CCL19 as a Chemokine Risk Factor for Post-Treatment Lyme

Topics with information and discussion about published studies related to Lyme disease and other tick-borne diseases.
Post Reply
dlf
Posts: 294
Joined: Sun 7 Apr 2013 15:36

CCL19 as a Chemokine Risk Factor for Post-Treatment Lyme

Post by dlf » Wed 6 Jul 2016 16:46

Hopefully, eventually the full-text version will become open access. In the meantime, it appears that this is abstract only. I would love to see the full report!

Clin Vaccine Immunol. 2016 Jun 29. pii: CVI.00071-16. [Epub ahead of print]
CCL19 as a Chemokine Risk Factor for Post-Treatment Lyme Disease Syndrome: A Prospective Clinical Cohort Study.
Aucott JN1, Soloski MJ2, Rebman AW2, Crowder LA3, Lahey LJ4, Wagner CA4, Robinson WH4, Bechtold KT5.

http://www.ncbi.nlm.nih.gov/pubmed/27358211
Abstract

Approximately 10% to 20% of patients optimally treated for early Lyme disease develop persistent symptoms of unknown pathophysiology termed post-treatment Lyme disease syndrome (PTLDS). The objective of this study is to investigate associations between PTLDS and immune mediator levels during acute illness and at several time points following treatment. Seventy-six participants with physician-documented erythema migrans and 26 healthy controls with no history of Lyme disease were enrolled. Sixty-four cytokines, chemokines, and inflammatory markers were measured at each visit for a total of 6 visits over 1 year. An operationalized definition of PTLDS incorporating symptoms and functional impact was applied at 6 months and 1 year following treatment completion, and clinical outcome groups were defined as Return to Health, Symptoms Only, and PTLDS. Significance analysis of microarrays identified 7 of the 64 immune mediators as differentially regulated by group. Generalized logit regressions controlling for potential confounders identified post-treatment levels of the T-cell chemokine CCL19 as independently associated with clinical outcome group. ROC analysis identified a CCL19 cutoff of > 111.67 pg/mL at one month following treatment completion as 82% sensitive and 83% specific for later PTLDS. We speculate that persistently elevated CCL19 levels among participants with PTLDS may reflect ongoing, immune-driven reactions at sites distal to secondary lymphoid tissue. Our findings suggest the relevance of CCL19 both during acute infection and as an immunologic risk factor for PTLDS during the post-treatment phase. Identification of a potential biomarker predictor for PTLDS provides the opportunity to better understand pathophysiology and to develop early interventions in the context of appropriate and specific clinical information.

duncan
Posts: 1370
Joined: Wed 5 Sep 2012 18:48

Re: CCL19 as a Chemokine Risk Factor for Post-Treatment Lyme

Post by duncan » Thu 7 Jul 2016 1:50

I wonder what the authors mean by "an operationalized definition of PTLDS..."

There are many things I like about Aucott and company, but he bothers me in the way it seems assumed that an active infection is not the issue. The assumptive close feeling to the abstract is unfortunate.

Btw, some would say the pathophysiology of Lyme symptoms following treatment of any sort is frequently known, i.e. it is continued active Lyme following ineffective therapy.

I think it is exciting that he has published a consistency in chemokine production between acknowledged acute cases, and cases that have had the misfortune of being labeled post-treatment Lyme disease syndrome.

dlf
Posts: 294
Joined: Sun 7 Apr 2013 15:36

Re: CCL19 as a Chemokine Risk Factor for Post-Treatment Lyme

Post by dlf » Thu 7 Jul 2016 6:35

Duncan wrote:
I wonder what the authors mean by "an operationalized definition of PTLDS..."
They created this "operationalized definition" in order to properly study patients who very specifically would be characterized as having PTLDS versus having other symptom sequelae that would not qualify as fitting the definition. He published this in 2013, probably in order to set the stage for the SLICE study which a lot of interesting findings are coming out from.

Development of a foundation for a case definition of post-treatment Lyme disease syndrome
John N. Aucott, Lauren A. Crowder, Kathleen B. Kortte
Corresponding Editor: Eskild Petersen, Skejby, Denmark

http://www.ijidonline.com/article/S1201 ... 5/fulltext

Summary

Objectives
The study objective is to demonstrate the clinical and research utility of an operationalized definition of post-treatment Lyme disease syndrome (PTLDS), as proposed by the Infectious Diseases Society of America.

