Friday, January 18, 2013

10 Questions on Borrelia Miyamotoi and Lyme Disease

I have been working diligently on a post about the pseudoscience and science of Lyme disease, in hopes of publishing it soon. However, given the recent news out of Yale University this week, I have decided to delay publication on that post because there is a lot to say about the research from Yale:

Yale research confirms Borrelia miyamotoi causing infection in US

A tickborne disease caused by spirochetes more closely related to relapsing fever spirochetes than Lyme disease spirochetes was found in 18 patients in southern New England and New York, according to research published in the New England Journal of Medicine January 17.

The infection - caused by spirochetal bacteria known as Borrelia miyamotoi - was detected in 21 percent of 14 patients with unexplained summertime febrile illness, 3 percent of 273 patients with Lyme disease (or suspected Lyme disease), and 1 percent of 584 healthy people from areas endemic for Lyme disease.

This study is one of a few which offer the indication that infection with Borrelia miyamotoi in North America is less common than its well-known more distantly related relative, Borrelia burgdorferi, the spirochete which causes Lyme disease.

It's estimated 2-3,000 people* in the United States may be infected with Borrelia miyamotoi annually - but due to it being an emerging infectious disease which is difficult to diagnose, how common it is and will be in the future remains to be seen.

In surveillance studies, anywhere from 1-16% of Ixodes scapularis ticks have been infected with Borrelia miyamotoi, depending on the region. This is about the same percentage range of Ixodes ticks which are infected with Borrelia miyamotoi in Russia and Western Europe.

In North America, Ixodes ticks infected with Borrelia miyamotoi have been found in the northeastern US, midwest, west coast, and Canada.

How Borrelia miyamotoi infection differs from Lyme disease

Early symptoms

Clinically speaking, an infection with B. miyamotoi has symptoms which overlap those of Lyme disease. They include fever, muscular aches and pains, joint aches, chills, sweats, vomiting (sometimes), headaches and fatigue, with a small portion also developing a rash such as with Lyme disease. Also, symptoms can be more severe than those found in Lyme disease and some patients may require treatment in a hospital.

The two most striking differences between B. miyamotoi infections and Lyme disease?

Usually there isn't a rash - the exact opposite of Lyme disease. One Russian study stated that more than 50% of patients documented with the disease did not have a characteristic rash. According to Dr. Peter Krause, only 10-15% of patients get a rash and it is usually smaller than those seen in Lyme disease.

Sometimes, people get cycling, spiking fevers. Studies demonstrated that some patients had episodes of high spiking fevers which occurred days or one to two weeks apart. These cyclical fevers and the lack of a rash map closely to symptoms found in relapsing fever - a spirochetal disease which is usually transmitted by soft-bodied ticks.

Here is an example of two patterns of fever and symptoms found in patients studied in Russia [pdf]:

Graph From: Humans Infected with Relapsing Fever
Spirochete Borrelia miyamotoi, Russia
Emerg Infect Dis. 2011;17:1816-1823
Note that two patients' patterns of fevers and symptoms differed, but a spiking fever with periods of normal temperature between fevers is common in relapsing fever. (These two patterns are not representative of all patients - other patients may have their own variation on how the disease process unfolds.)

Later stages of infection

Not much is known about later stages of infection with B. miyamotoi. This is because its study in human and animal hosts is relatively new, having been discovered only in 1995 in Japan.

However, one could potentially extrapolate how B. miyamotoi will behave after initial infection by looking at research on its genetically closest living relatives which are also relapsing fever spirochetes.

Borrelia miyamotoi's closest living relatives appear to be Borrelia hermsii and Borrelia lonestari.


Image from: Typing of Borrelia Relapsing Fever Group Strains.
Emerg Infect Dis. 2004 September; 10(9): 1661–1664.
doi: 10.3201/eid1009.040236

Testing for the presence of Borrelia miyamotoi

From both the patient's and the doctor's point of view, one troubling aspect of being infected with Borrelia miyamotoi is that even if the patient has a history of a tick bite and has symptoms which seem similar to those found in Lyme disease - a blood test for Lyme disease will be negative.

