Crucial differences between IDSA and ILADS guidelines

Had the thought slipped into his mind, he still might not have worried since he was clothed from feet to neck, wearing shoes, socks, pants, a light sweater, and a jacket over his shirt.

Later that day, back in his city apartment, he felt an irritation on his back. Self-examination revealed a small dark tick embedded in his skin. Extracting as much as possible of the little blood-sucker, he wrapped the remnants of its body in tissue paper, intending to have the tick tested for Lyme disease; if it was carrying the bacteria that cause Lyme, he would immediately seek medical help. Years ago, he had been bitten by a tick, hadn’t notice the bite, and had developed Lyme disease. Diagnosed and treated late, the infection persisted, with a number of prostrating symptoms. Now, the memory of his ordeal made him keep the tick. But as the days passed and the tick’s body decomposed, the young man never got around to bringing it to a qualified lab.

Two weeks after the young man’s country outing, he developed a rash on his chest, and he began to feel symptoms similar to those experienced during his first Lyme infection. Alarmed, he checked into the hospital, consulting the same doctor who had previously diagnosed and treated him. Mainly on the basis of the rash and the resemblance of past and current symptoms, the doctor prescribed oral antibiotics. Then the doctor ordered a Lyme antibody test to confirm that the man had been newly infected. The test was inconclusive. After a few weeks of treatment, the man’s symptoms cleared up, and he has since remained symptom-free.

This case came to my attention in January, after I had submitted my column about the latest guidelines for Lyme disease published by the Infectious Diseases Society of America (IDSA) in 2006. (1) How would a physician adhering to the IDSA recommendations handle it?

A press release from the Lyme Disease Association (LDA), issued in October 2006 when IDSA published its revised guidelines, noted that the "new IDSA guidelines advise against clinical discretion in determining whether or not patients have Lyme disease. Instead, they advise that doctors either see a characteristic rash known to occur in about half the patients, or that patients register positive on the two tests recommended by the Centers for Disease Control & Prevention (CDC) tests known to miss up to half the patients." (2)

The LDA, representing more Lyme patients than any other organization in the US, particularly chronic patients, promotes guidelines published by the International Lyme and Associated Diseases Association (ILADS) in 2004. (3) These guidelines call for a clinical diagnosis, allowing physicians to weigh far more than the characteristic rash and antibody tests in determining whether to treat for Lyme disease. How would a physician belonging to the International Lyme and Associated Diseases Society (ILADS) handle the case described in the opening of this column?

An article cited in the October LDA press release (4) led me to phone Daniel Cameron, MD, acquaint him with this early case of Lyme disease (emphasis added), and ask for his opinion on the crucial differences in the IDSA and ILADS recommendations for diagnosis and care of the young man. Dr. Cameron, the sole author of the cited study, was also the lead author of the published ILADS treatment guidelines. He has been practicing in Mt. Kisco, New York (Westchester County) for 19 years. Much of his recent clinical research has focused on Lyme patients who fail antibiotic treatment. His findings to date suggest that the overwhelming reason is because they were diagnosed and treated late.

Here is Dr. Cameron’s comparison:

The IDSA guidelines would not have recommended treatment for the tick bite. They suggest that a single dose of doxycycline (up to a maximum of 200 mg.) could be prescribed within 72 hours of the tick’s removal, but under the following conditions:

  1. if the tick is readily identifiable as a deer tick in the adult or nymph stage and is estimated to have been attached for 36 hours or more, based on engorgement level or certainty of the time of exposure to the tick;
  2. if ecologic information indicates that the local tick infection rate with Lyme is at 20% or more;
  3. if doxycycline is not contraindicated.

In the case detailed above, even if the tick had been tested and confirmed as a carrier (note that such testing is not recommended by the IDSA guidelines), a physician sticking to the IDSA guidelines would wait for the characteristic rash to appear–and be larger than two inches–before prescribing treatment.

I quote from the IDSA recommendations concerning the rash: "Erythema migrans (EM, the characteristic rash) is the only manifestation of Lyme disease in the US that is sufficiently distinctive to allow clinical diagnosis in the absence of laboratory confirmation."

Following the ILADS guidelines, a physician would make a clinical diagnosis, use clinical judgment in determining if the bite was sufficient reason to treat, and consider other manifestations (especially in the absence of the rash or antibody tests) in diagnosing and prescribing.

Both physicians would use oral antibiotics. The IDSA-guided physician would treat for a maximum of 21 days (the IDSA minimum is ten days). No follow-up visit would be scheduled, unless the patient subsequently showed signs of Bell’s Palsy, heart block, meningitis, or arthritis. An ILADS-guided physician would give oral antibiotics for a minimum of a month, follow up with an office visit to evaluate the patient’s response to treatment, and continue treatment if signs of prolongation manifested.

Toward the end of my phone conversation with Dr. Cameron, he emphasized that the case we had discussed was early Lyme disease. The IDSA and ILADS guidelines most clearly diverge in cases of persistent, recurrent, or refractory Lyme. He directed me to his website, Lymeproject.com, advising me to look at an article he recently published that refutes assumptions of a report on long-term treatment for Lyme disease; IDSA cites this reference as a major support for its guidelines.

