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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