Methods
Seventy-four patients with confirmed erythema migrans and 14 controls were enrolled. Patient-reported symptoms and health function (SF-36) were collected pre-treatment and at follow-up visits over 6 months post-treatment.

Results
Eight (11%) patients met our operationalized definition of PTLDS, which included self-reported symptoms of fatigue, widespread musculoskeletal pain or cognitive complaints, and functional impact as measured by a T score of <45 on the composite SF-36. No controls met the functional impact criteria. Forty-three (60% patients returned to their previous health status when measured at 6 months post-treatment. Twenty (28%) patients had either residual symptoms or functional impact, but not both, and did not meet criteria for PTLDS.

Conclusions
This operationalized definition of PTLDS allows for identification of those patients who are treated for early Lyme disease and have significant post-treatment illness, as they have both residual symptoms and impact on daily life functioning. With further refinement and improvement of this operationalized definition, the true incidence of PTLDS can be determined and future studies can be designed to examine its pathophysiology and treatment.
Duncan also wrote:
There are many things I like about Aucott and company, but he bothers me in the way it seems assumed that an active infection is not the issue. The assumptive close feeling to the abstract is unfortunate.

Btw, some would say the pathophysiology of Lyme symptoms following treatment of any sort is frequently known, i.e. it is continued active Lyme following ineffective therapy.

I think it is exciting that he has published a consistency in chemokine production between acknowledged acute cases, and cases that have had the misfortune of being labeled post-treatment Lyme disease syndrome.
I wouldn't be so quick to judge what he actually thinks about ineffective therapy or continued active Lyme. He seems to have positioned himself as a moderately minded researcher, intent on finding answers. If he were to declare one way or the other, I suspect his work would be viewed with skepticism on both sides. The work he and his colleagues is undertaking is truly valuable and needs to be done to actually start to figure out the many possible causes of the pathophysiology in different individuals. I think he is trying to create "the middle ground" in order to advance the science. I give him a lot of credit for at least trying to address the many issues of lingering symptoms when so many others are quick to write us all off.

Here are some snips from the full text to provide a little more context. I have bold texted and underlined a few passages that make me think that he really does have a grasp on reality.
3.1. Cohort characteristics

Seventy-four patients with confirmed early Lyme disease were enrolled. Three individuals (4%) were lost to follow-up, however they were not found to differ from the rest of the cohort on age, education level, income level, gender, or race. The characteristics of our study cohort (see Table 1) are similar to those previously reported in the literature for patients with Lyme disease.13

Over the course of the study (between 1 and 6 months post initial treatment of EM), seven patients were retreated. Three patients were retreated at 3 months post-treatment with intravenous ceftriaxone due to neuropathy verified by nerve conduction studies. Three patients were retreated immediately following the first treatment with oral antibiotics due to a persistent or enlarging EM rash. Two patients were retreated at 4 weeks post-treatment with oral antibiotics due to disabling fatigue. One patient was retreated twice, once for fatigue at 4 weeks post-treatment and again for neuropathy at 3 months post-treatment.the time of retreatment, four of the seven patients met both the symptom and functional impact criteria for PTLDS, with a range of the SF-36 composite score between T = 21 and T = 43. Of the seven retreated patients, three went on to meet our criteria for PTLDS at the 6-month follow-up visit. These sequelae and rates of retreatment are similar to those seen in other studies of early Lyme disease.

<snip>

With a consistent approach across studies, findings can more easily be compared and the true incidence of PTLDS can be determined. Additionally, incorporating quantitative and reproducible measures of symptoms (severity and course) and their impact on life functioning provides a stronger foundation for assessing the overall efficacy of potential new pharmacologic and non-pharmacologic treatment modalities for early and late Lyme disease. Most recent studies on the treatment of Lyme disease have focused on resolution of physical findings, such as the rash of early Lyme disease or the joint swelling of late Lyme disease, as objective parameters of treatment success. We suggest that outcome variables also include patient-reported symptoms and functional outcomes as part of the complete picture of treatment success. We recognize that the proposed framework is an initial step that will likely need further refinement. However, a uniform approach provides a starting point for the field in the identification of individuals with PTLDS to address questions about reasons for symptom persistence and identification of potential interventions.

Our goal with this study was to provide a useful framework that research and clinical communities could use to uniformly identify individuals with PTLDS. The international scientific community can and will continue to investigate the competing hypothesis regarding the pathophysiological underpinnings of the persistence of illness in the subgroup of individuals exposed to and treated for Lyme disease.43, 44, 45 The development of more sophisticated and sensitive biomarkers for B. burgdorferi, as well as the host immune response, will lay the groundwork to develop future chemotherapeutic approaches to PTLDS. Future biomarkers will be critical in understanding what role infection and autoimmunity play in the genesis of the patient's symptoms. Until then, the question of what role antibiotic or non-antibiotic therapy should play in the treatment of PTLDS will remain the subject of debate.

