Hunting the Elusive PTLDS Patient

Medical topics with questions, information and discussion related to Lyme disease and other tick-borne diseases.
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hv808ct
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Hunting the Elusive PTLDS Patient

Post by hv808ct » Sun 20 Sep 2015 19:15

Long-term Assessment of Post-Treatment Symptoms in Patients With Culture-Confirmed Early Lyme Disease. EricaWeitzner, et al. Clin. Inf. Dis. Sept 18, 2015.

Background. Lyme disease patients with erythema migrans are said to have post-treatment Lyme disease symptoms (PTLDS) if there is persistence of subjective symptoms for at least 6 months following antibiotic treatment and resolution of the skin lesion. The purpose of this study was to characterize PTLDS in patients with culture-confirmed early Lyme disease followed for >10 years.

Methods. Adult patients with erythema migrans with a positive skin or blood culture for Borrelia burgdorferi were enrolled in a prospective study beginning in 1991 and followed up at 6 months and annually thereafter to determine the long-term outcome of this infection. The genotype of the infecting strain of B. burgdorferi was evaluated

Results. One hundred twenty-eight subjects with culture-confirmed early Lyme disease, of whom 55% were male, were followed for a mean ± SD of 14.98 ± 2.71 years (median = 15 years; range = 11–20 years). Fourteen (10.9%) were regarded as having possible PTLDS, but only 6 (4.7%) had PTLDS documented at their last study visit. Nine (64.3%) had only a single symptom. None of the 6 with PTLDS at their last visit was considered to be functionally impaired by the symptom(s). PTLDS was not associated with a particular genotype of B. burgdorferi.

Conclusions. PTLDS may persist for >10 years in some patients with culture-confirmed early Lyme disease. Such long-standing symptoms were not associated with functional impairment or a particular strain of B. burgdorferi.


Comorbidities were common in study subjects, irrespective of whether they had PTLDS. Of the 14 subjects with PTLDS, 8 had been hospitalized for non–Lyme disease-related medical conditions over the follow-up period. For the 6 subjects with persistent symptoms until the final visit, 5 of the 6 had had an intercurrent hospitalization for a surgical procedure.

Of the 14 patients with PTLDS, none was considered to be functionally impaired because of PTLDS at their final study visit. Based on the first question on the SF-36v2 that 12 of the subjects with PTLDS completed, 9 (75%) characterized their health as good to excellent at that visit. Of the 3 subjects who characterized their health as fair to poor at their final visit, 1 did not have any symptom associated with their PTLDS at that visit, and for the other 2 the level of severity of the post-treatment Lyme disease symptoms was 2.2 and 6.1 (out of a maximum of 8), respectively. The first subject of the latter 2 also had a number of serious comorbidities, including post-traumatic stress disorder and a colovesical fistula.

To investigate other possible predisposing factors for development of PTLDS, we assessed the genotypes of the infecting B. burgdorferi strains that were originally cultured from the study subjects, but no pattern emerged that suggested that such symptoms are related to a specific strain of B. burgdorferi.

In our prior report, subjects with PTLDS were significantly more likely than those without PTLDS to have multiple EMs and to have had more symptoms on presentation. Similar trends were observed in this study, but statistical significance was not found.

An additional study limitation is that the cause of the same symptom over time may have been different but still attributed to the prior episode of Lyme disease, as fatigue, memory or concentration difficulties, and joint pains are very common symptoms, have multiple potential etiologies, and often arise as an individual ages.

Our study was not intended to determine whether retreatment with additional antibiotics may be beneficial for relieving persistent symptoms. Other studies have specifically addressed this issue but primarily for patients with post–Lyme disease syndrome rather than PTLDS as defined herein. These studies failed to provide convincing evidence of clinical benefit.

In summary, nonspecific symptoms in patients with culture-confirmed early Lyme disease may persist for up to 20 years in some cases. Such long-standing symptoms were not associated with functional impairment in this study.

RitaA
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Re: Hunting the Elusive PTLDS Patient

Post by RitaA » Sun 20 Sep 2015 19:32

Thanks so much for posting this, hv808ct.

