EVERYTHING YOU ALWAYS
WANTED TO KNOW
ABOUT THE CD57 TEST
By: GINGER SAVELY, RN, FNP-C
From coast to coast, frustrations abound among patients and
clinicians regarding the diagnosis of chronic Lyme disease.
Misinformed health care providers in Texas and surrounding states
consider the infection rare and non-endemic. They are inclined to
rule out Lyme disease based on the negative result of a laboratory
test that, unbeknownst to them, is highly insensitive. In the absence
of a reliable laboratory test or adequate experience in the
recognition of the varied and complex presentations of the illness,
most clinicians are ill-equipped to diagnose chronic Lyme disease.
Many patients suffer needlessly for years, hopelessly lost in the
maze of the health care system, looking for answers and enduring the
skepticism of practitioners inexperienced with the disease’s signs
What is needed is a better Lyme test or some other objective measure
to persuade the practitioner to consider the diagnosis of chronic
Enter the CD57 test! You may have heard the term “CD57″
tossed around on chat groups, or your Lyme-literate health care
provider may have even explained the test to you in one of your
moments of brain-fogged stupor. What is this number that sounds more
like a type of Heinz steak sauce than a lab test, and what in the
world does it have to do with Lyme disease?
Let’s start by going back to basic high school biology. You may
remember that white blood cells (a.k.a. leukocytes) are the
components of blood that help the body fight infections and other
diseases. White blood cells can be categorized as either granulocytes
or mononuclear leukocytes. Mononuclear leukocytes are further sub-
grouped into monocytes and lymphocytes.
Lymphocytes, found in the blood, tissues and lymphoid organs, attack
antigens (foreign proteins) in different ways. The main lymphocyte
sub-types are B-cells, T-cells and natural killer (NK) cells. B-cells
make antibodies that are stimulated by infection or vaccination. T-
cells and NK cells, on the other hand, are the cellular aggressors in
the immune system and are our main focus in the discussion that
Let’s pause a moment and introduce something you probably never
learned about in high school biology class: CD markers. CD, which
stands for “cluster designation”, is a glycoprotein molecule on the
cell surface that acts as an identifying marker.
Think of comparing
cells as comparing people. Humans are made up of innumerable
superficial identifying characteristics (such as hair color, eye
color, etc.) and so are cells. Cells probably have thousands of
different identifying markers, or CDs, expressed on their surfaces,
but 200 or so have been recognized and named so far.
Each different marker (or CD) on a cell is named with a number, which
signifies nothing more than the order in which the CD was discovered.
On any given cell there are many different cluster designation
markers (CDs), giving each cell its unique appearance and function
but also linking certain cells by their similarities (like grouping
all people with brown hair or all people with blue eyes). Cells that
have a certain kind of CD present on their surface are denoted as +
for that CD type (e.g., a cell with CD57 markers on its surface is
NK cells have their own specific surface markers. The predominant
marker is CD56. The percentage of CD56+ NK cells is often measured in
patients with chronic diseases as a marker of immune status: the
lower the CD56 level, the weaker the immune system. You may have
heard Chronic Fatigue Syndrome patients talk about their CD56 counts.
A smaller population of NK cells are CD57+.
A below-normal count has been associated with chronic Lyme disease by
the work of Drs. Raphael Stricker and Edward Winger. No one knows for
sure why CD57+ NK cells are low in Lyme disease patients, but it is
important to note that many disease states that are often confused
with chronic Lyme (MS, systemic lupus, rheumatoid arthritis) are not
associated with low CD57+ NK counts.
The good news is that for most
Lyme patients the CD57+ NK level increases as treatment progresses
and health is regained.
CD57 markers can also be expressed on other kinds of cells, including
T-cells, so it is important to distinguish between CD57+ T-cells and
CD57+ NK cells. Clinicians need to be aware that many testing
laboratories claiming to perform the CD57 test are actually looking
at CD57+ T-cells rather than CD57+ NK cells, which are the cells of
interest in chronic Lyme disease.
In order for a testing laboratory to measure the CD57+ NK level, it
first measures the percentage of lymphocytes that are CD57+ NK cells.
