribs, breaking out into sweats at night, "flash" fevers, and anemia. There were other less known symptoms as well, but these are among the most common. Fortunately, I think (I hope) I have beat this coinfection, and it has not beat me.

As it stands, the United States has seen a number of its own deaths due to Babesia, and according to an article in the New York Times, in coastal Rhode Island, the number of cases of Babesia are around 25% less than those of Lyme disease - in an area which is highly endemic for Lyme disease. And not only is Babesia becoming quite common in northeastern states - it's spreading to the northern midwest as well and was already found on the west coast.

One important thing to be aware of is not only can Babesia be transmitted by ticks - it can be spread through the blood supply via donations and transfusions. Thus far, there are twelve people who have died from Babesia spread through blood transfusions in the US. It is unknown, though, how many people may have been infected with Babesia through the blood supply and currently carry a more subclinical infection that may become more evident later.

There is currently no blood screening test available for donations and transfusions, and research is underway to develop such a test to avoid spreading more Babesia through the blood supply. So I highly recommend that if you have to get surgery and know this in advance, that you blood bank your own blood in preparation in case you need a transfusion.

You can view the dramatic video of the Today Tonight story here [4:46 minutes, plus short ad]:

Read this link for a full transcript of the show:

http://au.news.yahoo.com/today-tonight/latest/article/-/13207421/tick-timebomb/

For more information about Babesia and Babesiosis, check out these links:

Specific to Australia: http://lymedisease.org.au/about-lyme-disease/babesiosis/

About the Lifecycle: http://www.stanford.edu/group/parasites/ParaSites2006/Babesiosis/lifecycle.html

About Treatment: http://emedicine.medscape.com/article/780914-treatment

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12 One Pill Of Doxycycline Is Not Enough To Prevent Early Lyme Disease

This paper is being passed around the Lyme disease patient community that has everyone's attention. It's about the most effective timing and the use of one 200 mg capsule of doxycycline as prophylaxis to prevent Lyme disease after a tick bite.

The bottom line from the authors of the study: One 200 mg capsule of doxycycline is totally ineffective in preventing Lyme disease if it is administered 48 hours after a tick bite.

And even if administered in less than 48 hours, it is no guarantee of successfully preventing infection.

The following commentary comes from Dr. Elizabeth Maloney:

Since 2001 the IDSA has been recommending preventive treatment of a single dose of doxycyline for tickbites under certain narrow conditions.  Piesman et al. have just published a new article concluding that if the treatment is given as little as 24 hours after the bite, only 47% of the mice were cured. Piesman also concludes that "Prophylactic treatment was totally ineffective when delivered ≥2days (48hrs) after tick removal." The IDSA recommends treating if:

• Tick is estimated to have been attached for ≥36 hours (based upon how engorged the tick appears or the amount of time since outdoor exposure)

• Antibiotic treatment can begin within 72 hours of tick removal 

"If the person meets ALL of the above criteria, the recommended dose of doxycycline is a single dose of 200 mg for adults and 4 mg/kg, up to a maximum dose of 200 mg, in children ≥ 8 years"

In 2004 Zeidner et al. noted that the "sustained release" doxy was curative, but regular doxy only 43% effective. [ Antimicrob Agents Chemother. 2004 Jul;48(7):2697-9. Sustained-release formulation of doxycycline hyclate for prophylaxis of tick bite infection in a murine model of Lyme borreliosis.]

In 2008 Dolan et al. reported on the success of 14 days of exposure to antibiotic bait formulations..

Am J Trop Med Hyg. 2008 May; 78(5):803-5.
A doxycycline hyclate rodent bait formulation for prophylaxis and treatment of tick-transmitted Borrelia burgdorferi.Dolan MC, Zeidner NS, Gabitzsch E, Dietrich G, Borchert JN, Poché RM, Piesman J.

Abstract

The prophylactic and curative potential of doxycycline hyclate formulated in a rodent bait at concentrations of 250 and 500 mg/Kg was evaluated in a murine model of Lyme borreliosis. 

Both bait formulations prevented tick-transmitted Borrelia burgdorferi infection in 100% of C3H/HeJ mice (N = 16), as well as cured acute, established infection in mice (N = 8) exposed to bait for 14 days. 

Spirochete infection was cleared in 88.9% to 100% of infected nymphs feeding on mice fed 250 and 500 mg/Kg antibiotic bait formulations, respectively. These data provide evidence for exploring alternative techniques to prevent transmission of Lyme disease spirochetes.

