Hello everyone.
My name is Elli Theel, I am the director of the Infectious Diseases Serology Laboratory
here at Mayo Clinic in Rochester, Minnesota.
Today I will be talking about laboratory utilization management, specifically for diagnostic testing
for tickborne diseases.
Before we begin, these are my relevant disclosures, although I will not be talking about any specific
assays from these manufacturers.
So, diving right in, diagnostic testing for tickborne diseases can be tricky, and the
type of test ordered really depends on multiple aspects, including amongst other things, geographic
exposure, and timing of presentation post-symptom onset.
In an effort to simplify and optimize test ordering practices for suspected tickborne
illnesses, we at Mayo Clinic have put together an algorithm specifically for acute tickborne
disease testing, which you can see here, and I will go over today step by step.
This algorithm is available to anyone on the Mayo Clinic Laboratories website, so anybody
can have access to it.
If we dive right in, the algorithm starts here and if we zoom in, you can see it begins
with careful clinical evaluation that would drive suspicion for a tickborne illness, including
noting whether the patient is having illness during tick season, which is in most regions
of North America at least, would be during late spring, summer, and early fall seasons.
Those symptoms associated with tickborne illnesses are often non-specific, but include manifestations
like fever, chills, headache, muscle aches, joint pain, neck pain and skin rash, amongst
others.
Additionally, patients should have had a known exposure to ticks, not necessarily a known
tick bite, however.
And the epidemiology of tickborne infections at the place of exposure, or where the patient
was exposed, is also important for health care workers to be aware of.
Once symptoms and risk are established, we can move down the algorithm, starting at the
left, which outlines regions in North America that are at risk of infection with the first
pathogen which we’ll discuss, which is tickborne relapsing fever.
So, a bit more information on this pathogen, tickborne relapsing fever is caused by multiple
species in the Borrelia genus, including Borrelia hermsii and Borrelia turicatae.
These spirochete organisms are endemic in 14 western states as listed here, and in the
algorithm, and are transmitted by soft bodied ticks, which often reside in rustic cabins.
Diagnostic testing for at risk patients in the acute stage of disease includes microscopy
of peripheral blood smears to look for the extracellular spirochete as you can see pointed
out with the arrows in the image to the right.
Although not yet available at Mayo Clinic Laboratories, serologic testing to detect
antibodies to these organisms may be helpful in patients with at least 10 to 14 days of
symptoms who are negative by other testing methods, but for whom tickborne relapsing
fever does remain high on the differential.
The next branch off the algorithm focuses on patients who present with symptoms consistent
with and have had an exposure risk for Rocky Mountain Spotted Fever.
Zooming in on this branch, Rocky Mountain Spotted Fever is caused by infection with
Rickettsia rickettsii, an intracellular bacterial organism transmitted by multiple different
hard tick species and is particularly prevalent in a number of states in the central eastern
part of North America including North Carolina, Oklahoma, Arkansas, Tennessee, and Missouri,
as you can see in the maps to the right.
Importantly, without treatment, this infection can be rapidly fatal, and as a result, empiric
treatment is indicated for all at risk patients while awaiting lab test results.
Laboratory testing currently relies on detection of an antibody response to this organism,
by showing either seroconversion from antibody negative to antibody positive, or by documenting
a significant increase in IgG antibody titers over a 1 to 3 week period.
Due to this delay though, you can see why empiric treatment is indicated for at risk
patients.
Molecular testing is not routinely available or used at this time outside of the CDC or
certain public health laboratories.
So, the final branch of the tickborne diseases testing algorithm is perhaps the most complicated
and involves guidelines for testing for some of the most common pathogens, including Borrelia
burgdorferi, the causative agent of Lyme disease, Ehrlichia species, Anaplasma phagocytophilum,
Babesia species and Borrelia miyamotoi.
Many of these pathogens are transmitted by the same tick species, primarily Ixodes ticks
and as a result they have similar areas of endemicity as you’ll see.
As a result of this, co-infections are possible though and so testing for multiple pathogens
is sometimes important to consider.
So, starting with the geographic distribution for a few of these, you can see in dark purple
the states associated with the highest Ehrlichia and Anaplasma incidence rates, and in orange
you can see where Babesia infections are most frequently documented.
Borrelia miyamotoi, a spirochete also associated with causing a tickborne relapsing fever but
transmitted through Ixodes species ticks, instead of the soft bodied ticks, although
Borrelia miyamotoi distribution is not shown on these maps due to its transmission by Ixodes
species ticks, we would expect it, or it is typically found, in the Northeastern United
States as well, similar to the distribution of Babesia and Anaplasma.