Dr. Cameron’s article, "Generalizability in Two Clinical Trials of Lyme Disease," (5) takes aim at the study by Klempner et al. published in The New England Journal of Medicine in 2001. (6) The Klempner study, conducted with funds from the National Institutes of Health (NIH), has become generalized in the medical literature–and decidedly so by insurance companies–as definitive proof that 12 weeks of antibiotics for sick Lyme patients makes no difference. Dr. Cameron’s critique makes it clear that the Klempner trial is not useful when dealing with a broader population.

The Lyme Disease Update, published by the LDA in 2004, (7) also critiques the Klempner study:

Klempner et al. found no statistically significant difference between the group receiving antibiotics and the group receiving placebo. These findings have not fostered a consensus of opinion among the clinical research community. To cite two reservations: clinical experience suggests that Lyme patients sick enough to require IV antibiotics may not respond to one month of treatment, and adding oral antibiotics for two more months may not benefit them either.

One of the aspects of the case referred to in this column that had puzzled me was the inconclusive antibody test, despite the tick bite and the onset of symptoms. I sought a quick explanation from Dr. Cameron. When antibiotics work, killing the Lyme bacteria, he said, it frequently prevents the generation of antibodies.

Dr. Cameron’s answer raised questions about IDSA’s insistence on relying on positive serology in diagnosing and treating Lyme disease. I phoned Nick Harris, PhD, the founder and CEO of IGeneX, Inc., in Palo Alto, California. IGeneX is a specialty reference laboratory for Lyme and other tick-borne diseases. Dr. Harris participated in the CDC meeting at Dearborn, Michigan, in 1995, where the CDC redefined its serologic criteria for Lyme disease. He spoke against the two-tiered testing proposal, the deletion of the 31kDa and 34kDa antigenic proteins (which struck him as incredible), and the limited utility of the IgM Western blot. (8) "All of these actions," he said, "caused a reduction in the testing sensitivity. (9) They also, by the way, had the potential effect of increasing the potential market size of a new Lyme vaccine under development at the time."

Apparently, ventured Dr. Harris, "IDSA feels the benefit of the two-tiered CDC system is the virtual 99% specificity. However, the tremendous downside is the lack of sensitivity when this testing system is used outside of the parameters for which it was designed. This two-tiered system was predicated on three events:

  1. A known tick bite in a highly endemic area;
  2. an EM rash;
  3. testing within two to four months of the tick bite.

"These are flawed parameters. Even in the best of cases, we can see from the studies of Engstrom et al. (10) that 20% of the EM positive patients with a known tick bite may test negative, and another 20% only tested positive on one of the studies’ six testing events."

In addition, Dr Harris pointed out, "by having an insensitive ELISA as the first step many patients are tested either too early (within days of a tick bite) or years after the event; in all these cases, the screening ELISA is negative and the patient is told they are Lyme negative."

"A test system cannot have everything," he said in summing up. "There is a trade off between sensitivity and specificity. That is why the FDA has set 95% specificity as the standard for approved tests. At IGeneX, for example, we’ve developed a Western Blot as a stand-alone-test that has a specificity of better than 95%, using only two antibody defined bands, but it gains 20% or more sensitivity (depending on when in the disease process the test is used)."

"Where do we go from here?" I asked Dr. Harris at the end of our phone interview.

"Currently, the Lyme community is in a crisis," he observed. "We need a simple, inexpensive testing approach to help determine who has been exposed to the Lyme bacteria. Then we need more studies in the clinical research literature that clarify our understanding of chronic Lyme disease. Finally, we need to leave MDs much more discretion than the IDSA guidelines do, so they can make clinical determinations about Lyme disease that result in adequate treatment for both early- and later-stage patients."

Notes

  1. Cohen MA. CT attorney general investigates restrictive Lyme guidelines. Townsend Letter. April 2007.
  2. Smith P. New IDSA guidelines forbid doctors from using clinical discretion in diagnosing Lyme disease. LDA. October 10, 2006.
  3. ILADS. Evidence-based guidelines for the management of Lyme disease. Expert Rev. Anti-infect. The. 2004; 2(1): Suppl.
  4. Cameron D. Consequences of treatment delay in Lyme disease. Journal of Evaluation in Clinical Practice. In press.
  5. Cameron D. Generalizability in two clinical trials of Lyme disease. Epidemiologic Perspectives and Innovation. November 2006.
  6. Klempner MS, et al. Two controlled trials of antibiotic treatment in patients with persistent symptoms and a history of Lyme disease. New Engl. J. Med. 2001; 345 (2): 85-92.
  7. Cohen MA. Lyme Disease Update. New Jersey: Lyme Disease Association; 2004.
  8. Ibid. 31-32, 123-124.
  9. Sensitivity refers to a test’s degree of ability to detect as many cases as possible. Specificity is the ability of a test to exclude false positives.
  10. Engstrom, et al. Immunoblot interpretation criteria for serodiagnosis of early Lyme disease. J Clin Microbiol. 1995;33:419-427.

Continue reading here: Lyme Disease Treatment Guidelines Development

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