Townsend's New York Observer
by Marcus A. Cohen

Lyme Disease: Impact of the CDC Surveillance Criteria on Patients
My first Townsend column about Lyme disease (April 2004) opened with a startling fact: this tick-transmitted infection is the most prevalent vector-borne disease in the US. According to recent CDC statistics, Lyme cases constitute 95% of all reports for such diseases.¹ The remaining 5% includes the mosquito-transmitted West Nile Virus, sensationally publicized but by no measure affecting as many Americans as Lyme.

That earlier Townsend column pointed to the narrowly-defined surveillance criteria for reporting cases issued by the Center for Disease Control and Prevention (CDC) as a significant reason for uncertainty over the incidence of Lyme.

This column reviews the CDC criteria, differentiates them from authoritative guidelines generally available for diagnosing Lyme, and spotlights the inadequacies and inherent problems in the two main serologic tests required by the CDC. It then describes how misuse of the CDC surveillance criteria has had an adverse impact on diagnosing and treating Lyme, and on the prevalence of persistent or recurrent cases.

CDC Surveillance Criteria
For Lyme Disease the CDC definition calls for a physician-diagnosed erythema migrans (EM) rash, a slightly flat or raised reddish lesion, or a positive antibody test together with one major system involvement. The EM lesion, which in less than half of all cases appears at the site of the tick bite shortly after infection and then spreads in the shape of a "bull's eye," is widely considered in itself pathognomonic for Lyme.

In patients with no EM who require serologic testing, the CDC calls for an Enzyme-Linked Immunosorbent Assay (ELISA). The ELISA indirectly detects antibodies in the patient's serum that react to antigens (proteins) present in the Lyme pathogen: such antibodies indicate exposure to the pathogen. Under the CDC surveillance criteria for Lyme, a negative ELISA is cause for rejection of a case report. If the ELISA is positive or equivocal, the CDC next requires Western blot tests for more definite evidence. The National Institute of Allergy and Infectious Disease (NIAID) regards this test as the most helpful in confirming exposure to Lyme.

Western blot tests (or immunoblot tests) look at antibodies directed against a broad range of antigens present in the Lyme pathogen. In a patient having antibodies to a particular antigen, a "band" will form at a certain place on the immunoblot. By reading the "band" patterns formed by the spectrum of antibodies to the Lyme pathogen, labs doing Western blots can determine with greater specificity than ELISAs do whether a patient's immune response is specific for Lyme infection.

Major Diagnostic Guidelines
Practice guidelines developed by the NIH and the Infectious Disease Society of America (IDSA) advise physicians suspecting Lyme disease to make a clinical diagnosis. A clinical diagnosis in Lyme should be based either on a history of exposure in an area endemic for Lyme-transmitting ticks and identification by a physician of the EM lesion (in the early stage of disease), or recognition by physicians of characteristic clinical signs and confirmation by lab findings
.
Note: The CDC, in its own public statements, has advised that it has not issued guidelines for diagnosis of Lyme; the CDC guidelines concern only surveillance. A CDC representative made the distinctions clear at a hearing in Connecticut in 2004:
"Surveillance case definitions are created for the purpose of standardization, not patient care.... Whereas physicians appropriately err on the side of over-diagnosis, thereby assuring they don't miss a case, surveillance case definitions appropriately err on the side of specificity, thereby assuring that they do not inadvertently capture illnesses due to other conditions."²

Absence of EM and Uncharacteristic Forms
The first Townsend column about Lyme stressed that in one-fifth to one-half of patients the EM rash never appears or it appears in an atypical form. Because of the EM's complex, diverse presentation, even physicians evaluating patients in areas endemic for Lyme can fail to recognize this "signature" lesion.

At an FDA hearing on antimicrobials for early infection, Raymond Dattwyler, a rheumatologist at SUNY, Stony Brook, Long Island, told the FDA that "one guy at our hospital was teaching the house staff that erythema migrans was always a flat lesion...if there was any edema in the lesion...it couldn't be erythema migrans." Dattwyler showed his colleagues at Stony Brook culture-positive lesions that were raised, dispelling their misimpression.³

Lyme ELISAs: General Deficiencies
Crucial deficiencies of the Lyme ELISA are its relative lack of specificity and sensitivity. (Specificity refers to this test's ability to exclude patients without Lyme, sensitivity to its ability to detect patients with Lyme.) The ELISA can show false positive in patients with periodontal disease and syphilis, for example, which have certain proteins in common with Lyme spirochete. In addition to error caused by cross reactivity, different labs doing Lyme ELISAs vary in their results. (There is little standardization.)

