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Introduction

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 tick-borne diseases. 

Disclosures

Before we begin, these are my relevant disclosures, although I will not be talking about any specific assays from these manufacturers. 

Testing algorithm available on Mayo Clinic Laboratories website

So, diving right in, diagnostic testing for tick-borne 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 tick-borne illnesses, we at Mayo Clinic have put together an algorithm specifically for acute tick-borne 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 tick-borne 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 tick-borne illnesses are often nonspecific, 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 tick-borne 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 tick-borne relapsing fever. 

Tick-borne relapsing fever

So, a bit more information on this pathogen, tick-borne 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 tick-borne 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.

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 tick-borne 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.

Geographical location and annual incidence

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 tick-borne 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 tick-borne 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 U.S. 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 bull's-eye 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 tick-borne 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 tick-borne agents are indicated below. 

Testing for ehrlichiosis, anaplasmosis, babesiosis and B. miyamotoi infections

But I’ll go through these in a little bit more detail, starting with the non-Lyme disease tick-borne 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.

Testing for Lyme disease

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 Oct. 6 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 tick-borne 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. 

Testing

And finally, a detailed summary of all the available Lyme disease diagnostic tests available through Mayo Clinic Laboratories are listed here on this slide. 

Questions?

Contact us: mcleducation@mayo.edu

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