Although the full article wasn't available at the time, there was an earlier discussion about it in the following thread:

Long-term QOL in patients with early LD

http://www.lymeneteurope.org/forum/view ... f=5&t=5812

duncan
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Re: Hunting the Elusive PTLDS Patient

Post by duncan » Sun 20 Sep 2015 20:08

I would love to ask Wormser and his pals about his selection criteria and definitions.

Not to mention why - it appears to me - he believes a population of six qualifies as a meaningful study (only six possibly PTLDS patients finished the assessment process, and it would seem the authors qualified the claim of no functional impairment based on those six.) It is possible I am misinterpreting that; if I am, I would request someone clarify my error.

I am not so confident these six were truly PTLDS candidates. Isn't a syndrome a cluster or set of multiple symptoms?

I think it would benefit the entire Lyme community if study results in general were subject to a public inquiry, where the authors had to defend their findings to individuals not necessarily sympathetic to the study teams' results.

RitaA
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Re: Hunting the Elusive PTLDS Patient

Post by RitaA » Sun 20 Sep 2015 21:08

Here is some published correspondence related to the article. It cannot be cut and pasted, however it can be read online and printed.

http://cid.oxfordjournals.org/content/e ... 32.extract
Correspondence

Lyme Disease Comparators

by Joan Crawford, Neurosupport Centre, Liverpool England
http://cid.oxfordjournals.org/content/e ... 33.extract
Correspondence

Reply to Crawford

by Gary P. Wormser et al
http://cid.oxfordjournals.org/content/e ... 04.extract
Correspondence

Study Design Questions Regarding Long-Term Assessment of Health-Related Quality of Life in Patients With Culture-Confirmed Early Lyme Disease

by Rosalie Greenberg, Medical Arts Psychotherapy, Summit, NJ
http://cid.oxfordjournals.org/content/e ... 06.extract
Corespondence

Reply to Greenberg

by Gary P. Wormser et al
Edited to add:

As has happened in the past, I am able to view and print something in full the first time, however subsequently clicking on the same link later on only provides me with a very short extract. If I have time later today or tomorrow, I'll try to pick out a short and relevant extract or two from each correspondence listed above.

RitaA
Posts: 2768
Joined: Thu 1 Jul 2010 8:33

Re: Hunting the Elusive PTLDS Patient

Post by RitaA » Sun 20 Sep 2015 21:53

Here's one extract from the correspondence "Reply to Crawford" that I wanted to share right away because this issue is raised so often here on LNE:
We do agree with Ms. Crawford that our study does not provide data on the outcome of Lyme disease patients with a delayed diagnosis, a topic that deserves further investigation.

duncan
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Re: Hunting the Elusive PTLDS Patient

Post by duncan » Sun 20 Sep 2015 22:03

Thanks for hunting those down, RitaA.

I wonder what most readers will see if they take the time to peruse the findings. Could it be the Conclusion, that may to some read like a dismissal of claims that PTLDS can be disruptive and even disabling for sufferers?

Who does this study help? Who is its target audience?

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

Re: Hunting the Elusive PTLDS Patient

Post by dlf » Sun 20 Sep 2015 23:19

I suspect the answer to your question Duncan can be found in the following:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4480264/

Clin Infect Dis. 2015 Jul 15; 61(2): 248–250.
Published online 2015 Apr 17. doi: 10.1093/cid/civ279
PMCID: PMC4480264
Editorial Commentary: Life After Lyme Disease
Paul G. Auwaerter

How might this study inform physicians and patients seeking care or explanation of problems that may or may not be related to Lyme disease? Given the high rates of nonspecific, subjective symptoms such as pain and fatigue in the general population, for those with erythema migrans, it should help suppress concerns that the effects of early Lyme disease are likely to cause lifelong debilitation. For patients with difficult-to-resolve, less well-understood problems without good evidence of B. burgdorferi infection, this study offers evidence that treated erythema migrans is not likely a significant driver of chronic health problems in the United States. For this latter group, this study offers little solace and, much like William James more than a century ago, thoughtful physicians are left listening to patients without a clear understanding of mechanisms or effective solutions.
In short, it seems to be designed to allay the fears (and any possible feelings of guilt) on the part of physicians, that somehow they might not be doing the right thing by dismissing or ignoring patients' complaints of ongoing symptoms after recommended treatment has been provided. As to alleviating the fears of patients, who are the ones experiencing these ongoing symptoms, well Auwaerter seems to be living in some other dimension. The Twilight Zone, maybe.