From its studies, the College of American Pathologists concluded that commercially available ELISAs yield too many false positives and false negatives (they are not sensitive enough), and therefore they should not be used as an initial serologic screen in the CDC's two-step testing for antibodies to Lyme.⁴

Concerns About the CDC's Interpretation of Western Blots
When the CDC revised its surveillance criteria in Dearborn in 1996, it selected five of ten Western blot bands for IgG and two of three bands for IgM as indicative of Lyme disease. IgM bands help diagnose Lyme in the early acute stage, IgG bands help in later stages. ("IgG" stands for "Immunoglobulin G," a class of antibodies commonly circulating in blood and especially active against bacteria, proteins foreign to the body, and viruses. "IgM" are antibodies of high molecular weight, appearing early in the immune response, replaced by lower weight IgG antibodies.)
Note: The CDC chose for diagnostic purposes the bands most frequently found to be positive in Lyme test results.

The CDC redefinition included bands 31kd and 34kd, for outer surface proteins A and B (OspA, OspB) respectively, which are very specific for Lyme pathogen and therefore significant in detecting the disease. It included one band, 41kd, a common antigen for flagella-bearing microorganisms.

Dr. Nick Harris, an expert on Western blots, was invited to serve on a committee at the Dearborn conference. Reaching him by phone at his lab in California, I asked for a sound-byte opinion of the conference. "It was billed," he said, "as a consensus meeting. But it was a consensus meeting only in the sense that the participants were expected to consent to revisions of the CDC surveillance criteria previously decided in closed session."

He then faxed me a paper he published in 1998, titled, "An Understanding of Laboratory Testing for Lyme Disease."⁵ It gives much more than a byteful about the CDC revisions. I'm sharing several passages here, reserving a larger discussion with Dr. Harris on the drawbacks of serologic tests in Lyme for a more suitable time:
"If the intention were only for public health surveillance and reporting of disease, these changes would not have caused a problem. Unfortunately, these recommendations became the standard in most areas and especially with insurance companies. That was unfortunate because the Dearborn meeting was not supposed to be about setting national standards for Lyme disease diagnosis; rather it was to be a discussion regarding the Western blot during early Lyme disease....

"The criteria for a positive Western blot to B. burgdorferi...are very conservative and require 5 to 10 antibody bands for IgG positivity; the original recommendations do not even recognize equivocal or borderline results if less than five bands are detected. The cut-off assumes that all Lyme patients have similar immune systems. They ignore the diversity of the immune response seen in other diseases....

"It is important to note that a positive IgG and/or IgM Western blot only implies exposure to B. burgdorferi. It is only part of the test battery and is not confirmatory for Lyme disease. It does not mean the patient has Lyme disease; that is a clinical diagnosis. It must also be kept in mind that these antibody tests are not static: they change over time. A patient negative in the Western blot may seroconvert to a positive pattern with treatment. Conversely, a patient could redevelop an IgM response, suggestive of a recurrent infection."

The Problem of Seronegativity
ELISAs and Western blots are likely to fail in patients not producing detectable antibodies, especially in later Lyme when antibodies present in the blood can fall to extremely low levels.⁶ One study found that only 70% of patients with documented disease showed a significant antibody response.⁷ Another study found that only 3 of 14 patients, culture-positive for the Lyme spirochete, had positive antibody titers.⁸ Yet another study found roughly 20% of patients with Lyme to be seronegative; and these seronegative patients, whose immune system may be least able to defend against Lyme infection, may be the sickest.⁹

A statement by NIAID cautioned that "until better tests are available, the diagnosis of Lyme disease must be based on characteristic clinical findings in which the results of laboratory tests play a supportive role."¹⁰

Noting that ELISAs and Western blots give false negatives and false positives, the FDA issued the following advisory: These tests, the FDA warned, "should only be used to support a clinical diagnosis of Lyme disease and should never be the primary basis for making diagnostic or treatment decisions."¹¹ The same FDA advisory urged retesting in certain cases where the ELISA and Western blot show negative results.