In 2011 Wisconsin Journal of Medicine published a review detailing the failure of one-dose doxycycline prophylaxis and proposing an alternative, more effective treatment option. (Maloney, B. The management of Ixodes scapularis bites in the upper Midwest. WMJ. 2011 Apr;110(2):78-81; quiz 85.) 

The full text article is available at: http://www.wisconsinmedicalsociety.org/_WMS/publications/wmj/pdf/110/2/78.pdf

This month Peisman and Hoigaard note that "prophylactic treatment was totally ineffective when delivered ≥2days after tick removal." [2 days = 48 hrs]

Ticks Tick Borne Dis. 2012 Mar 13. [Epub ahead of print] Protective value of prophylactic antibiotic treatment of tick bite for Lyme disease prevention: An animal model. Piesman J, Hojgaard A.

Abstract

Clinical studies have demonstrated that prophylactic antibiotic treatment of tick bites by Ixodes scapularis in Lyme disease hyperendemic regions in the northeastern United States can be effective in preventing infection with Borrelia burgdorferi sensu stricto, the Lyme disease spirochete. 

A large clinical trial in Westchester County, NY (USA), demonstrated that treatment of tick bite with 200mg of oral doxycycline was 87% effective in preventing Lyme disease in tick-bite victims (Nadelman, R.B., Nowakowski, J., Fish, D., Falco, R.C., Freeman, K., McKenna, D., Welch, P., Marcus, R., Agúero-Rosenfeld, M.E., Dennis, D.T., Wormser, G.P., 2001. Prophylaxis with single-dose doxycycline for the prevention of Lyme disease after an Ixodes scapularis tick bite. N. Engl. J. Med. 345, 79-84.). 

Although this excellent clinical trial provided much needed information, the authors enrolled subjects if the tick bite occurred within 3days of their clinical visit, but did not analyze the data based on the exact time between tick removal and delivery of prophylaxis. An animal model allows for controlled experiments designed to determine the point in time after tick bite when delivery of oral antibiotics would be too late to prevent infection with B. burgdorferi. 

Accordingly, we developed a tick-bite prophylaxis model in mice that gave a level of prophylactic protection similar to what had been observed in clinical trials and then varied the time post tick bite of antibiotic delivery. We found that two treatments of doxycycline delivered by oral gavage to mice on the day of removal of a single potentially infectious nymphal I. scapularis protected 74% of test mice compared to controls. When treatment was delayed until 24h after tick removal, only 47% of mice were protected; prophylactic treatment was totally ineffective when delivered ≥2days after tick removal. 

Although the dynamics of antibiotic treatment in mice may differ from humans, and translation of animal studies to patient management must be approached with caution, we believe our results emphasize the point that antibiotic prophylactic treatment of tick bite to prevent Lyme disease is more likely to be efficacious if delivered promptly after potentially infectious ticks are removed from patients.

---

There is only a very narrow window for prophylactic treatment to be effective post tick removal.

In my opinion, a study like this one should have been done long ago. How many studies were used to make the original determination that one 200 mg capsule of doxycycline would be an appropriate method of prophylaxis against Lyme disease? 

 And the obnoxious thing is, I was given this treatment! I had a tick bite, I had an EM rash, I was concerned about Lyme disease - and the first doctor I saw said there was no Lyme disease in the area in which I had been bitten, but I was given the one pill of doxycycline as some sort of consolation prize... The implication from the doctor being that the bite was most likely nothing to worry about and the pill being given to me to placate me.

Well, this prophylaxis apparently was not very prophylactic, now, was it?

I am pretty sure I saw the doctor 3-4 days after the tick bite, when I was given the prescription paper to fill it for one capsule of doxycycline.

This prophylactic approach never made sense to me from the day I first learned about the one pill preventative.

Since my failed experience of preventing Lyme disease, I've learned that different strains/subspecies of Borrelia burgdorferi disseminate at different rates, with different bacterial loads from different bites. If infection is present - one pill is hardly going to stop it. And if a coinfection is present, it may have an impact on the immune system which is hard to predict and may alter how effective an antibiotic is on the big picture.