This is because Borrelia miyamotoi is genetically distant enough from Borrelia burgdorferi that the antibodies produced in response to miyamotoi seldom cross react with those of Borrelia burgdorferi.

So how do you test for the presence of Borrelia miyamotoi?

If you're a microbiologist and do not have access to antibody testing, have an acutely ill patient in front of you with a current flare up of symptoms including spiking fever, a blood smear and dark field microscopy might yield a positive result for Borrelia miyamotoi - as it does for other relapsing fever spirochetes.

But most family physicians will likely want to order a blood test using PCR and/or an antibody test specifically designed for relapsing fever in order to detect infection.

In a study of 47 Russian patients found to have infections with Borrelia miyamotoi, presence of infection could be detected using an ELISA (EUROIMMUN AG, L├╝beck, Germany) for major Borrelia burgdorferi sensu latu genospecies found in Europe - but it could not discriminate (sort) specific antibodies against any of these species.

Given that ELISA tests for Borrelia other than Borrelia burgdorferi sensu strictu are hard to come by in the US and Canada, the detection of Borrelia miyamotoi using standard Lyme disease ELISA may not work in North America.

Instead of a standard North American Lyme disease ELISA or EUROIMMUN AG, an ELISA or Western Blot for relapsing fever which contains GlpQ protein - an antigen which is non-reactive to Borrelia burgdorferi antibody - can be used to detect infection with Borrelia miyamotoi.

This information should serve as a cautionary tale for the doctor:

If a patient has been in an environment where ticks are found and has Lyme disease-like symptoms or a summer flu, consider relapsing fever as a differential diagnosis - especially if the patient does not recover as they would from a flu and has a negative Lyme disease ELISA.

Blood tests and PCR are most likely to yield a positive result when a sample is taken during a patient's spiking fever and the height of symptoms because that is when spirochetemia is peaking. With each relapse of infection, the number of spirochetes in the blood is reduced - thus making it less likely to obtain positive test results the later it is during the course of infection.

Treatment

So far, all the research points to the same antibiotics being used for Lyme disease as being effective for treating relapsing fever, and this extends to infections with Borrelia miyamotoi. In addition to amoxicillin, tetracycline, and doxycycline, relapsing fever has also been treated with chloramphenicol with success. Intravenous ceftriaxone may be required for more severe illness.

If a patient with Borrelia miyamotoi is treated with antibiotics and continues to suffer from high spiking fevers and other symptoms, retreatment may be needed with intravenous antibiotics. Co-infections such as babesiosis and ehrlichiosis should be investigated as they can produce similar symptoms.

In a 2011 study on Russian patients treated for Borrelia miyamotoi infection, this was the treatment and outcome:

Therapy consisted of ceftriaxone, 2 g intravenously every 24 hours for 2 weeks (42 patients) or doxycycline 100 mg orally every 12 hours for 2 weeks (2 patients). Two patients received no antimicrobial drug while hospitalized; 1 later received doxycycline at home, and the other was readmitted to the hospital for relapse and received ceftriaxone.

Outcome

Some relapsing fever strains can cause severe illness, and without treatment these strains have a high rate of case fatality. So far, B. miyamotoi lies along a spectrum of illness which appears to range from mild to moderate severity, but even so, infection should be treated with antibiotics immediately to avoid complications.

The good news is that most people who are infected with relapsing fever and are treated promptly with antibiotics go on to recover. The same will probably apply to infection with B. miyamotoi based on research published to date - but the true picture remains uncertain until more patients are diagnosed, treated, and proper follow-up is completed.

Complications

Are the complications found in Borrelia miyamotoi infections going to be the same as those found in Lyme disease? Given that it is genetically closer to relapsing fever spirochetes and more distant to Borrelia burgdorferi, one could speculate that it may have characteristics and complications common to relapsing fever - but without further research, it is unclear.

The risk for infected untreated pregnant women to pass on infection to the fetus in utero with a negative outcome (e.g. miscarriage; defects) might be more likely than it is in Lyme disease. Infection of the central nervous system may also occur more rapidly than it typically does in Lyme disease. But this is speculative, due to being based on research where there is variability in severity and outcome across relapsing fever strains.