Summary of Problems with All Diagnostic Tests
Problems with the diagnostic tests for Lyme, the serologic tests in particular, vitally affect whether patients are diagnosed accurately and thus receive prompt, adequate treatment. Since the Dearborn revisions in 1996, the CDC's surveillance criteria have relied heavily on a two-step serologic requirement; a positive ELISA, then Western blots showing positive only on the restrictive pattern of bands approved by the CDC. Misapplied, this two-step requirement has contributed substantially to the difficulties in clinically diagnosing, treating and preventing sequelae in Lyme disease.

In a Townsend column this coming fall, I'll elaborate on the utility and limitations of lab tests for Lyme. Here, I'll quote from a paper on medical and legal aspects of Lyme disease that sums up the "diagnostic testing dilemmas." The summary includes tests by polymerase chain reaction (PCR) and tests of cerebrospinal fluid (CSF):
"The ELISA test lacks sufficient sensitivity to be useful. The Western blot has a greater sensitivity, but (with the possible exception of IgM antibodies) reflects past infection and will miss between 20-30% of cases that are seronegative. This drawback is particularly evident using the national surveillance case definition criteria. The PCR has great specificity, but its yield is poor given the sparsity of organisms in the host, particularly in body fluids. Tests of CSF suffer from the same defects as those of serum and may miss between 20-43% of patients with active infection. The current state of diagnostic testing cannot demonstrate the eradication of B. burgdorferi (because negative test results do not mean an absence of infection). Conversely, demonstration of active infection is not feasible as a matter of routine, given the insensitivity of the PCR test and the impracticality of culture tests. Hence the diagnosis of Lyme disease remains primarily clinical, with the focus on vector exposure and symptoms that reflect the multisystemic nature of the disease."¹²

Conclusion
US Senate committee language included in a Congressional Appropriations Act in 2002 expressed concern about misapplication of the CDC surveillance criteria for Lyme:
"The Committee is distressed in hearing of the widespread misuse of the current Lyme disease surveillance case definition. While the CDC does state that 'this surveillance case definition was developed for national reporting of Lyme disease; it is NOT appropriate for clinical diagnosis,' the definition is reportedly misused as a standard of care for healthcare reimbursement, product (test) development, medical license hearings, and other legal cases. The CDC is encouraged to aggressively pursue and correct this misuse of this definition. This includes issuing an alert to the public and physicians, as well as actively issuing letters to places misusing this definition."¹³

The word "reportedly" signaled to me that the Senate had gotten enough of an earful from affected parties to encourage the CDC to be more forceful in explaining its surveillance requirements for Lyme, but not nearly enough to hold the CDC accountable for misuse of these criteria. Puzzled as to how such misapplications occur, given the number of public advisories about misuse, I interviewed Pat Smith, President of the Lyme Disease Association, Inc. (LDA).

Ms. Smith is constantly in touch with Lyme patients, physicians and advocates throughout the US. She hears firsthand about the difficulties that numerous patients experience in getting diagnosed, treated, and reimbursed for proper, timely care, particularly patients with persistent Lyme. Physicians tell her about the pressures exerted upon them by insurers, colleagues, and sometimes public officials not to diagnose chronic Lyme, not to treat long-term, not to put in for reimbursement of lengthy antibiotic therapy. She regularly attends and testifies at government hearings on Lyme, where she listens to witnesses making the same complaints. The gist of her understanding of how the CDC surveillance criteria have been misused follows.

It is mandatory for physicians to report Lyme cases to the state departments of health. The health departments send forms to physicians to document these cases; this varies a bit state to state. The health departments then call on physicians to describe and verify many cases. Note: The health departments only forward cases to the CDC that fit the national surveillance criteria, so many reports of clinically-diagnosed Lyme never reach the CDC. Physicians, who've spent time and money documenting clinically-diagnosed cases, eventually grow discouraged. Some stop reporting to the health departments for these reasons.

According to information Ms. Smith has received from physicians, doctors who continue to diagnose and treat chronic or recurrent Lyme often show up on the "radar" of insurers. The insurers, she's learned, may notify these doctors that their use of antibiotics is much higher than normal, warning the physicians that if they don't cease prescribing antibiotics at these high levels the insurers will sever their relationship with them. In some instances insurers have actually told patients that the treatment they've received doesn't meet CDC guidelines (which don't exist for clinical diagnosis and care).

