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Finally, in setting up a nationwide standard for a positive WB, one
makes several assumptions -- that all strains of Bb will provoke
similar immune responses in all patients, that all patients will mount
a measurable immune response when exposed to Bb, and that the IgG
immune response will persist in an infected patient. Unfortunately,
none of these is always true. Therefore, a judicious interpretation
of Western blot results in a clinical setting should take into account
both the vagaries of the human immune response and the possibility that
strain variations in Bb might produce unusual banding patterns.

The CDC criteria for a positive WB are as follows:

* For IgM, 2 of the following three bands: OspC (21-25), 39 and 41.
* For IgG, 5 of the following ten bands: 18, OspC (21-25), 28, 30,
39, 41, 45, 58, 66 and 93.

How were these recommendations arrived at? The IgG criteria were taken
pretty much unchanged from a 1993 paper by Dressler, Whalen, Reinhardt
and Steere [2]. In this study, the authors performed immunoblots on
several dozen patients with well characterized Lyme disease and a
strong antibody response and looked at the resulting blot patterns.
By doing some fairly involved statistical analysis, they could
determine which bands showed up most often and which best distinguished
LD patients from control subjects who did not have LD. They found that
by requiring 5 of the 10 bands listed, they could make the results the
most specific, in their view, without sacrificing too much sensitivity.
("Sensitivity" means the ability of the test to detect patients who
have the disease, "specificity" means the ability of the test to
exclude those who don't. Usually, an increase in one of these measures
means a decrease in the other.)

The IgM criteria were determined in much the same fashion (by different
authors in different papers). Fewer bands are required here because
the immune response is less mature at this point. Several studies have
shown that the first band to show up on a Lyme disease patient's IgM
blot is usually the one at 41 kDa, followed by the OspC band and/or
the one at 39. The OspC and 39 kDa band are highly specific for Bb,
while the 41 kDa band isn't. That's why the 41 by itself isn't
considered adequate. Here's the rub, though: the CDC doesn't want the
IgM criteria being used for any patient that has been sick for more
than a month or two. The thinking here is that by this time an IgG
response should have kicked in and the IgM criteria, because they
require fewer bands, are not appropriate for patients with later

A number of criticisms have been offered of the CDC criteria since
their adoption in 1994. The first is centered on the CDC's failure to
make any qualitative distinction among the various bands that can show
up on a patient's Western blot. A number of Lyme disease researchers
feel that different bands on a WB have different relative importance --
that "all bands are not created equal." For example, many patients
with Lyme disease will show reactive bands at, say, 60 and/or 66 kDa.
However, these correspond to common proteins in many bacteria, not
just Borrelia burgdorferi, and so are of limited diagnostic usefulness,
especially in the absence of other, more species-specific bands. The
band at 41 kDa corresponds to Bb's flagella (the whip like organelles
used for locomotion -- Bb has several) and is one of the earliest to
show up on the Western blots of Lyme disease patients. But for some
reason it is also the most commonly appearing band in control subjects.
This may be due to the fact that many people are exposed to spirochetes
at some time in their lives and so their sera might cross react with
this protein.

On the other hand, certain other bands are considered highly specific for
Bb -- the aforementioned 31 kDa band, for example, or 34 (OspB) or 39 or
OspC (anywhere between 21 and 25). The 83 and 94 kDa bands are also
thought to be species-specific. Many Lyme disease scientists believe
that any patient whose IgG Western blot exhibits bands at, say, any
three (or even two) of these locations almost certainly has Lyme
disease, regardless of whether or not any other bands are present. They
feel that these bands on a Lyme Western blot are simply more meaningful
than other, less specific ones and that a rational interpretation of a
WB result should take this into account. Unfortunately, this does not
often happen, and will happen even less with the new CDC criteria.

A second criticism of the CDC Western blot criteria is that they fail
to include the 31 and 34 kDa bands. This does indeed seem like an odd
decision, since antibodies with these molecular weights correspond to
the OspA and OspB proteins of B. burgdorferi, which are considered to
be among the most species-specific proteins of the organism. So why
didn't Dressler et al. include them? Answer: These bands tend to
appear late if at all in Lyme disease patients, and did not show up
with great frequency in the patients that the Dressler et al. group
studied (though they did show up sometimes). As a result, they weren't
deemed to have much diagnostic value and didn't find their way onto the
CDC hot list. However, while the absence of either of these bands from
a patient's immunoblot result does not rule out Lyme disease, their
presence is hardly meaningless. Thus, many Lyme disease experts
believe it is a serious mistake to exclude these two antibody proteins
from the list of significant bands. The CDC's decision to do so seems
particularly strange in light of the fact that it is the OspA component
of Bb that is being used as the stimulating antigen in the ongoing
experimental Lyme disease vaccine trials. As one immunologist remarked
shortly after the 1994 CDC conference, "If OspA is so unimportant, then
why the heck are we vaccinating people with it?"

Finally, it is important to keep in mind that no matter how carefully
the Western blot test is carried out and interpreted, its usefulness,
like that of all tests that measure B. burgdorferi antibodies, is
ultimately contingent on the reliability of the human immune response as
an indicator of exposure to B. burgdorferi. There are several
scenarios in which the lack of a detectable antibody response may
falsely point to a lack of B. burgdorferi infection. First, it is well
established that early subcurative treatment of Lyme disease can
abrogate the human immune response to B. burgdorferi [3]. Although
this is not thought to be a common phenomenon, a recent comparative
trial for the treatment of erythema migrans found that a majority of
patients who failed early treatment and suffered clinical relapse were
seronegative at the time of relapse [4]. Even treatment for
disseminated Lyme disease, in which the patient's IgG immune response
was previously well-established, can render a patient seronegative
after treatment despite post-treatment culture-positivity for
B. burgdorferi [5,6].

In addition, patients with Lyme disease may not test positive for
exposure to B. burgdorferi because their antibodies to the organism are
bound up in immune complexes [7]. Once steps are taken to dissociate
these immune complexes, free antibody can be detected; however, this
is not routinely done when performing serologic tests for Lyme disease.
Finally, an indeterminate number of patients with late Lyme disease are
simply seronegative for unknown reasons [8]. The actual percentage of
such cases as a proportion of all Lyme disease cases is impossible to
estimate, since most studies of late Lyme disease enroll only
seropositive patients, which tends to reinforce the circular and
erroneous notion that virtually all patients with late Lyme disease
are seropositive.

It should also be noted that a positive Western blot is not necessarily
an indication of active Lyme disease. A patient's immune response to
B. burgdorferi can remain intact long after curative treatment for a
Lyme infection; therefore, the results of a Western blot assay should
always be interpreted in the context of the total clinical picture.

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