1 What Does The Reinfection Study Have To Do With Chronic Lyme or Post Lyme Disease?

Last week, a number of media outlets wrote articles referring to a study published in the New England Journal of Medicine (NEJM), "Differentiation of Reinfection from Relapse in Recurrent Lyme Disease".

Since I wanted to see what was actually stated in the study, I acquired a copy of the full text of this publication to see for myself why the authors might have given some journalists the impression that chronic Lyme disease - or even post Lyme disease syndrome - does not exist.

Side note: One important thing to know is that at the time I wrote this entry, I had not read the accompanying editorial by Dr. Steere which was published in NEJM. Given that the current entry was written based only on the study itself and has gotten quite lengthy, I will be writing separately about the editorial in the future.

Summing it up

After reading through the paper, if I had to give a one sentence summary of what this study accomplished, this sentence at the end of it summed it up fairly well:

"These data, in conjunction with available clinical and epidemiologic evidence, show that repeat episodes of erythema migrans in appropriately treated patients were reinfections and not relapses."

If I'm to take it at face value, what this study does is provide evidence that when patients were properly treated early for previous erythema migrans (EM) rashes in the past and they presented with new EM rashes with obvious tick bites - they almost always contained a different kind of Lyme disease than one with which the patients had previously been infected. And with early treatment of patients found with new EM, most of those patients will go on to be fine until they are reinfected again.

Seems to make sense to me.

This is what the study appears to have discovered, so at first glance I had yet to see what the findings in this paper have to do with evidence that chronic Lyme disease does not exist. Nor did I see where this study provides evidence that post Lyme disease syndrome does not exist, either.

However, after digging a little deeper, I found one statement which suggested that data found in this study implied that chronic Lyme disease does not occur:

"[...] some persons have attributed recurrent episodes of erythema migrans to relapses in patients treated with recommended courses of antibiotic therapy; they cited experiments in animals that showed persistence of B. burgdorferi despite antibiotic treatment."

This was about as close as I could get to finding a statement in the study that chronic Lyme disease does not occur, as the majority of the content of the paper focuses on the fact that new erythema migrans are associated with new infections.

But one thing which I have stated before was that when it comes to Lyme disease, the rash is not the disease. The rash is a symptom of early infection. Untreated, it will eventually disappear. It may never recur during the same episode of infection. And in the meantime, depending on the strain one has, host factors, and without proper treatment, the infection will disseminate and spread to areas of the body far removed from where the rash first appeared.

Because the patients in this study were treated either during the first sign of cutaneous infection or very early disseminated infection, they were far more likely to have been successfully treated than patients for which there was a delay in treatment or patients who were improperly treated (say with a shorter duration, or possibly a less effective or an incorrect antibiotic) earlier.

Anyway, I have a few remarks on the paper:

On the significance of EM rashes under other conditions

One of the concerns I mentioned elsewhere after reading online article after article was that journalists had not mentioned how EM rashes were relevant not only as a symptom of early infection but at other points.

To some degree - and to my satisfaction - one paragraph of the study covered other reasons EM rashes would appear outside of the first sign of infection, and mentioned that an EM rash can show up and disappear only to reappear in untreated patients and also inappropriately treated patients.

This is important to note, and I would hope that family and urgent care doctors can use the presence and timing of an EM rash relative to other symptoms to determine when more treatment is required. Dr. Jorge Benach has stated that satellite EM rashes which erupt within weeks to months after the initial EM are a sign of disseminated infection.[1] Dr. Brian Fallon of the Columbia University Lyme and Tickborne Disease Research Center has also made the same observation.[2] Combined with other clinical evidence and symptom presentation, patients with these rashes may require additional oral or intravenous antibiotic treatment.

Patients with new EM rashes have been reinfected.

In addition to the summary statment cited earlier, one should take note of this particular passage in the study:

"Patients were treated with standard courses of antibiotics at each episode of erythema migrans, with subsequent resolution of the skin lesion or lesions."

The key words to keep in mind here are: "erythema migrans" and "appropriately treated patients".

This study is about early acute Lyme disease including early disseminated infection. The patients who were followed during the course of the study were all treated for signs of early acute Lyme disease - not late stage, persisting disease.