Facts and uncertainties

It is known that in many cases, Borrelia miyamotoi - unlike Borrelia burgdorferi - is transmitted transovarially in deer ticks. This means the female tick infects her offspring, which produces infected larvae. These larvae will go on to molt and become infected nymphs. (Transovarial infection is rare to nonexistent in Borrelia burgdorferi.)

It is also known that relapsing fever spirochetes in soft-bodied ticks reside in tissues throughout the tick - whereas Lyme disease spirochetes are only found in the midgut.

Thus a significant question arises: What role does a relapsing fever spirochete play in relation to its hard-bodied tick host, and how soon can a tick transmit infection with Borrelia miyamotoi after attachment? This appears to be unknown.

Other questions based on how other relapsing fever strains also present themselves: How neurotropic is Borrelia miyamotoi? Can it become a latent infection, as was discovered in other relapsing fever strains? How rapidly does it differentiate into different serotypes found in different tissues?

The answers to these questions - and more - are also unknowns until this bacteria is studied more carefully. Similar questions may also arise in research on Borrelia lonestari in Amblyomma americanum ticks - another relapsing fever type spirochete found in a hard-bodied tick.

* Jan 19, 2013 Edited to add: Dr. Peter Krause offered a more recent estimate of 3-4,000 cases of B. miyamotoi occur in US annually.



Image Credit: Photography by Alan R. Walker, of Borrelia theileri infecting the blood plasma of a cow. Giemsa stained. Borrelia theileri is closely related to both B. lonestari and B. miyamotoi, and causes bovine Borreliosis in cattle. Source: http://commons.wikimedia.org/wiki/File:Borrelia-theileri-cow.jpg

References

Human Borrelia miyamotoi Infection in the United States
N Engl J Med 2013; 368:291-293 January 17, 2013 DOI: 10.1056/NEJMc1215469 http://www.nejm.org/doi/full/10.1056/NEJMc1215469

Carl-Johan Fraenkel, Ulf Garpmo,Johan Berglund. Determination of Novel Borrelia Genospecies in Swedish Ixodes ricinus Ticks. J. Clin. Microbiol. September 2002 ; 40:9 3308-3312 doi:10.1128/JCM.40.9.3308-3312.2002 http://jcm.asm.org/content/40/9/3308.full

Rebaudet, Stanislas, and Philippe Parola. Epidemiology of relapsing fever borreliosis in Europe. FEMS Immunology & Medical Microbiology 48.1 (2006): 11-15. http://onlinelibrary.wiley.com/doi/10.1111/j.1574-695X.2006.00104.x/full

Sarah A Hamer, Graham J Hickling, Rich Keith, Jennifer L Sidge, Edward D Walker, and Jean I Tsao. Associations of passerine birds, rabbits, and ticks with Borrelia miyamotoi and Borrelia andersonii in Michigan, U.S.A. Parasit Vectors. 2012; 5: 231.
Published online 2012 October 11. doi: 10.1186/1756-3305-5-231 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3497883/

Scott, M. C., et al. High-Prevalence Borrelia miyamotoi Infection Among Wild Turkeys (Meleagris gallopavo) in Tennessee. Journal of medical entomology 47.6 (2010): 1238-1242. http://www.bioone.org/doi/abs/10.1603/ME10075

Mun J, Eisen RJ, Eisen L, Lane RS. Detection of a Borrelia miyamotoi sensu lato relapsing-fever group spirochete from Ixodes pacificus in California.
http://www.ncbi.nlm.nih.gov/pubmed/16506458

Ogden, Nick H., et al. Investigation of genotypes of Borrelia burgdorferi in Ixodes scapularis ticks collected during surveillance in Canada. Applied and environmental microbiology 77.10 (2011): 3244-3254. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3126474/

Fukunaga M, Takahashi Y, Tsuruta Y, et al. Genetic and phenotypic analysis of Borrelia miyamotoi sp. nov., isolated from the ixodid tick Ixodes persulcatus, the vector for Lyme disease in Japan. Int J Syst Bacteriol 1995;45:804-810
http://ijs.sgmjournals.org/content/45/4/804.full.pdf

