by Joseph J. Burrascano Jr., MD

Tick-borne relapsing fever (TBRF) is a surprisingly common but often overlooked infection that all practitioners that treat Lyme disease need to know about. Contrary to textbook descriptions, TBRF may present exactly as does Lyme disease; but because it is caused by a different group of Borrelia, Lyme disease tests probably will not detect it and you will be left with a case of “seronegative Lyme.” Because there is much misinformation and the latest findings are not widely distributed, I wrote this article to shine much-needed light on this important infection.

What Is TBRF?

That is an excellent question because the answer can differ, depending on how you define TBRF. It has been defined by clinical presentation, by tick vector, by genetics and by serotype. However, each of these approaches has exceptions and limitations. I will go through each one in turn. Complicating matters is the broad diversity of TBRF Borrelia species – worldwide, eighteen species have been identified so far with at least seven known to be present in North America.

Can TBRF Be Classified by Clinical Presentation?

Maybe not, as we will see. Classic TBRF is described as having “recurring febrile episodes that last ~3 days and are separated by afebrile periods of ~7 days duration.”¹ Each febrile episode involves a ‘crisis.’ “During the ‘chill phase’ of the crisis, patients develop very high fever (up to 106.7°F) and may become delirious, agitated, tachycardic and tachypneic. Duration is 10 to 30 minutes. This phase is followed by the ‘flush phase’, characterized by drenching sweats and a rapid decrease in body temperature. During the flush phase, patients may become transiently hypotensive. Overall, patients who are not treated will experience several episodes of fever before illness resolves.”¹

What causes these cycles? TBRF Borrelia express surface antigens that undergo cyclic variation over time due to programmed changes in expression of the genes that code for them (plasmid genes VSP and VLP). The ability to switch expression among distinct genes with the resulting change in surface antigens allows escape from an individual host’s immune response and can also cause late-appearing IgM antibodies.

One would think that clinicians would not miss an illness with such an extreme presentation, but according to a recent study, this type of dramatic picture may represent a subset of cases, and a Lyme-like presentation may in fact be the more common one.

The study: 543 US patients with suspected Lyme (not TBRF) were tested for Lyme and for TBRF using advanced immunoblotting, which has the ability to differentiate these two groups. Surprisingly, despite expecting Lyme, 28% were positive for Ab to TBRF and not to Lyme!

These patients did not have the “classic” acute TBRF presentation. Clinically, they resembled Lyme patients and if this testing were not done, they either would have been diagnosed as having seronegative Lyme, or possibly would have been misdiagnosed completely. So classifying this by clinical presentation is a big mistake.

Can TBRF Be Classified by the Tick Vector?

Traditionally, TBRF has been defined as being carried by a group of soft ticks called collectively Ornithodoros ticks (however, this is not always the case). These rather remarkable ticks have a lifespan of 10 to 20 years and can endure starvation for more than five years. Once infected, these ticks remain infected for the rest of their lives. In addition, infection by at least one relapsing fever Borrelia, B. turicatae, is maintained transovarially, meaning that ticks can be born infected, do not have to take an initial blood meal to acquire the Borrelia, and that even larvae may transmit infection. Whether all TBRF Borrelia do this has not been studied.

Ornithodoros ticks have a unique ecology. Attached ticks are rarely seen because these ticks are rapid feeders; they remain attached for only 5 to 30 minutes and because bites are painless, they usually go unnoticed. In addition, transmission of TBRF Borrelia occurs within seconds of the tick bite, and the tick can feed multiple times!

Tick-borne relapsing fever is caused by a different group of Borrelia than the Borrelia that causes Lyme.

These ticks do not live in the grass; they live in crevices, which can include wood cracks, leaf litter and caves, but they can also live in small- and medium-size mammal nests and dens, both indoors and outdoors, meaning that houses and out buildings can become infested.

After feeding, ticks return to their crevice, ready to emerge again, stimulated by heat – campfires, wood stoves, even from turning on your house’s heat. The bottom line is that they can infect more than campers and hikers.

Are Ornithodoros Ticks Easy to Identify?