Based on this, I suspect the authors want readers to take away from their study is that these 17 patients who have an EM rash and are treated early in their infection have successful resolution of their Lyme disease - and any new EM rashes they have are a sign of a new infection which requires more antibiotics.

In other words: Early treatment is the key to greater success in treating Lyme disease effectively.

The value of finding different OspC RST types in different EMs.

The keystone of the study is the evidence that different OspC RST types are found in each episode of EM when patients are followed over time.

What does OspC RST strain mean? Citing a definition from an earlier paper:

"Two genetically linked typing systems, one based on sequence variation of outer surface protein C (OspC) and the other on ribosomal RNA intergenic spacer type (RST), have been used to classify US B. burgdorferi strains.

OspC typing divides B. burgdorferi strains into 21 genetically distinct types, 16 of which have been identified in the northeastern United States and RST divides B. burgdorferi into three groups.

RST1 corresponds to OspC genotypes A and B; RST2 corresponds to OspC types F, H, K, and N; and RST3 corresponds to the remaining 10 OspC types, including D, E, G, and I.

In the northeastern United States, infection with OspC type A (the most common RST1 strain) or OspC type K (the most common RST2 strain) accounts for approximately 60% of Lyme disease cases; and all of the OspC types within the RST1 and RST2 groups account for approximately 80% of cases. RST3, the least common type, is the most diverse, although infection with OspC type I accounts for approximately half of the RST3 cases.

Because RST typing of isolates may miss differences within groups and because OspC typing may lead to small groups, more information for clinical correlations can be obtained from the use of both typing systems."[3]

The above description of how OspC RST typing is taken from the paper, "Borrelia burgdorferi RST1 (OspC Type A) Genotype Is Associated with Greater Inflammation and More Severe Lyme Disease".

What is known not only from this paper but from many other papers is that different genotypes of Borrelia burgdorferi exist and may affect the clinical presentation of Lyme disease over time.[4-11]

And as time goes on, new genotypes are also found to spread hematogenously. However, it is important to keep in mind that just because a genotype can disseminate easily does not mean it is going to cause as much inflammation or have a particular tissue tropism.

For example:

"[...] However, when mice were infected by tick bite, as in the natural infection, RST 1 isolates displayed higher densities in blood, but the number of spirochetes in the heart or bladder was similar with either RST 1 or RST 3 strains (14). This suggests that in the natural infection, smaller numbers of RST 3 organisms, which may not be detectable in blood, are still able to spread to the joints and cause infection there. Consistent with this observation, the frequencies of B. burgdorferi genotypes in human patients in the current study were similar in EM skin lesions and in joints. Thus, it seems that all 3 RSTs have a similar predilection for dissemination, but larger numbers of RST 1 organisms are more often detectable in blood."[12 ]

According to research to date, the B. burgdorferi RST1 (OspC type A) genotype - followed by the RST3 (OspC type I) genotype - cause greater inflammation and more severe disease than other genotypes, establishing a link between spirochetal virulence and host inflammation.[ 3]

It gets more complicated from here. Researchers are still learning how these different genotypes and subtypes interact with their hosts and host immunity.

According to research (as is stated above) OspC type A RST1 and OspC type K RST2 account for approximately 60% of Lyme disease cases in the northeastern United States.

Judging from other publications, northeastern US OspC genotypes more or less break down into this list:

- Osp type K RST2 accounts for about 40% of that 60%.
- OspC type A RST1 accounts for 20% of that 60%.
- 20% of northeastern United States genotypes are mostly other RST1 and RST2 types.
- The remaining 20% are a mix of RST3 which is dominated by OspC I RST3.

That these different genotypes exist and have different pathogenicity is a fairly recent discovery and it is only just beginning to be understood.

More is understood about more common OspC types than less common RST3 strains which are highly variable and found less frequently in animal and human hosts. Additional research on these genotypes is needed.

So what kind of OspC RST types did patients have in this study on reinfection? It's a good question to ask, because if patients have genotypes of Borrelia burgdorferi which are more likely to lead to dissemination, then they (potentially) have a greater chance of invading more immune-privileged spots, such as joints, tissues, organs, and the central nervous system.