Jonas Bunikis, Jean Tsao, Ulf Garpmo, Johan Berglund, Durland Fish, Alan G. Barbour.
Typing of Borrelia Relapsing Fever Group Strains. Emerg Infect Dis. 2004 September; 10(9): 1661–1664. doi: 10.3201/eid1009.040236 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3320305/

Scoles, Glen A., et al. A relapsing fever group spirochete transmitted by Ixodes scapularis ticks. Vector Borne and Zoonotic Diseases 1.1 (2001): 21-34. http://online.liebertpub.com/doi/abs/10.1089/153036601750137624

Tamar Halperina, Nadav Orrb, Regev Cohena, Tal Hasina, Nadav Davidovitchc, Eyal Klementa, Raid Kayoufa, Gad Banethd, Dani Cohenb, Miri Yavzoria. Detection of relapsing fever in human blood samples from Israel using PCR targeting the glycerophosphodiester phosphodiesterase (GlpQ) gene. Acta Tropica. Volume 98, Issue 2, May 2006, Pages 189–195 http://www.sciencedirect.com/science/article/pii/S0001706X0600074X

Schwan TG, Schrumpf ME, Hinnebusch BJ, Anderson DE Jr, Konkel ME. GlpQ: an antigen for serological discrimination between relapsing fever and Lyme borreliosis. J Clin Microbiol 1996;34:2483-2492 http://jcm.asm.org/content/34/10/2483.full.pdf

Karan' LS, Koliasnikova NM, Toporkova MG, Makhneva MA, Nadezhdina MV, Esaulkova AIu, Romanenko VV, Arumova EA, Platonov AE, Maleev VV. [Usage of real time polymerase chain reaction for diagnostics of different tick-borne infections]. [Article in Russian] Zh Mikrobiol Epidemiol Immunobiol. 2010 May-Jun;(3):72-7. http://www.ncbi.nlm.nih.gov/pubmed/20734723

Alan G. Barbour, Jonas Bunikis, Bridgit Travinsky, Anne Gatewood Hoen, Maria A. Diuk-Wasser, Durland Fish, and Jean I. Tsao. Niche Partitioning of Borrelia burgdorferi and Borrelia miyamotoi in the Same Tick Vector and Mammalian Reservoir Species. Am J Trop Med Hyg. 2009 December; 81(6): 1120–1131. doi:10.4269/ajtmh.2009.09-0208 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2841027/

Relapsing Fever. Columbia University Lyme and Tickborne Diseases Research Center. http://www.columbia-lyme.org/patients/tbd_relapsing.html

Researchers discover new tickborne infection. WTNH News 8. January 18, 2013 http://www.wtnh.com/dpp/news/health/researchers-discover-new-tick-borne-infection

10 comments:

  1. is there a western blot test for b. miyamotoi? i have late stage lyme and certainly had the cyclical fevers. in fact, i still get fevers every few weeks, despite treatment. unlike the russian patients, i only got 1g rocephin/day, which i also feel is too low for my weight.

    the worst part of my illness has resolved, but much lingers. having been treated with antibiotics & not having acute symptoms anymore, i'm certain i'd test negative on an elisa. if there is a western blot test for b. miyamotoi that reflects igg antibodies i might be able to finally resolve this debacle.

    does such a test exist?

    many thanks!

    ReplyDelete
  2. Hi lemonlyme,

    There is as of yet no specific easily available blood test for B. miyamotoi. In its early stages, it may be detected by a trained lab pathologist using dark field microscopy and a blood smear from the patient - blood which is best collected when the patient has recently had a tick bite and is also having a high fever. Past this very early stage, the longer the infection continues, the more difficult it is to detect the bacteria in blood samples - either in a smear or serological testing.

    You might want to refer to this CDC page with information on testing for tickborne relapsing fever, as it comes closest to B. miyamotoi in terms of classification of the spirochete: http://www.cdc.gov/relapsing-fever/clinicians/#labtest

    Note there that serological tests for relapsing fever, but they aren't that widely available and have high variability - that is, you will get different results from different labs. Also note that these tests for relapsing fever are more likely to pick up other strains of relapsing fever (non-miyamotoi) and it's not clear to me how B. miyamotoi will pick up on these tests.