Maybe not. Soft ticks are relatively larger than hard ticks and have a rounded, swollen appearance. However, they can be almost impossible for the average person to distinguish from an engorged Ixodes tick, as demonstrated in these photographs:

Not only can it be difficult to tell these ticks apart, some TBRF Borrelia have hard tick vectors: B. miyamotoi – vector is Ixodes; B. lonestari – vector is Amblyomma americanum. In addition, there are occasional literature reports that other RF Borrelia were found in hard ticks in Europe. So classifying them by vector does not work.

Can TBRF Be Classified by Their Genetic Sequences?

This gets tricky because genetic sequencing is typically done on a specific gene – for example, the flagellin gene. However, you can also sequence other genes and even the telomere. The problem is the family tree that results looks different for each method, making precise groupings of families of Borrelia impossible.

Can TBRF Be Classified by Serotyping?

Serotyping (based on expressed surface antigens) is problematic due to antigenic variation; so to be accurate, one needs to measure multiple types of each surface antigen. This is the basis of advanced immunoblotting. In fact, before the advent of such advanced tests, many researchers gave up on trying to name each new variant and simply classified them together as “the relapsing fevers.”

Do We Need to Worry About TBRF?

Yes!
“TBRF is typically considered a disease of outdoor enthusiasts and impoverished persons living in primitive conditions. However, our study suggests emergence of B. turicatae in metropolitan areas.”² “Evidence indicates the endemicity of Ornithodoros turicata ticks in San Antonio, Dallas, and Austin, the seventh, ninth, and eleventh largest cities in the United States.”²

“The University of Tennessee reported that in 2009, during fall hunting season, 58% of turkeys tested positive for B. miyamotoi.”³

“In the USA, several species of RFB have been reported to cause disease in humans, including B. miyamotoi, B. hermsii, B. lonestari, B. parkeri, and B. turicatae …. and a fourth Borrelia species, B. coriaceae, infects ticks, although human infection has not yet been identified.”⁴

“TBRF has been reported in 49 of the 50 United States.”⁵ Worldwide Distribution: TBRF has also been reported in Central and South America; Borrelia hispanica, B. persica, and B. miyamotoi are important causes of TBRF in Europe and Asia; B. hispanica, B. crocidurae, and B. duttonii are important causes of TBRF in Africa.

Clinical Presentations of TBRF

As mentioned earlier, generally two types of presentation have been reported – the classic ,relapsing and remitting fevers type, which may at times be confused with Rickettsias, viruses, Babesia and malaria, and the apparently more common Lyme-like presentation. However, recently many clinicians have reported that infection with B. miyamotoi seems to be a blend of the two; and because its vector is a hard tick, some have separated this out, calling it “Borrelia miyamotoi disease.”

Laboratory Testing

Some TBRF species may be visible on blood smears, but only in the acute stage of a crisis. While insensitive, false positives can nevertheless occur, and species cannot be determined.

PCR testing at large commercial labs is available but for B. miyamotoi only. IGeneX offers a PCR that is genus-specific, therefore may detect many different species of TBRF and will identify and report B. miyamotoi if found. However, PCRs are only sufficiently sensitive during early or acute stages of the disease and in the immunosuppressed, including very ill, late stage patients.

Serologic testing for TBRF presents several curve balls. For example, most TBRF express p41 and this can give rise to a false positive Lyme ELISA; on a Lyme western blot, a single band 41 in a suspected Lyme patient may therefore represent an unexpected TBRF infection. In addition, OspC is present in several TBRF species, another potential reason for false positive Lyme serologies.

When doing serologic testing for TBRF, note that large commercial labs offer an IFA, but for B. hermsii only. You can get a GLP protein-based ELISA for B. miyamotoi, but this is only one protein antigen and therefore prone to false negatives; it is like having only one band to read on a western blot.

On the other hand, the best serological test is the TBRF ImmunoBlot offered by IGeneX. This method uses recombinant antigens that are specific to multiple individual species. This allows for detection of a broad array of TBRF Borrelia and can even identify them by species when the test is positive. The use of recombinant technology not only allows for expanded species detection, it is inherently more sensitive and more specific than ELISAs, IFAs and western blots, especially in early disease where sensitivity is 67%. Another feature of this test method is that a positive IgM, even in late disease, has a specificity of greater than 98%, meaning that a late positive IgM is unlikely to be a false positive. Significantly, the TBRF ImmunoBlot does not cross react with Lyme Borrelia.