One of the things I've learned in the past couple of weeks of doing research on Russian web sites about how patients are affected by Lyme disease and what treatments are given to patients there is that there is more of a sense of urgency of treating Lyme disease early and also aggressively. This is not to say that the Russian approach of managing Lyme disease is the best overall - they too have a problem with chronic Lyme disease - and so far as I can see, have not found the perfect treatment for it.

But if what I read so far is to be taken into account, then their approach has been to treat Lyme disease as early as possible and have doctors remove ticks as soon as one has a tick bite because research has shown the earlier a tick is removed properly, the greater the risk is reduced in transmitting infection.

In addition to encouraging immediate professional tick removal and early treatment during the acute stage, a number of medical clinics and web sites recommend a few days of prophylactic doxycycline - rather than one pill.

I am still looking for Russian research papers which support this approach - so perhaps take this information with some caution. But here are two sites which mention this approach which would appear to be legitimate resources:

First site, the equivalent of city council pages for  Lipetsk:

From an order marked:

ORDER KM Lipetsk region from 09.09.2004 N 523, SEC in the Lipetsk region dated 04.08.2004 N 78-ns, "ESTABLISHMENT OF Surveillance of Ixodes tick-borne borreliosis in the region" (with "GUIDELINES", "PLAN OF SCIENTIFIC AND PRACTICAL WORK on the prevalence of Ixodes tick-borne borreliosis in Lipetsk region for 2004 - 2005 HS. ")

Administration of Lipetsk Region

DEPARTMENT OF HEALTH
on September 9, 2004 N 523

SEC in the Lipetsk Region
on August 4, 2004 N 78-ns

ORDER ON Surveillance FOR Ixodes tick-borne borreliosis -- Excerpt:

"Carry an emergency antibiotic prophylaxis should be based only on display in the pathogen attached ticks. In the case of the pathogen in the vector and not later than 3 days. of tick suction in patients prescribed a course of doxycycline at 0.1 x 1 time per day for 5 days (children under 8 years of this antibiotic is not indicated).

Later on the third day from the time course of doxycycline tick suction extended to 10 days. Other antibiotics, which can be used for preventive treatment, drugs are prolonged penicillin: bicillin 3 or retapen (ekstentsillin) at a dose of 2.4 million units. intramuscularly once after a skin test on the individual tolerance of antibiotic.

Has a high efficiency combination drug amoxicillin with clavulanic acid (amoxiclav) to 0.375 g, 3 times a day, 5 days.

When carrying out emergency prophylaxis following should be considered (Appendix 9):
- Epidemiological history - a fact suction to the skin of ticks;
- Results of microbiological studies, parazitologo - detection of Borrelia in the attached ticks by dark-field microscopy or PCR;
- Start of antibiotic timing - as soon as possible after the suction (after the 5th day of tick suction inappropriate use of approved schemes), early prevention of borreliosis - a day after the suction of an infected tick Borrelia - can be recommended only when a negative result of the study attached ticks in the ELISA CEA antigen;
- A good individual tolerability of recommended antibiotics;
- Carrying antibiotics under medical supervision;
- Follow-up visit within 1 - 3 months after the course of antibiotic prophylaxis in SDS"

In Russian:

ПРИКАЗ УЗ Липецкой области от 09.09.2004 N 523, ЦГСЭН В Липецкой области от 04.08.2004 N 78-пв "ОБ ОРГАНИЗАЦИИ ЭПИДЕМИОЛОГИЧЕСКОГО НАДЗОРА ЗА ИКСОДОВЫМ КЛЕЩЕВЫМ БОРРЕЛИОЗОМ В ОБЛАСТИ" (вместе с "МЕТОДИЧЕСКИМИ РЕКОМЕНДАЦИЯМИ", "ПЛАНОМ ПРОВЕДЕНИЯ НАУЧНО-ПРАКТИЧЕСКОЙ РАБОТЫ ПО ИЗУЧЕНИЮ РАСПРОСТРАНЕНИЯ ИКСОДОВОГО КЛЕЩЕВОГО БОРРЕЛИОЗА НА ТЕРРИТОРИИ ЛИПЕЦКОЙ ОБЛАСТИ НА 2004 - 2005 ГГ.")

2.8. Экстренная антибиотикопрофилактика ИКБ

Проводить экстренную антибиотикопрофилактику следует только на основании индикации возбудителя в присосавшемся клеще.

В случае обнаружения возбудителя в переносчике и не позднее 3 сут. после присасывания клеща пациентам назначают курс доксициклина по 0,1 х 1 раз в сутки в течение 5 дней (детям до 8 лет данный антибиотик не назначают).