    Right now, a serological test which does include detection of B. miyamotoi is being developed, and depends on finding a response to GlpQ (which I mentioned in my post above). No news on when that test will be ready, unfortunately.

    In general, though, whatever treatment you are getting for Lyme disease should also work for treating B. miyamotoi. Rocephin should do the trick and treat B. miyamotoi if you do have it - though this is based on research on other relapsing fever spirochetes and not specifically on miyamotoi.

    If you are concerned that you are not getting enough antibiotics for your current weight, mention it to your prescribing doctor. If you are dissatisfied with your current doctor and think he is treating you improperly or inadequately after making your requests, consider asking someone you trust for a referral to another doctor.

    I'm glad to hear the worst part of your illness has resolved, and sorry that you continue to have symptoms. Sometimes the remaining symptoms can be caused by a coinfection such as Babesia, which you can ask your doctor about and ensure any coinfections are tested for and ruled out. Sometimes remaining symptoms may be a sign of damage from the initial infection and takes time to heal. These possibilities are something that you should discuss with your doctor, since he knows about the specifics of your case and history.

    Good luck, and best wishes for your continued improvement!

    ReplyDelete
  3. Imugen Inc. in Norwood, MA. supposedly can now test for Borrelia Miyamotoi. It's hard to tell from Imugen's website that testing is available. While trying to find information I emailed one of the professors whose lab had identified the bacteria. He was the one that informed me of the tests availability. My clinic spoke to Imugen on Wednesday and were going to send a blood sample in for testing on Thursday. Now I just have to wait and see if the test is going to provide some answers.

    ReplyDelete
  4. Hi Anonymous,

    Thank you for the news from Imugen, Inc. and their ability to test for Borrelia miyamotoi. It does look like they have a series of tests they can conduct in their lab for this particular Borrelia, based on this pdf linked to from their home page: Borrelia Miyamotoi Media Release.

    It's an in-house series using PCR, genetic sequencing, and amplification - and while these methods can be reproduced in other labs, this isn't the same as having a commercially available Western Blot with GlpQ which any doctor can order.

    That might be coming in the future - but not now. Which is why I wondered if B. miyamotoi would be positive on blood tests for other relapsing fever spirochetes - it might be easier in some parts of the country to get one of those tests and cheaper than using Imugen's current process.

    To learn about the kind of process they likely used, I suggest reading the Laboratory Methods section of this paper on Russian Borrelia miyamotoi infected patients: Humans Infected with Relapsing Fever Spirochete Borrelia miyamotoi, Russia - http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3310649/.

    ReplyDelete
  5. In late June I had high fever (103.5F), chills, low BP for 3 days. (I had been hiking in a tick prone area of NYS about 10 days earlier.) I went to ER and blood test showed low platlets and elevated liver enzymes. They suspected a blood infection so I was admitted. I was given an intravenous antibiotic (it may have been chloramphenicol). The fever went away the next day and I was discharged a day later. Since they did not suspect a tick borne illness I stopped taking the antibiotics. I returned to somewhat normal activities but felt weak and tired.
    I returned to my gym workouts about 10 days later. I came home after the workout and went to bed and the fever returned. It peaked at 104 with chills, then abated after 3 days. Again, I felt weak and tired even after the fever subsided. I went to an infectious disease specialist a few days later and he immediately identified it as a tick borne illness. He suspected anaplasmosis or ehrliciosis. (I had a congestion in the upper chest that turned that he thought was a sign of anaplasmosis.) He tested for all the tick borne illnesses as well as other blood serology. He noted that the platets and liver enzyme level were still a bit off but improving from the earlier levels when I was hospitalized. He also noted I was anemic (family and friends told me I was very pale during this time). He put me on 200mg regimen of Doxycycline for two weeks. I began feeling better with this and the fever did not return during the two weeks.
    About a week later I returned to the gym and had a couple of workouts. I did not feel great, but I was able to get through. About 2 days after the last gym workout (10 days after I ended the doxycycline) I had another milder episode of fever (but no chills), it spiked one night, then lasted another two days, but at a much lower level. I also had abdominal pain, which I did not have with the earlier episodes. (I was thinking this was a virus, unrelated to the earlier fevers). The doctor had me start a second two week round of doxycycline, which I just finished yesterday.
    I am curious to know if you suspect that this was Borrelia miyatotoi since the blood tests did not identify any other tick borne illness.