Based on a review of the overall breakdown of different OspC RST types in this study, they did align somewhat with previous research on northeastern United States genotypes.

OspC K RST2 was the dominant genotype found in skin, followed by a mix of OspC RST3 types then OspC RST1. That OspC RST3 types were more common than OspC RST1 differed from earlier research. Blood samples were somewhat different than those found in skin, with a combination of RST1 and RST3 types collectively outnumbering OspC RST2.

There are some data sets which were not collected during this study which I would have wanted to see. For one thing, Borrelia burgdorferi samples were not taken from synovial fluid or cerebrospinal fluid (CSF) for OspC RST typing. We would also be missing any data from tissue biopsies as these are not routinely done, and are rather invasive for the patient. On the immunological side, the genetic backgrounds of patients with specific HLA-DRs were not revealed.

How this study does (or doesn't) relate to Chronic Lyme disease or post Lyme disease syndrome

Patients with early disseminated infection were said to have had fever, arthralgias, headache, or fatigue which were present during the first episode of EM. The authors expanded on this point over time, demonstrating that in these 17 patients, early disseminated infection and more invasive genotypes (such as ospC A RST1 or ospC I RST3) were handily cured with a prompt course of antibiotics and that any future symptoms would be related to a new infection and not a relapse.

Based on the OspC type data, the only way I can see that this study might be trying to disprove the existence of chronic Lyme disease is the authors' position that the evidence demonstrates that the same virulent strains found during the first episode EM rash that were treated were not present during the second episode in any patient. Therefore, by their deduction, the Borrelia bacteria did not persist in the time between EM rash episodes.

In their opinion, evidence of a relapse would have been shown if the patient's samples demonstrated that the same Borrelia burgdorferi genotype would be present during both episodes of EM.

However, is this the only conclusion one can draw from such a study? I have unanswered questions about it.

Can the genetic background and varying immune system responses affect the course of Lyme disease in host mammals? (I already know the answer is yes here, but what I know is mostly about animal models. Is enough known about this as it relates to people?)

How likely it is that an existing genotype of Borrelia burgdorferi found in tissues and CNS will migrate to the blood and EM rashes during ticks feeding on humans?

In the study, given that in two patients the genotype of Borrelia burgdorferi from one skin sample did not match the genotype of that found in blood during the same episode, is there a possibility that in a handful of cases, antibiotics could successfully treat the EM rash produced by one genotype while not successfully treating a more virulent and invasive genotype if the infection had advanced for some time without treatment - say to more remote tissues such as organs or the CNS?

Could a previous infection with a Borrelia burgdorferi genotype with specific tissue tropism coexist with the onset of an EM rash containing a new genotype?

What happens if a patient has previous infection in which no EM rash was present or seen and it goes untreated - then that patient acquires a new infection with an EM rash on top of the first infection?

I don't know the answer to these questions or how likely these scenarios are, but I suspect the last one I mention above is not entirely uncommon.

Either way, based on the patient background which is supplied in this study we cannot know because patients are reported as being treated successfully during the early stages of infection.

I also don't know how often it occurs that a patient has persisting symptoms after initial treatment for Lyme disease and a new erthyema migrans is never seen during the course of their persisting symptoms.

Given my experience as a patient, I can only make the observation that other patients in my situation seldom report seeing new rashes during the course of their condition. I think researchers should take a close look at the subset of those patients who are most severely ill and are housebound - they are an important subgroup to study because their odds of reinfection are very low.

Related to this, there is one immediate key difference I also see between the patient group studied and chronic Lyme disease patients:

The patient population in this group received a course of antibiotics each time an EM rash presented itself. Because they were treated early, presumably they had a good chance at recovering completely from their infection.

Chronic Lyme disease patients and their doctors alike report that many chronic Lyme disease patients' conditions are discovered late, and symptoms and serology often reflect those of late stage Lyme disease patients - not early acute or early disseminated patients.

It is this difference which makes me wonder about the applicability of such a study to a condition such as chronic Lyme disease or post Lyme disease syndrome.