Then an absolute count is calculated by multiplying that percentage
by the patient’s total lymphocyte count. The standard normal range
for the absolute CD57 NK count is 60 to 360 cells per microliter of
This wide range was established based upon test results of
hundreds of healthy patients. By these laboratory standards, a test
result below 60 cells per microliter would be considered below normal
and therefore associated with chronic Lyme disease. However, a recent
study of my Austin patients has led me to believe that 100 cells per
microliter is a more reliable threshold separating Lyme patients and
When Drs Stricker and Winger discovered that CD57+ NK cells are low
in chronic Lyme patients and tend to increase with patients’ clinical
improvement, an opportunity arose for Lyme-literate practitioners to
utilize a handy tool to aid in the diagnosis of chronic Lyme disease,
to follow treatment progress, and to determine treatment endpoint.
Just as AIDS patients have always held great store in their CD4 T-
cell count, Lyme patients now have a fairly reliable marker of the
status of their illness.
It is important to remember that the CD57 result is just a number;
far more important is the patient’s clinical status. An old professor
of mine used to say, “treat the patient, not the lab test!” There is
still much we do not know about the CD57 marker and what other
factors may lower or raise it.
However, overall, the CD57+ NK count
is a useful tool in diagnosing and treating chronic Lyme disease in
most patients. As a measure of immune status, it provides an indirect
measure of bacterial load and severity of illness. Furthermore, in a
patient who has a negative or indeterminate Lyme test but is highly
suspect for the disease, the clinician may utilize the CD57+ NK count
as one more piece in the complex puzzle of a Lyme disease diagnosis.
Postscript: If you would like your health care provider to order the
CD57 NK test for you, your blood sample needs to be drawn into an
EDTA tube (lavender top) on Monday through Thursday and sent
immediately to either LabCorp in Burlington, NC, or Clinical
Pathology Laboratories (CPL) in Austin, TX.
LabCorp and CPL are the
only two labs that perform this test properly. Quest does NOT. The
LabCorp test code is #505026 and is named HNK1 (CD57) Panel. The CPL
test code is #4886, CD57 for Lyme disease.
The test is time-sensitive
and must be performed within 12 hours of collection, so blood should
not be drawn on a Friday or results may be inaccurate.
CD 57 Test Info
CDC States- Other Types of Laboratory Testing
Some laboratories offer Lyme disease testing using assays whose accuracy and clinical usefulness have not been adequately established. Unvalidated tests available as of 2011 include:
• Capture assays for antigens in urine
• Culture, immunofluorescence staining, or cell sorting of cell wall-deficient or cystic forms of B. burgdorferi
• Lymphocyte transformation tests
• Quantitative CD57 lymphocyte assays
• “Reverse Western blots”
• In-house criteria for interpretation of immunoblots
• Measurements of antibodies in joint fluid (synovial fluid)
• IgM or IgG tests without a previous ELISA/EIA/IFA
A CD 57 could be in normal range with terminal Borreliosis although Borreliosis is not usually terminal in a direct fashion. Acute carditis or complete heart block for example could be terminal without significant immune dysregulation of innate specific CD cell counts. My experience is that in overwhelming or severe immune dysregulation especially with multiple tbds the CD 57 is in low ranges and slow or never responds.
Likewise, a patient can clinically respond after compliant, complex, long treatment plans yet maintain a low level. These patients are in remission but usually closer to relapsing than recovered patients who also recover their CD 57 response. Obviously the CD 57 is not a black and white, yes or no test, although a zero CD 57 is an ominous sign at the start of rx.
The recent article on CD 57 counts which found no difference in those recovered after treating Lyme disease from those who did not have Lyme disease had questionable methodology. The baseline CD 57 counts before rx and then after rx are very important and I don't think this was in the study/ ;and in those who recover completely ( especially when the sample is such a small number, 12 ) one is more likely to find matching normal CD 57 counts. It seems an oxymoron that the methodology would have included those who did not respond to short term "appropriate" treatment- because there likely is a study position that that is a very rare event if at all.
Comment to above blog by LLPA
I would recommend that he/she come to ILADS in October, and discuss his views on testing with the testing experts, including Nick Harris, Jyotsna Shah, Ray Stricker and Ginger Savely. It's grossly unfair, and I believe unprofessional, for a doctor to put something out anonymously on a blog, challenging the dedicated work of those who have done so much to shed a bit of light on testing.
