I want to talk about this idea of persistent Borrelia infection for a bit. This post deals with patients who previously had documented Lyme disease, either clinically or serologically (some did not have blood tests, but had the EM rash.) There is some history to this research focus that I want to share.
One often cited report (Bayer 1996) found B. burgdorferi DNA in the urine of 72/97 patients with previously documented bull’s eye rash who had received multiple courses of antibiotics, while finding it in none of the controls. This finding was very exciting for the chronic Lyme community. However, closer investigation revealed some problems. PCR looks for a certain sequence of DNA and makes many copies of it so that it can be detected. The sequence of DNA this study used was for OspA, a protein that has been considered diagnostically useless for decades. (The reason for this is because other proteins of similar size often crossreact. Some blots use OspA as a marker and it is often the source of positive bands in an otherwise negative test.) Anyway, a lot of microorganisms have similar genes and DNA sequences, especially those that help with infection and increase survival. In order to know for certain that the PCR amplified the OspA sequence from B. burgdorferi instead of a similar organism, it has to be sequenced. But they didn’t do that in this study. One study did find that OspA antibodies were found in patients with severe Lyme arthritis (Akin 1999 – not that Akin.)
Another study found that Borrelia DNA was only found in 8% of urine samples from patients with Bull’s eye rashes who had not received treatment. This study was a lot less fast and loose with the PCR specifications.
A really important point here is that detection of DNA is not necessarily an indicator of active infection. There are several notable instances in which organisms or DNA persist in the human body following infection without causing symptoms or immune response. A good example of this is the chicken pox virus. Varicella persists in nerve cells for life following resolution of infection. Sometimes, this reactivates as shingles, but most people never have any further infection. In some of these patients with inactive Varicella infection, DNA can be detected in fluids.
I also find that people really want to compare the behavior and lifecycle of Borrelia to Treponema, the agent that causes syphilis. They do this because they are shaped the same and feel logically they should behave the same. Don’t make that mistake. Just because they look alike doesn’t mean they are alike. Please consider that MRSA is found as round cells in groups (cocci in clusters), as is Micrococcus luteus, one of the world’s most common lab contaminants, which is completely harmless.
In 1998, Phillips reported that his group had identified a way to reliably grow Borrelia in culture. B. burgdorferi does not grow well in culture; in fact, it is thought that less than 1% of microorganisms can be grown in pure culture. He further stated that he had cultured B. burgdorferi from 43/47 chronic Lyme patients.
I have some weird first hand history that I’m going to disclaim here: a couple of groups tried to replicate this finding while I was in college and it was something I followed. I did some lab work in college on difficult to cultivate organisms so I was interested to see what they had done. The lynch pin of the whole cultivation was the media, or the substances prepared for the organism to grow in. The recipe for this media specifically included Detroit tap water, and for obvious reasons, tap water can be highly variable in conditions that matter for growth, like concentration of metals, etc. One of the groups that tried to replicate this experiment actually found that the media made with the recipe provided killed B. burgdorferi (Marques 2002). Another group was also unable to replicate the data (Tilton 2001).
One of the things people get hung up on regarding chronic infection is the fact that you can continue to have symptoms for a long time after treatment. Another thing I see a lot is that patients with neuroborreliosis often test negative for active infection, but have ongoing symptoms. They feel this wouldn’t happen if there was no active infection. But there is huge precedent for this happening. Some organisms are known to induce a change in immune behavior that can later cause symptoms or even organ damage despite years of being infection free. The most well characterized instance of this follows infection by Streptococcus, which can cause rheumatic fever and other complications. We will take a look at how the immune system responds to Borrelia in another post.
Something that really irritates me is when an article groups dissimilar things together so that people will think they are alike and will say, look at this table of 30 animal models for persistent infection in Lyme disease. I’m looking at one right now that includes references from 1990-2012 and lists rodent, dog, monkey and horse models of persistent infection. And then at the bottom, you see that only some of them mean persistent treatment AFTER infection. Some of these were done in vitro (meaning using animal cells, not a live animal) and some were done in vivo. This data is all over the map. It uses culture, histology, PCR and xenodiagnosis in various combinations. Persistence does not equal infection and clinical symptoms, even in these models.
It’s frustrating because as a scientist, I can actually buy into the idea of persistent infection. I just can find very, very little solid data to support it. Most of the papers on this topic in the last fifteen years are published by one of a handful of papers and are published by a single author. When one person repeatedly publishes alone on the same topic, it is a big red flag. It literally means there is no one “on the ground” vetting what has been written. When you publish a paper, it is submitted for peer review, but it is very difficult for this process to detect any slight of hand with the data. That is why you work in groups and make sure the process is reproducible. When four scientists put their names on a paper, there is more of a perception that the data is real, because at least four people who understand the consequences are saying it’s true. When one person publishes alone for years, it is really suspect. Especially when that person was previously caught falsifying data for a project funded by a federal grant in the 90’s.
So I guess the bottom line is that I would not be surprised if at some point, data came out that a small percentage of people needed longer antibiotic treatment to eradicate active symptomatic infection. But I haven’t seen anything that convinces me yet. The data places me more into the camp that Borrelia infection causes a long term immunologic dysfunction that induces symptoms in previously infected patients.
I know you’re wondering if I’m going to talk about Lyme cysts. I am. In the next post.
Akin E, McHugh GL, Flavell RA, Fikrig E, Steere AC. The immunoglobulin (IgG) antibody response to OspA and OspB correlates with severe and prolonged arthritis and the IgG response to P35 correlates with mild and brief arthritis. Infect Immun 1999;67:173-181.
Phillips SE, Mattman LH, Hulinska D, Moayad H. A proposal for the reliable culture of Borrelia burgdorferi from patients with chronic Lyme disease, even from those previously aggressively treated. Infection 1998;26:364-367.
Marques AR, Stock F, Gill V. Evaluation of a new culture medium for Borrelia burgdorferi. J Clin Microbiol 2000;38:4239-4241.
Tilton RC, Barden D, Sand M. Culture of Borrelia burgdorferi. J Clin Microbiol 2001;39:2747-2747.
Bayer ME, Zhang L, Bayer MH. Borrelia burgdorferi DNA in the urine of treated patients with chronic Lyme disease symptoms: a PCR study of 97 cases. Infection 1996;24:347-353.
Stricker RB, Johnson L. Persistent infection in chronic Lyme disease: does form matter? Research Journal of Infectious Diseases 2013.