Patients with late stage Lyme disease are less effectively treated with antibiotics and can be refractory to treatment; studies cited in the 2006 IDSA Lyme disease treatment guidelines indicate that a fair percentage of late stage Lyme disease patients do not fully recover after antibiotic treatment - though the reason why is not entirely clear.[13]

Development of an autoimmune-like condition has been hypothesized by the IDSA and various researchers as being the cause for persisting symptoms after initial infection, while other researchers suspect persisting infection might occur in some patients.

In the end...

The study provides evidence that in 17 patients who are properly treated with antibiotics shortly after EM rashes appear, their infections resolve and they get new infections.

If one supports a model of chronic Lyme disease and thinks that Borrelia burgdorferi can persist in the human host past initial treatment, then this study won't provide evidence either way as to whether or not this is the case:

Part of the definition of chronic Lyme disease hinges on patients having been treated late in infection and/or treated improperly early in infection only to go on to develop later stage Lyme disease in the future.

If one applies this definition, it is important to note that none of the patients in this study had a delay in treatment and proceeded to late stage symptoms before receiving antibiotic treatment. None of the patients were reported as showing signs or symptoms of Lyme disease between episodes of EM rashes; patients experienced only acute Lyme disease which was promptly treated. None of the patients were remarked as being part of the 10% of patients with acute Lyme disease who experience early antibiotic failure, either.[13]

The study participants fit the characterization of the majority of Lyme disease patients who successfully recover from Lyme disease with early treatment - but it does not characterize those patients who do not.

Conversely, if one supports a model of post Lyme disease syndrome, this study won't provide evidence either way as to whether or not this is the case:

None of the patients in this study were reported on followup after a six month interval after any EM rash and subsequent treatment as having developed symptoms indicative of post Lyme disease syndrome. None of the patients were remarked upon as having any particular HLA-DR associated with the development of antibiotic refractory Lyme arthritis - or any potential marker for post Lyme disease syndrome.

If patients have been symptom-free between episodes, this suggests that early treatment aborted the possibility of more serious infection, that patients had a genetic background which made it less likely they would develop antibiotic refractory Lyme arthritis, and/or perhaps early treatment in this small group led to avoidance of post Lyme disease syndrome as well.

Things I Ponder:

• The good news: If the results of this study can be extrapolated to a larger patient base, early treatment of Lyme disease as soon as one sees a new EM rash is more likely to lead to a positive outcome for the patient.
• The bad news: This study says nothing about patients who either neither see a tick bite nor get a rash yet begin show other clinical signs of Lyme disease. Doctors have no easy way of diagnosing these patients and current IDSA guidelines do not cover management of such patients.
• Patients were treated during early to early disseminated infection, when they were most likely to have a positive outcome from antibiotic treatment regardless of the genotype found in their samples.
• There is no information provided about the health and quality of life of enrolled patients. Do they have any preexisting conditions? Have they ever been diagnosed with any condition with symptoms which overlap with those of Lyme disease? How does one make the distinction between these conditions and any symptoms associated with any stage of Lyme disease outside of an EM rash?
• The timing, method, and duration of antibiotic treatment for each patient for each episode was not disclosed. Did all patients receive a course of oral doxycycline, or did some with more disseminated infections receive IV Ceftriaxone? This could have an impact on having a positive post-treatment outcome.
• Regardless of which treatment patients received, how can family and urgent care doctors apply the data from this study to their practice? Hopefully they will see an EM rash and treat patients immediately, but unfortunately this does not always happen in clinical practice as not all EM rashes are properly diagnosed. (e.g. ringworm, eczema, etc.)
• If infections had advanced past the early stage, I wonder which genotypes would have been found in other sample types had they been taken (synovial, CSF, other tissues). Would they have matched earlier research in previous papers or would they have been different?
• Over time, is there a change in the kind of genotypes which infect human hosts? Do these genotypes have a "competitive" nature? How much lateral gene transfer occurs?
• This study applies to the northeastern United States and to infections from Ixodes scapularis ticks. It does not apply to tick bites from Lone Star ticks, which are beginning to outnumber Ixodes scapularis ticks in some areas of the northeast and may carry different infections.
• The public needs to be reminded that different ticks can carry different infections and look for other symptoms of those which may not be EM rashes.
• Babesiosis and Rocky Mountain Spotted Fever are two other infection which come to mind where prompt treatment is necessary.