Позже третьего дня от момента присасывания клеща курс доксициклина продлевается до 10 дней. Другими антибиотиками, которые могут быть использованы для превентивного лечения, являются препараты пролонгированного пенициллина: бициллин-3 или ретапен (экстенциллин) в дозе 2,4 млн. ед. внутримышечно однократно после проведения внутрикожной пробы на индивидуальную переносимость антибиотика.

Высокой эффективностью обладает комбинированный препарат амоксициллина с клавулановой кислотой (амоксиклав) по 0,375 г 3 раза в сутки 5 дней.

При проведении экстренной антибиотикопрофилактики необходимо учитывать следующее (приложение 9):
- данные эпидемиологического анамнеза - факт присасывания к кожным покровам иксодовых клещей;
- результаты паразитолого-микробиологических исследований - выявление боррелий в присосавшихся клещах методом темнопольной микроскопии или ПЦР;
- сроки начала антибиотикопрофилактики - как можно раньше после присасывания (позже 5-го дня после присасывания клеща использование рекомендованных схем нецелесообразно), ранняя профилактика боррелиоза - через сутки после присасывания зараженного боррелиями клеща - может быть рекомендована только при отрицательном результате исследования присосавшегося клеща в ИФА на антиген КЭ;
- хорошая индивидуальная переносимость рекомендуемых антибиотиков;
- проведение антибиотикопрофилактики под контролем врача;
- контрольное обследование через 1 - 3 месяца после проведенного курса антибиотикопрофилактики на ИКБ.

Source: Network of Lipetsk Region http://lipetsk.news-city.info/docs/sistemsv/dok_oegvgi/index.htm

And then here's another, for Nizhny Novgorod State Medical University, which has been around since 1920:

"At the present time in Nizhny Novgorod and the region is high infection of ticks with borreliae, there are also ticks infected with tick-borne encephalitis. You must know the pattern of action in the case of tick suction.

First, you must remove the tick, while maintaining its viability. You can do it yourself or by contacting the trauma center in your area.

Remote mite be sent to study in Nizhny Novgorod Research Institute of Epidemiology and Microbiology. Academician I. Blokhina (St. Georgia 44, 433-76-55, 434-17-71, www.micro.nnov.ru). Within a day you will get the result of the study.

If the tick was infected with Borrelia, to conduct preventive 10-day course of doxycycline (T. Doxiciclini 0,1 to 1 m, 2 times a day).

If the tick was infected with tick-borne encephalitis, showed immunoglobulin, but the free drug can qualify only if after the bite was not more than 4 days."

The above, in Russian:

"В настоящее время на территории Нижнего Новгорода и Нижегородской области высока инфицированность клещей боррелиями, встречаются также клещи, инфицированные вирусом клещевого энцефалита. Необходимо знать схему действий в случае присасывания клеща.

Во-первых, клеща необходимо удалить, сохранив его жизнеспособность. Сделать это можно самостоятельно либо обратившись в травмпункт Вашего района.

Удаленного клеща необходимо отправить на исследование в Нижегородский НИИ эпидемиологии и микробиологии им. академика И.Н. Блохиной (Ул. Грузинская 44, 433-76-55, 434-17-71, www.micro.nnov.ru). В течение 1 суток Вам предоставят результат исследования.

В случае, если клещ был инфицирован боррелиями, необходимо проведение профилактического 10-дневного курса доксициклина (T. Doxiciclini 0,1 по 1 т. 2 раза в день).

Если клещ был инфицирован вирусом клещевого энцефалита, показано введение иммуноглобулина, но на бесплатный препарат можно претендовать лишь в том случае, если с момента укуса прошло не более 4 дней."

Source: http://www.nizhgma.ru/studentu/kafedry/infekc/uchmat/klesh/


So far as I can see, the use of a longer period of prophylactic treatment is advised - but the public health department also makes an effort to test the tick you have had on you for the presence of bacteria and viruses. The turn around time is less than 24 hours for results.

The only problem with this approach is that if you get a tick bite which is not obvious and it is not found right away, the odds of getting Lyme disease and/or Tick-borne encephalitis (TBE) are greater. Treatment may come too late to help a patient - particularly in the case of  TBE, where immunoglobulin for TBE and antiviral medication will only help if administered in under 72-96 hours after the tick bite.

