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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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