    ReplyDelete
  6. Hi Frederick,

    Welcome to Camp Other blog.

    First, a disclaimer: I am not a medical doctor, so anything I tell you here is for educational purposes and not medical advice. Please consult a medical doctor for follow up and advice on your situation.

    I really don't know what is wrong, and suggest that it's best to talk to a doctor about your concerns and make sure you have the right diagnosis (look for rule outs, rule ins) so you are properly treated.

    If you yourself are concerned that you might still have a tickborne illness and want peace of mind so you can rule them out and want to take that specific kind of concern to a doctor, then in your position with the information given I would check out Babesia again and get a sequential blood smear (ask a good tickborne diseases pathologist about this - it isn't a one smear test) and possibly FISH test for Babesia. Anemia and some sense of chest congestion (do you feel a sense of banding or constriction around your ribs?) can be due to Babesiosis, and sometimes the first test doesn't show up positive. One can have a very small percentage of infected red blood cells and be sick yet still have a negative smear.

    I don't know whether or not Borrelia miyamotoi is at work here, either. You would have had to have had your blood studied under a darkfield microscope during one of your episodes of fever for the best shot at providing evidence it's there.

    At this stage in the game, you might want to see if you can talk to a doctor again, and check to see if they can get the test for Borrelia miyamotoi from Imugen mentioned above (or perhaps talk to Dr. Joseph Gugliotta in New Jersey, who identified a case of B. miyamotoi in a woman there; ask him for advice.)

    There has been some discussion about whether or not doxycycline is always effective for treating Borrelia miyamotoi infection, and if IV Ceftriaxone is needed more often. I don't know; I only know that the Russian study above showed 2 patients required IV antibiotics after doxycycline failed to clear the infection. If it turns out you have Borrelia miyamotoi, you would have to discuss further treatment with a doctor who has confirmed it.

    ReplyDelete
  7. Thanks for that response.
    My doctor called me this morning to tell me that my latest bloodtest came back positive for anaplasmosis, which is what he initially thought I had. This was the third time this was tested for; his thought was that the antibodies had taken some time to become detectable in the blood.

    ReplyDelete
  8. Hi Frederick,

    I'm happy to hear that the doctor has gotten in touch with you and confirmed that you have anaplasmosis. Hopefully with treatment for it, you will be back on the road to recovery.

    See, this is why I make my disclaimer - the best I can do is offer an educated guess based on your symptom description and history. But I don't have the answer, and I highly recommend anyone talk to a doctor who is knowledgable about tickborne diseases.

    Had your doctor taken up my suggestions, it could have provided additional info. that could have helped you - but getting a positive anaplasmosis result is something concrete to work with today.

    Good luck, and please stop by later letting us know how you're doing.

    CO

    ReplyDelete
  9. My doctor contacted Imugen who said the GlpQ protein ELISA is not available. It appears they are backing down on offering this test. Any idea why?

    ReplyDelete
  10. Anonymous,

    I don't think Imugen has been offering an ELISA for Borrelia miyamotoi - unless I've missed something. They offer PCR testing of whole blood for Borrelia miyamotoi:

    Imugen info sheet on Borrelia miyamotoi and testing

    The important excerpt from the above page:

    "Since there is no characteristic rash of other pathognomonic clinical feature, laboratory testing is necessary to make this diagnosis. IMUGEN offers a specific whole blood PCR test for evaluating suspected acute cases of B. miyamotoi infection. In the future there will be serologic tests available for acute and convalescent specimen testing. Presently this organism is not culturable."

    A .pdf from their site, also:

    Borrelia miyamotoi - Press Release from Imugen

    I don't have any further information, but you can give them a call and ask what the status is of the test and how to prep your sample:

    (781) 255-0770 (Massachusetts) or 800-246-8436

    The other thing you could do is call Igenex and ask them if they can test for Borrelia miyamotoi - and if not, if they know someone near you who can. Note that Igenex is on the west coast, so time is of the essence to get a sample to them if you are on the east coast.

    ReplyDelete

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