There are three reasons I suspect Russia is more aggressive in its approach:

1) While the odds of getting TBE are lower than the odds of getting Lyme Borreliosis, TBE has a much higher risk of leading to acute severe illness and death. The older one is when they are infected with TBE, the higher the odds are of serious complications and fatality.

2) The most common strain of Borrelia people are infected with in Tomsk - a highly endemic area of Russia - is B. garinii, and a specific type of B. garinii quickly disseminates to the CNS more quickly than other strains. To prevent neuroborreliosis and widespread dissemination to other organs, a longer prophylactic course is needed as soon as possible.

3) Polymicrobial or coinfection is not uncommon. It is possible to be infected with both Lyme Borrelia and TBE, or more than one strain of Borrelia burgdorferi, and perhaps throw in Anaplasmosis in there as well. One has to be very careful of how to treat such cases - if TBE is present, it must be treated first since it moves fast, is more dangerous, and early antibiotic use is contraindicated in its presence.

All this said, I do wonder how it was determined that prophylaxis should be 5-10 days, based on circumstances surrounding the bite. This is a much longer course than the IDSA has suggested.

And frankly, this sort of treatment is what I wish I had if it would have prevented the situation in which I now find myself.

If you found this post interesting and informative, you may want to read this one as well:
http://campother.blogspot.com/2010/12/dr-david-volkmans-letter-to-idsa-lyme.html

Addendum [April 29, 2012]: I wanted to add the following passage from a paper from The Canadian Entomologist:

"Studies of the transmission dynamics of B. burgdorferi in I. scapularis indicate that the risk of transmission of strain B31 by a single bite from an infected tick is about 2% and that the risk increases with the length of time that the tick is attached (Hojgaard et al. 2008). 

When a tick first attaches, spirochetes are still found in the midgut and are producing outer-surface protein A (OspA), which helps spirochetes adhere to a midgut protein, TROPSA. When feeding begins, the spirochetes are exposed to warm mammalian blood and lowered pH, and OspA is downregulated while OspC is upregulated. Spirochetes then migrate from the midgut to the salivary gland and transmission to the vertebrate host can be achieved (e.g., Hojgaard et al. 2008). This delay in transmission explains why transmission is reduced when ticks are removed within 24 h of attachment (Hojgaard et al. 2008). 

In Europe, transmission of B. burgdorferi s.s. and B. afzelii by I. ricinus occurs in less than 24 h, but the risk of transmission still increases over time (Kahl et al. 1998; Crippa et al. 2002). In a further complication of the host—tick—pathogen interaction, B. burgdorferi s.l. is able to increase expression of an Ixodes salivary protein, Salp 15, to protect against complement-mediated killing of Borrelia by the host's innate immune system (Ramamoorthi et al. 2005). This protective effect was greater when the vector was I. ricinus rather than I. scapularis (Schuijt et al. 2008). The early expression of ospC appears to be essential for B. burgdorferi to escape innate immunity and disseminate in the host (Gilbert et al. 2007), and yet persistent infection of the host is only possible when ospC is downregulated after infection because acquired antibodies to OspC allow the spirochetes to be cleared (Tilly et al. 2007). Current understanding of the interactions of tick saliva and B. burgdorferi is discussed in Anderson and Valenzuela (2007)."

Source: http://www.bioone.org/doi/full/10.4039/n08-CPA04

Janet L.H. Sperling, Felix A.H. Sperling. Lyme Borreliosis in Canada: Biological Diversity and Diagnostic Complexity from an Entomological Perspective. The Canadian Entomologist 141(6):521-549. 2009 doi: http://dx.doi.org/10.4039/n08-CPA04

The above passage is important to note because it outlines the fact that the rate of transmission of spirochetes from the tick to its host varies based on a number of factors including Borrelia strain, the type of tick involved, Salp15 production levels, expression of ospC, and length of time the tick has been attached.

Based on this research, it is clear additional research is needed to determine if strains of Borrelia burgdorferi other than B31 in Ixodes scapularis and Ixodes pacificus would have differing transmission times tested under the factors mentioned. The same sort of studies would be beneficial for Europeans on Ixodes ricinus and other European Ixodes ticks.

[Edited March 22, 2012 - First paragraph said "100 mg capsule of doxycycline", was changed to "200 mg capsule of doxycycline".]


Image credit: Doxycycline 100 mg capsules. By Shorelander, Wikimedia Commons.

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