I get the impression from several ILADS docs that to the best of our knowledge, a low CD57+ natural killer T-cell count may be specific to Lyme and/or coinfections, but is not particularly sensitive. In other words, some people with Lyme/coinfections have a low count, but some people symptomatic for Lyme/coinfections have a count within normal ranges. Although an increased count from low to normal range is a likely indicator of improved immune functioning, a count within normal range is not necessarily a good indicator of treatment outcome.
In my opinion, the best explanation for this is that in Lyme disease, chronic activation of inflammatory cytokines activates IFN-gamma, which excessively stimulates IDO and tryptophan catabolism, resulting in tryptophan depletion and neurotoxically high levels of tryptophan catabolites.
This phenomenon is known to reduce proliferation of cytotoxic CD8+ T-cells in HIV infection, cancer, chronic hep B, and chronic hep C. It also significantly strips CD8+ T-cells of their cytotoxic capacity, even when those T cells remain viable, and proliferation rates are only moderately reduced. If this also occurs with CD57+ natural killer T-cells, it would explain the clinical observations I’ve been hearing about.
The 60-360 normal range was established based upon results of 1000 random "healthy" subjects. Dr. Ed Winger who is the one who first started doing the test at LabCorp is the one who told me this.
The CD57 study XXX presented at ILADS a few years ago showed the normal diurnal and day to day variation to be quite large - as much as a 50% variation in any given day (in both sick and well subjects). It also showed that asymptomatic subjects had levels consistently above 100 ( which I have since used as my cut off for normal, rather than 60).
Ray Stricker tried for years to get Quest to do the test exactly like LabCorp did but for some reason they wouldn't do it. I hate to be a skeptic, but based on our past experience with Quest, I'll "believe it when I see it" that they will consistently perform the test according to the Winger/Stricker guidelines. But, hopefully they will!
We have all been aware for several years that LabCorp was the only lab that provided CD57 reports that were reproducible and matched the clinical picture. Specifically, Quest Labs did not even include the specific "CD57+, CD3 -, CD8 -" cell in their lymphocyte subset analyses.
That specific cell is a surrogate marker for Lyme activity -- (when it is down the disease is active, and with recovery it returns to normal.) (Yes, that's just like the HIV marker -- CD4 or T4 Helper cell -- which also reliably estimates the patient's status.)
Almost a year ago, after more than half a dozen phone calls to the Nichols/Quest Lab in California, I persuaded them to add it to their report. It was easy to add it, since the instrument was counting all of those markers, it just wasn't reporting this group.
I have a small number of patients who do not get reimbursed for LabCorp and they are covered by Quest. It took this long for me to realize that i had never seen a "normal" CD57 from Quest. In fact, they don't even print a reference range! I used the LabCorp 60 - 360, since I knew that the technology was very accurate, and there should not be a significant difference from one lab to another. Well, recently my wife was not her old energetic self, and I ordered a CD57 from LabCorp, and sent a split from the same specimen to Quest. I was delighted with the 96 from LabCorp, but very distressed by the 23 reported by Quest.
Both labs reported both the % and the absolute counts, and they didn't match! I went back to the Nichols branch, and spoke to one of the physicians, who implied that this variation was within reasonable limits! I refused to accept that, and she agreed to perform another, at no charge -- as did the LabCorp person. Shortly later, I got a call from the Quest doctor.
She had discovered that LabCorp was giving the % OF TOTAL LYMPHS, while the Quest computer was calculating the % OF TOTAL WBC"S !!! When recalculated the results were deliciously similar, in favor of the healthy result. They have promised me that the program will be changed, since the LabCorp method was adopted from the discovery team, and the Quest method was simply an incorrect assumption.
Now, all we have to figure out is what is the OPTIMUM RANGE, because the classical analysis of the results by the Bell-shaped curve MUST BE SERIOUSLY SKEWED TO THE LOW END, SINCE THE ONLY PEOPLE BEING TESTED UP TO NOW EITHER HAVE LYME OR ARE SUSPECTED OF HAVING IT. IF WE WATCH THE RESULTS FROM QUEST FOR A FEW MONTHS, ONCE THEY HAVE CHANGED THE PROGRAM, THEY WILL BE ABLE TO PROVIDE A BETTER REFERENCE RANGE, SINCE THEY NOW REPORT IT ON ALL THEIR TESTS, WHILE IT STILL REQUIRES SPECIAL ORDER AT LABCORP.