The present challenges are to move toward a more uniform and comprehensive evaluation and follow-up of patients after initial antibiotic treatment of Lyme disease, including the use of quantitative measures of patient reported symptoms and close observation of patients for issues that may require early retreatment after initial therapy. Physician-observed, objective findings, such as the development of meningitis, cranial nerve palsy, or radiculopathy, represent one well agreed upon indication for retreatment with antibiotics.7 In addition, retreatment for early persistent or recurrent patient-reported symptoms in the initial weeks or months after completion of initial antibiotic therapy remains an area that is hinted at in the literature but not specifically addressed in the current literature.41, 42 At the same time, it is equally important to investigate the role of psychological variables, such as coping patterns, the presence of pre-Lyme psychopathology, and the possible vulnerabilities that put an individual at risk for developing chronic symptoms. Or alternatively, there should be consideration of the adaptive coping skills that serve to protect individuals from the full impact of persistent symptoms on their emotional and physiologic functioning. As this work goes forward, it is critical that the clinical community has valid and reliable ways to identify individuals who are in need of further evaluation and treatment. That is good medical care.

duncan
Posts: 1370
Joined: Wed 5 Sep 2012 18:48

Re: CCL19 as a Chemokine Risk Factor for Post-Treatment Lyme

Post by duncan » Thu 7 Jul 2016 12:50

You've raised good points, dlf.

Nevertheless, his language concerns me.

If I treat my Lyme with 2 days of doxy, then stop, and I treat AGAIN with 2 days of doxy, etc - am I retreating every two-three days? Almost inherent in using "retreat" is the idea that conventional treatment is proper and sufficient. But we know in up to 20 percent of acute cases conventional treatment fails Lyme patients.That is a poor percentage in the world of medicine. I can't help but wonder how worse it is for late stage patients.

Yet his wording seems to me to suggest this debate over what constitutes proper treatment is either not on the table, or it gets lost in the copy and what I feel is bias-laden verbiage.

Even little things like "patient self-reported symptoms", which has the feel of insurance speak, in aggregate leaves me wondering. He seems to perhaps want to placate the Old Guard by acknowledging overt symptoms are better, and doesn't realize in doing so he has cast symptoms like exhaustion and poor mental acuity and pain in a questionable light. Another example: What in the world is "post-treatment phase"? Is that even a thing?

Word choice matter. If one's narrative assumes a bias, even an inadvertent one, that bias can influence readers. With most clinicians reading only abstracts (if they read this stuff at all), every inference or impression that works against a particular stance in the debated Lyme quarter counts.

What might the average reader walk away with after reading stuff like this? The good news is with Aucott, at least the reader walks away with a feeling that these patients are very sick (not sure readers walk away thinking they are still infected though). But they may also walk away - I think - with the feeling this "illness" might have little if anything to do with Lyme anymore, other than the genesis of the patients' current conditions.

dlf
Posts: 294
Joined: Sun 7 Apr 2013 15:36

Re: CCL19 as a Chemokine Risk Factor for Post-Treatment Lyme

Post by dlf » Thu 7 Jul 2016 17:29

duncan, you've also raised good points.

First for anyone who has had problems accessing the full text to "Development of a foundation for a case definition of post-treatment Lyme disease syndrome" using the link I provided, there is an easier way to access this. I have no idea why that link doesn't work and the text wouldn't fully activate as a link, but this new link will take you to the abstract. When there, click on the open access box on the top right side of the page.