Just as in Lyme, the best way to get laboratory confirmation of infection is to test using multiple methods. Here, the obvious choice is immunoblotting plus PCR. Another advantage of testing by both methods is that it may uncover immune defects; a PCR-positive patient with disseminated disease should have a positive serological response and if they do not, then immune dysfunction is suspect.

Because of the clinical similarity of TBRF to Lyme in many cases, it is imperative that TBRF testing be included in the evaluation of a suspected Lyme patient, especially one who has a history of Lyme seronegativity.

Treating TBRF

As far as we can tell, treatment regimens for TBRF and Lyme are similar; there are virtually no useful published studies on antibiotic susceptibility for this group of pathogens. However, it is known that TBRF can be a chronic illness, can involve the central nervous system, can involve the heart, can involve the joints, and can induce chronic fatigue. This similarity to Lyme in disease process dictates similar approaches to treating late and chronic cases.

Additional useful advice is to be careful when initiating treatment because in the classical form of TBRF, if treated during a crisis, severe Herxheimer reactions may ensue – hypotension, cardiac arrhythmias, etc. Even in the non-classical, Lyme-like presentation, unusually strong Herxheimer-like reactions can still occur.⁶

Concluding Thoughts

TBRF is far more common than previously recognized, geographically widespread, and can be very similar in clinical features to Lyme. Therefore, the obvious takeaway is that one must always consider and test for TBRF when evaluating a Lyme patient, especially one who has had a history of Lyme seronegativity. Laboratory confirmation with TBRF-specific ImmunoBlots and if necessary, PCR, is essential to document the diagnosis. Doing so is not only good medical practice, it will allow us, over time, to get a better feel for the presence of any important differences between these two groups of Borrelia, and no doubt will inform us on the best management practices.

Keep detailed records, share your info, and publish!

References

1. https://www.cdc.gov/relapsing-fever/clinicians/index.html
2. Bissett JD, et al. Detection of Tickborne Relapsing Fever Spirochete in Austin, Texas, USA. Emerging Infectious Diseases. 2018;24(11):2003-2009.
3. Kessler M, What is the Borrelia miyamotoi Infection? August 17, 2015.
4. Middelveen MJ, et al. Relapsing fever Borrelia in California: a pilot serological study. Int J Gen Med. 2018 Sep 21;11:373-382.2018.
5. Borreliosis (Tick-Borne Relapsing Fever) https://igenex.com/tick-talk/borreliosis-relapsing-feverdisease/
6. Dworkin MS, et al. Tick-Borne Relapsing Fever. Infect Dis Clin N Am. 2008;22:449–468
   
   

Dr. Burrascano was raised in Montauk, New York, a small fishing village located 120 miles east of New York City. Montauk became known for a condition called “Montauk Knee,” a peculiar monoarthritis, and for the occurrence of unusual “spider bites” that resembled a bullseye and responded to penicillin treatment. Later it was found that the towns in the Montauk area, which includes East Hampton New York, where Dr. Burrascano opened his medical practice in 1981, had the highest case rate of Lyme disease in the world. In addition, tick flagging assays in these towns revealed pockets in which 100% of the ticks were infected with Borrelia.

It was in this setting that Dr. Burrascano began his medical practice. Through the 1980s he saw many patients with these and other seemingly mysterious conditions. It was then that he collaborated with key colleagues including Alan MacDonald, Willi Burgdorfer, Bernard Berger, and others to work out the clinical details of Lyme disease- presentation, laboratory features, and diagnosis, and the very earliest meaningful studies on treatment. The culmination of this body of work is his now-classic monograph “Diagnostic Hints and Treatment Guidelines on Lyme Disease” which had been translated into many languages and has always been offered free of charge to all who wanted a copy. It has been suggested that this work formed the basis of the modern, currently accepted view of Lyme and related tick-borne diseases, including how difficult it can be to diagnose and treat and the wide spectrum of its potential presentations.

He was a founding member and director of both the International Lyme and Associated Diseases Society (ILADS) and its educational arm, the International Lyme and Associated Diseases Educational Foundation (ILADEF). One of the first ILADS members to host clinical clerkships, his dedication to practitioner education continues to this day through his conference presentations, webinars and writings. Dr. Burrascano closed his practice several years ago and began work in the biotech arena as a research project analyst and occasional project manager; however he still does consultancy work for business entities and fellow practitioners in the Tick-borne diseases field.