Insurers have complained to state medical boards about physicians they believe to be diagnosing and treating Lyme outside CDC guidelines, and they've recommended that patients file similar complaints to the boards. Physicians who feel that Lyme is overdiagnosed, that persistent infection is rare, or that extended antibiotic therapy is inappropriate, have complained as well to state medical boards about colleagues who diagnose and treat long-term disease.

Ms. Smith couldn't offer precise estimates of the percentages of patients and physicians adversely affected by misapplication of the CDC's surveillance criteria. Her impression, though, is that the percentage is "huge" for patients. The LDA has therefore devoted much time to educating federal and state officials in the legislative and executive branches of government about the effect misapplication of the CDC surveillance criteria has had on patient care.

In 2003, for example, the LDA arranged a meeting in the Washington, DC, headquarters of the Secretary of the Department of Health and Human Services (HHS). Many high officials of the CDC and NIH attended in person or through teleconferencing. An urgent matter on the agenda was the necessity of obliging the CDC to issue letters to physicians and statements to the public that clearly explain — and encourage — proper use of its surveillance requirements.

The LDA has also proposed that the CDC maintain a dual tracking system for Lyme: one "track" to record only cases that fit the strict national surveillance criteria; the second to record all clinically-diagnosed cases not fitting the case definition for incidence. Such a dual system, says Ms. Smith, would better reflect the actual total number of Lyme cases, motivate doctors to report cases, and remove the stigma of diagnosing patients whose cases don't meet the national surveillance criteria.

Novelist Amy Tan speaks about that stigmatization in its broadest, most harmful sense in her preface to the LDA's upcoming Lyme Disease Update: Science, Policy & Law:
"As a patient, I have joined a club of people with a stigmatized disease that many doctors do not want to treat. While I have been lucky enough to find a doctor who is willing to provide open-ended treatment — and I have the means to pay for it — many of my fellow Lyme patients have gone without appropriate care. As a consequence, they have lost their health, their jobs, their homes, their marriages, and their lives."

Correction: Toward the end of my column on the ABCs of Lyme Disease (Townsend Letter, April 2004), I wrote that diagnostic tests for confirmation of tick-borne infections associated with Lyme have the same deficiencies that tests for Lyme have. Untrue: the section on coinfections in the Lyme Disease Update supplies accurate information about the relative reliability of these tests.

References
1. Center for Disease Control, Recommendations for the use of Lyme disease vaccine, MMWR, 6/4/99; Vol 48 (Issue RR-7).
2. Mead P, Statement at hearing on Lyme disease prevention and control, Connecticut Attorney General's Office, 1/29/04.
3. Weintraub P, Conflicts of interest in Lyme disease, LDA (Jackson, New Jersey), 2001.
4. Bakken LL et al., Interlaboratory comparison of test results for detection of Lyme disease by participants in the Wisconsin State Laboratory of Hygiene/College of American Pathologists Proficiency Testing Program, J Clin Microbiol, 1997;35(3):537-543.
5. Harris NS, An understanding of laboratory testing for Lyme disease, J Spirochetal & Tick-borne Diseases, 1998, Vol 5 (Spring/Summer):16-26.
6. NIAID, NIAID collaboration yields new test for Lyme disease, NIH News Advisory, 6/18/01.
7. Aguero-Rosenfeld ME et al., Evolution of the serologic response to Borrelia burgdorferi in treated patients with culture-confirmed erythema migrans, J Clin Microbiol, 1996:34(1):1-9. Also: Aguero-Rosenfeld ME et al., Serodiagnosis in early Lyme disease, J Clin Microbiol, 1993;31(12):3090-3095.
8. Rawlings JA et al., Isolation of Borrelia Spirochetes from patients in Texas, J Clin Microbiol, 1987;25(7):1148-1150.
9. Donta ST, Tetracycline therapy for chronic Lyme disease, Clin Infect Dis, 1997;25 Suppl 1:S52-S56
10. NIAID Diagnosis of Lyme disease: available at http://www.niaid.nih.gov/dmid/lyme/diagnosis.htm.
11. FDA, Lyme disease test kits: potential for misdiagnosis, FDA Medical Bulletin, 1999; Summer (Final Issue).
12. Johnson L et al., Treatment of tick-borne diseases: a medicolegal assessment, publication pending.
13. Departments of Labor, Health & Human Services, Education, & Related Agencies Appropriations Act 2002.

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