http://www.ncbi.nlm.nih.gov/pubmed/23462300


On the question of treatment. In the case of the Aucott studies, what they were treated with as the first line protocol is clearly stated:
The current study is part of a larger cohort study of Lyme disease and PTLDS in which participants were treated with a 3-week course of oral doxycycline and followed post-treatment for a period of up to 2 years.6 The current study focused on the time period from time of diagnosis of Lyme disease through 6 months post-treatment, including visits immediately post-treatment (approximately 3 weeks after the first), 4 weeks post-treatment, and 3 months post-treatment. During the initial visit, at time of diagnosis, demographic information and medical history were recorded. At all study visits, participants underwent a physical exam, a clinical interview that included symptom reporting, interval medical history and medication usage, and self-administered the 36-item Short Form Health Survey, Version 2 (SF-36).
You will note that this length of treatment is the longest treatment period recommended in the 2006 IDSA Lyme Guidelines, which advise 10 to 21 days. If one were to set out to demonstrate that the recommended treatment is ineffective, you need to study patients who have been treated to the maximum limit of the guidelines. Then you can begin to delineate just how many patients don't have their symptoms resolve and how many of those are so debilitated that they can then be categorized as having "PTLDS". In this case:
To determine the impact on life functioning specific to individuals with PTLDS, we created a composite score based upon our previous research using the SF-36 in an early Lyme cohort.15 An ANOVA revealed that the three groups differed on this composite score (F(2) = 7.46, p = 0.001), with post-hoc analyses demonstrating that the PTLDS symptom-positive group differed significantly from the PTLDS symptom-negative group (p < 0.001) and the control group (p = 0.01); however the PTLDS symptom-negative group did not differ significantly from the control group (p = 0.83). Using this composite score, there were eight individuals who were PTLDS symptom-positive who were below the cut-off of T = 45, and there was a clearer division between patients with symptoms who endorsed impact on life functioning and those who did not (see Figure 2b). Using these criteria, twenty (28%) patients had either residual symptoms or functional impact, but not both, and did not meet criteria for PTLDS. Forty-three (60%) patients returned to their pre-Lyme health status when measured at six months post-treatment. When compared to using the physical component score and mental component score provided by the SF-36, our composite score performed better in distinguishing between the three patient populations (see Figures 2c and 2d); no significant differences between the three groups were seen in either the physical component score (p = 0.1381) or the mental component score (p = 0.1766). There was an even distribution of those individuals who were retreated with a second course of antibiotics among all three outcome groups.
Only 60% of patients returned to their pre-Lyme health status when measured at six months post-treatment, leaving 40% of patients with either residual symptoms or functional impact, or both. That only 11% in this study were so debilitated as to qualify as having PTLDS (some of whom were 're-treated' based on the most liberal interpretations of the guidelines) shows how stringent the definition is. In the real world, patients even with outright treatment failure are often not recognized and provided with the full amount of treatment suggested as being advisable. Treatment protocols that demonstrably leave 40% of early acute stage patients without symptom resolution need to be revisited and changed. In order to change things in the real world, it needs to be demonstrated unequivocally that the much touted fixes just don't work.

The IDSA is ubiquitous, powerful and unwilling to do studies that will prove that their recommendations are wrong (for obvious reasons). So, how do you think any researcher could go about proving that the IDSA has been consistently wrong about treatment, if not how Aucott is proceeding?

The only way to do this, as far as I can see, is by doing solid evidence-based scientific research on well characterized human cases.This won't happen with just one or two studies and would have to be a methodical process that moves from step A to B. I have no idea whether Aucott actually does think that Lyme is (or might be in 'some' patients) persistent or not because he is careful not to suggest any answer at all. Nonetheless, each patient he studies provide more and more clues into individual patient circumstances and whatever he believes will be influenced by the weight of his findings.

duncan, you wrote:
Word choice matter. If one's narrative assumes a bias, even an inadvertent one, that bias can influence readers. With most clinicians reading only abstracts (if they read this stuff at all), every inference or impression that works against a particular stance in the debated Lyme quarter counts.
I couldn't agree more! I sometimes think that study authors don't recognize just how their words will be interpreted. I also think that in many cases, for those trying to create the "middle ground" in research, they could very well believe that if they openly show a particular hand, they might justifiably feel that it could get chopped off. I suspect that in order to actually get funding and get published many researchers pander to the IDSA. If they want to work and advance the science, I don't see that they have any choice in this. Maybe he truly believes the IDSA dogma but, only he would know for sure. However, I do sometimes wonder how open-minded researchers feel when they look into a mirror.

User avatar
ChronicLyme19
Posts: 564
Joined: Mon 11 Aug 2014 17:42
Location: NY, USA

Re: CCL19 as a Chemokine Risk Factor for Post-Treatment Lyme

Post by ChronicLyme19 » Sun 10 Jul 2016 20:53

Please correct me if I'm wrong, but aren't most of Aucott's studies on CDC positive patients or ones with classic bullseyes?

If so that's leaving out huge portions of the patients, which in my opinion are probably the ones that are most likely to suffer long terms symptoms if they don't have a good initial immune response.
Half of what you are taught is incorrect, but which half? What if there's another half missing?

Post Reply