When Columbia University posted a press release in February 2018 about a promising new proof-of-concept study of the Tick-Borne Disease Serochip (TBD Serochip), the press office soon had to amend the announcement with an update for the public: no, the test is not available yet; no, you can’t enroll in a clinical trial or send specimens; and no, they don’t know when it will be ready.
Has the university received a lot of public inquiries about the TBD serochip?
“Indeed we have!” said Tim Paul, editorial director of communications, via email.
The excitement around the TBD Serochip is just one sign of how eager the public is for a better tick-borne disease test.
Lyme disease and other tickborne diseases are on the rise in the United States. As the geographic range of ticks expands, perhaps due to climate change, infections are occurring in new locations. The number of reported tickborne diseases more than doubled in the United States between 2004 and 2016, according to the U.S. Centers for Disease Control and Prevention.
Lyme disease treatment – an oral antibiotic against the Borreliaburgdorferi bacterium — is most effective when administered in the early stages of infection. Delayed treatment can lead to long term damage to the nervous system or joints, and many patients fear the disease will become chronic if diagnosed late (although the CDC maintains that most people respond well to treatment even in later stages of the disease).
Yet diagnosing Lyme disease early can be tricky. Many patients do not notice the initial tick bite and early symptoms of Lyme disease may be vague. Only 70 to 80 percent of infected individuals develop a telltale erythema migrans rash. Meanwhile, current tests, which measure Lyme disease indirectly through the antibodies a person’s body creates to fight the disease, tend to perform poorly in the early weeks of an infection because it takes time for antibody production to rise to detectable levels. By some estimates, traditional serology-based test methods identify fewer than 40% of patients with early disease.
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For Lyme disease, the most common tick-borne disease in the United States, the CDC has recommended the same testing process since 1995: a serology-based two-tiered algorithm. The first tier is an immunoassay, then if the immunoassay results are positive or equivocal, it is followed by the second tier, a Western blot. To address the issue of false negatives for early-stage infections, the CDC suggests a provider consider treatment based on clinical presentation alone if the patient has had symptoms for less than 30 days, and offer a repeat immunoassay a few weeks later to confirm the diagnosis.
Serology has remained the only technique employed by all of the FDA-approved Lyme disease tests, according to a 2016 review in the Journal of Clinical Microbiology (DOI: 10.1128/JCM.03394-15), even while molecular and “-omics” methods have transformed other realms of clinical microbiology diagnostics.
Enzyme-linked immunosorbent assays (ELISA), which are typically used as the first step in the two-tier algorithm, have improved over the years, with targets that are more specific to Borreliaburgdorferi and less likely to cross react with other infectious agents. Yet their performance is still best when they are paired with Western blots, and Western blot testing has many limitations, including low sensitivity for early stage infections and a labor-intensive, somewhat subjective process.
Some researchers are now advocating for new testing algorithms, in particular a two-ELISA algorithm, where an initial positive or equivocal ELISA result is followed by a second ELISA assay that has slightly different targets. They find this method effective and also 27.1% to 44.0% cheaper than the two-tier algorithm with Western blot. A 2018 study comparing three variations of immunoassay-only algorithms found them all accurate, and in some cases even better than the traditional two-tier algorithm. However, the CDC still recommends the traditional two-tier algorithm.
For the other tick-borne diseases, the diagnostic options are limited. Immunofluorescent assays are available for Babesia, Anaplasma, Ehrlichia and Rickettsia, although accuracy varies by laboratory. Some tick-borne viruses can be detected by specialty labs. For other tick-borne diseases, such as Southern tick-associated rash illness (STARI), there are no immunoassays available. There are no commercially available tests that simultaneously detect multiple tick-borne disease agents.
New tests on the horizon
That explains why the TBD Serochip has gotten so much attention this year and piqued the interest of the public. U.S. National Institutes of Health director Francis Collins even highlighted the February TBD Serochip study in a blog post in June, noting that it was developed by NIH-funded researchers. The TBD Serochip is a serological test, like the commercially available tests today. However, it detects multiple targets based on a variety of newly identified antigenic proteins, so it has the potential to be more specific to Borrelia than other than previous tests. Also, it can detect antibodies to multiple tick-borne pathogens simultaneously. The first version of the TBD Serochip can detect Lyme disease, babesiosis, and anaplasmosis, as well as human monocytic ehrlichiosis, Rocky Mountain spotted fever, Heartland virus, and Powasan virus. New pathogens can be added to the assay as new targets are discovered, in a process that the researchers say would take only about 4 weeks.
The lead author of the TBD Serochip journal article, Rafal Tokarz, PhD, told Infectious Disease Advisor in March 2018 that the challenge now is to improve the test and make a simpler version that can be used by clinical laboratories.
“Although our test works quite well, we are still validating it and are trying to make it even more comprehensive by including additional agents that we did not include in the first version of the test,” Tokarz said.
Tokarz told Clinical Laboratory News in July 2018 that the TBD Serochip in its current form would still be useable by specialty labs only, but the goal is to make it a point of care test. He predicted the test would be available for clinical use within the next two years.
The TBD Serochip is just one possible approach to better tick-borne disease testing.
Researchers at the CDC and elsewhere are working to develop tests for tick-borne diseases based on metabolomics, which is the technique of finding a unique signature of metabolites in a person’s blood that corresponds with a certain disease.
A promising proof-of-concept study was published in 2015 showing that liquid chromatography-mass spectrometry could be used to detect a biosignature of 44 “molecular features” that correctly classify early Lyme disease patients versus healthy controls. A follow-up study in 2017 showed that the same technique could distinguish between early Lyme disease and STARI, which is a tick-borne illness that causes a rash similar to Lyme disease. There is currently no diagnostic blood test for STARI because the causative agent is unknown.
Meanwhile, other researcher groups are searching for molecular diagnostic techniques to identify tick-borne diseases. A non-for profit organization called Translational Genomics Research Institute (TGen) announced in 2017 it had raised hundreds of thousands of dollars from patient advocacy groups to develop LymeSeq, a DNA-based test to detect “multiple strains of Lyme bacteria.” Their goal, as of 2016, was to use next generation DNA amplicon sequencing to detect “over 22 strains of Lyme bacteria, all major co-infections and non-Lyme causes of disease like influenza or staph in a single blood test.”
Some reference laboratories already offer polymerase chain reaction (PCR) blood tests for Lyme disease, but with the caveat that they may be used as an aid to diagnosis but are not diagnostic alone. In general, direct detection of the spirochete bacteria that cause Lyme disease bacteria has not worked clinically because there are so few bacterial cells in the body. As a result, the sensitivity of PCR to B. burgdorferi DNA in blood, plasma, or serum samples from patients with Lyme disease is low.
While academic researchers pursue these new directions, in vitro diagnostics developers appear to be focusing on improving on serology-based tests that are already available, making them faster and easier to use.
For example, Quidel announced in August 2018 that its Sofia 2 Lyme fluorescent immunoassay received FDA 510(k) clearance and a CLIA waiver. The assay, which runs on the 2-pound benchtop Sofia 2 Fluorescent Immunoassay Analyzer, requires only a fingerstick whole blood sample. It detects IgM and IgG antibodies to Borrelia burgdorferi, returning a result in 3 to 15 minutes. With its new CLIA waiver, the assay can now be used in physician offices or clinics.