Well, this is what came to mind after reading this study.

Any questions? Comments?

Next up: Reviewing Dr. Steere's accompanying editorial...

Citations:
1) Dr. Jorge Benach. Presenting at SB Southampton Dean's Lecture Series. Video posted Apr. 20, 2010. http://www.youtube.com/watch?v=TR-aY_S8q2E Approximate Timestamp: 40:20. "Multiple EM rash is sign of disseminated Lyme disease and requires IV or parenteral antibiotics."
2) Columbia University Lyme and Tick-borne Diseases Research Center, http://columbia-lyme.org/patients/ld_lyme_symptoms.html Downloaded November 21, 2012.
3) Strle K, Jones KL, Drouin EE, Li X, Steere AC. Borrelia burgdorferi RST1 (OspC Type A) Genotype Is Associated with Greater Inflammation and More Severe Lyme Disease. Am J Pathol. 2011 Jun;178(6):2726-39.
4)Wormser GP, Brisson D, Liveris D, et al. Borrelia burgdorferi genotype predicts the capacity for hematogenous dissemination during early Lyme disease. J Infect Dis 2008;198:1358-1364
5) Wormser GP, Liveris D, Nowakowski J, et al. Association of specific subtypes of Borrelia burgdorferi with hematogenous dissemination in early Lyme disease. J Infect Dis 1999;180:720-725
6) Seinost G, Golde WT, Berger BW, et al. Infection with multiple strains of Borrelia burgdorferi sensu stricto in patients with Lyme disease. Arch Dermatol 1999;135:1329-1333
7) Liveris D, Varde S, Iyer R, et al. Genetic diversity of Borrelia burgdorferi in Lyme disease patients as determined by culture versus direct PCR with clinical specimens. J Clin Microbiol 1999;37:565-569
8) Jones KL, Glickstein LJ, Damle N, Sikand VK, McHugh G, Steere AC. Borrelia burgdorferi genetic markers and disseminated disease in patients with early Lyme disease. J Clin Microbiol 2006;44:4407-4413
9) Wang IN, Dykhuizen DE, Qiu W, Dunn JJ, Bosler EM, Luft BJ. Genetic diversity of ospC in a local population of Borrelia burgdorferi sensu stricto. Genetics 1999;151:15-30
10) Dykhuizen DE, Brisson D, Sandigursky S, et al. The propensity of different Borrelia burgdorferi sensu stricto genotypes to cause disseminated infections in humans. Am J Trop Med Hyg 2008;78:806-810
11) Wei-Gang Qiu, John F. Bruno, William D. McCaig, Yun Xu, Ian Livey, Martin E. Schriefer, and Benjamin J. Luft. Wide Distribution of a High-Virulence Borrelia burgdorferi Clone in Europe and North America. Emerg Infect Dis. 2008 July; 14(7): 1097–1104.
12) Strle K, Jones KL, Drouin EE, Li X, Steere AC. Analysis of Borrelia burgdorferi Genotypes in Patients with Lyme Arthritis: High Frequency of RST 1 Strains in Antibiotic-Refractory Arthritis. Am J Pathol. 2011 Jun;178(6):2726-39.
13) Wormser GP, Dattwyler RJ, Shapiro ED, et al. The clinical assessment, treatment, and prevention of Lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis 2006;43:1089-1134

Additional Resources:

• An update on the diagnosis and treatment of early Lyme disease: "focusing on the bull's eye, you may miss the mark".
• Detection of established virulence genes and plasmids to differentiate Borrelia burgdorferi strains. http://iai.asm.org/content/early/2012/01/23/IAI.06326-11.short
• Crowder CD, Matthews HE, Schutzer S, et al. Genotypic variation and mixtures of Lyme Borrelia in Ixodes ticks from North America and Europe. PLoS One 2010;5:e10650-e10650. http://www.plosone.org/article/info:doi/10.1371/journal.pone.0010650
• Whole-genome sequences of thirteen isolates of Borrelia burgdorferi. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3028687/
• Blog entry: Let's Not Be Rash About Erythema Migrans
  
  
  
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