And then of course, we have the most common tickborne illness both in North America and
in Europe, which is Lyme disease, caused primarily by Borrelia burgdorferi here in the United
States.
And it too has a similar distribution as to what we just saw with Anaplasma and Babesia.
And as you can see, similar to those two pathogens is found primarily in the upper midwest and
northeastern states, although the geographic range has definitely increased and expanded
over the past decade or so moving further and further into more central and southern
US states.
So, once geographic location has been established where the patient has been exposed, the next
part of the algorithm is based on the presence or absence of an erythema migrans or bullseye
rash, which develops at the site of a tick bite in roughly 70 to 80% of patients who
have been recently infected with Lyme disease.
For individuals who develop this rash, testing for Lyme disease is actually not indicated,
as that is a pathognomonic sign of infection.
The recommendation in these patients is to treat for Lyme disease and to monitor for
symptoms related to other potential tickborne pathogens.
If on the other hand there is no erythema migrans rash, for symptomatic patients, we
recommend consideration of empiric treatment for ehrlichiosis and anaplasmosis while awaiting
test results for these other pathogens, and the recommended testing options available
through Mayo Clinic Laboratories for these other tickborne agents are indicated below.
But I’ll go through these in a little bit more detail, starting with the non-Lyme disease
tickborne pathogens including Ehrlichia, Anaplasma, Babesia and B. miyamotoi.
For patients with appropriate exposure history and symptoms consistent with infection with
either of these organisms, the decision between what type of test to order, whether molecular
or serologic, really depends on a number of factors, including test availability and the
duration of patient symptoms prior to presentation for clinical care.
For patients with less than 7 to 10 days of symptoms, the preferred diagnostic testing
is molecular, or PCR, based for direct detection of genetic material from the organism.
While a positive result from these assays is conclusive for recent infection, a negative
result may not actually rule it out.
For patients where infection is still suspected, or who have had more than 7 to 10 days of
symptoms, serologic testing to probe the immune response to the pathogen is recommended.
Although a specific serology test for B. miyamotoi is not offered currently at Mayo Clinic Laboratories,
for the remaining three pathogens, we do offer a semi-quantitative immunofluorescence immunoassay
that provides an antibody titer.
High antibody titers suggest recent infection, although serial testing is often necessary
to document either seroconversion or a significant rise in antibody titers to confirm infection.
Turning to diagnostic testing for Lyme disease, similar to the previous pathogens, molecular
and serologic testing are available, however, unlike the other tick-borne pathogens, serologic
testing is actually the preferred method for testing for Lyme disease.
And the reason for this is that molecular testing, at least at this time, is simply
insensitive, likely due to both the transient as well as low level bacteremia that’s associated
with infection.
As you can see in the table, testing of blood and spinal fluid is actually associated with
mean sensitivities of just 18 to 22%.
However, testing of suspected erythema migrans lesion biopsies or synovial fluid is associated
with higher PCR sensitivity rate, as you can see.
And it is really just in these circumstances that we recommend molecular testing for Lyme
disease –specifically in patients with joint pain as well as in patients with abnormal
appearing erythema migrans rashes, an example of which is shown on the upper right.
Given the pathognomonic nature of a classic erythema migrans rash, as we discussed before
though, diagnostic testing in these patients is not indicated and they can be treated empirically.
Aside from these scenarios, serologic testing remains the method of choice and testing is
performed using either the standard or modified two-tiered testing algorithm, both of which
are available through Mayo Clinic Laboratories.
For further information on the difference between these algorithms, I will refer you
to a prior Hot Topic, entitled Modified Two-Tiered Testing for Lyme disease, which was presented
on October 6th in 2021.
Going back to the algorithm, as you’ll see, the remaining sections really provide some
test interpretation guidance and recommend additional testing on an as needed basis.
For example, for patients negative by PCR for tickborne pathogens, but for whom clinically
the diagnosis cannot be ruled out, we would recommend follow up testing using a serologic
assay.
Also, for patients with Lyme disease who also present with neurologic symptoms, we would
recommend ordering the Lyme disease antibody index assay to help determine whether intrathecal
anti-Borrelia antibody synthesis is occurring, which would be consistent with neuroinvasive
Lyme disease.
And finally, a detailed summary of all the available Lyme disease diagnostic tests available
through Mayo Clinic Laboratories are listed here on this slide.