This response was in regards to another "study" in the preceding series leading up to this one.

http://www.ncbi.nlm.nih.gov/pubmed/25447620

Long-term assessment of fatigue in patients with culture-confirmed Lyme disease.
Wormser GP1, Weitzner E2, McKenna D2, Nadelman RB2, Scavarda C2, Nowakowski J2.
Am J Med. 2015 Feb;128(2):181-4. doi: 10.1016/j.amjmed.2014.09.022. Epub 2014 Oct 15
Abstract
BACKGROUND:
Fatigue is a common symptom with numerous causes. Severe fatigue is thought to be an important manifestation of post-treatment Lyme disease syndrome. The frequency with which severe fatigue occurs as a long-term sequela in prospectively followed patients with Lyme disease is unknown.
METHODS:
Patients with culture-confirmed Lyme disease who originally presented with erythema migrans have been evaluated annually in a prospective study to determine their long-term outcome. In 2011-2013, subjects were evaluated for fatigue using an 11-item Fatigue Severity Scale (FSS-11) that has been used in studies of post-treatment Lyme disease syndrome. An FSS-11 score of ≥4.0 is indicative of severe fatigue.
RESULTS:
A total of 100 subjects were assessed, 52% of whom were male; the mean age was 64.9 years (range, 42-86 years). The mean duration of follow-up was 15.4 years (range, 11-20 years). Nine subjects had severe fatigue but in none as a consequence of Lyme disease. Only 3 subjects were thought to possibly have persistent fatigue from Lyme disease. The FSS-11 value for these 3 individuals was less than 4, averaging 2.27, and none had functional impairment.
CONCLUSIONS:
Severe fatigue was found in 9 patients (9%) with culture-confirmed early Lyme disease at 11 to 20 years after presentation, but was due to causes other than Lyme disease. Fatigue of lesser severity was possibly due to Lyme disease, but was found in only 3% of 100 patients, and therefore is rarely a long-term complication of this infection.
It was one of a number that all pretty much used the original cohort from these two:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC228718/
J Clin Microbiol. 1996 Jan;34(1):1-9.
Evolution of the serologic response to Borrelia burgdorferi in treated patients with culture-confirmed erythema migrans.
Aguero-Rosenfeld ME1, Nowakowski J, Bittker S, Cooper D, Nadelman RB, Wormser GP.

http://www.ncbi.nlm.nih.gov/pubmed/8644761
Am J Med. 1996 May;100(5):502-8.
The clinical spectrum of early Lyme borreliosis in patients with culture-confirmed erythema migrans.
Nadelman RB1, Nowakowski J, Forseter G, Goldberg NS, Bittker S, Cooper D, Aguero-Rosenfeld M, Wormser GP.
Between June 1991 and September 1993, a prospective study was conducted at the Lyme Disease Diagnostic Center of the Westchester County Medical Center to isolate Borrelia burgdorferi systematically from patients with Em, and to characterize the clinical manifestations of patients with culture-documented infection. Skin biopsies and/or needle aspirates of the advancing margin of primary lesions, and blood specimens from adult patients were cultured for B burgdorferi in modified Barbour-Stoenner-Kelly medium at 33 degrees C.
B burgdorferi was recovered from 79 patients (49 [62%] males) ranging in age from 16 to 76 years old (mean, 43 +/- 14 years old). Maximum EM diameter (mean, 16 +/- 10 cm; range, 6-73 cm) was a function of EM duration (mean 6.7 +/- 6.4 days; range, 1-39 days) (correlation coefficient = 0.7; P < 0.001). Twenty (25%) patients had noted a tick bite at the site of the primary lesion a mean of 10 days (range, 1-27 days) before onset. Multiple EM lesions (range, 2-70) were present in 14 (18%) patients. Systemic symptoms were present at the time of culture in 54 patients (68%) including fatigue (54%), arthralgia (44%), myalgia (44%), headache, (42%), fever and/or chills (39%), stiff neck (35%), and anorexia (26%). Thirty-three patients (42%) had at least one objective finding on physical examination in addition to EM, including 18 (23%) with localized lymphadenopathy, 13 (16%) with fever (t > or = 37.8 degrees C), seven (9%) with tender neck flexion, six (8%) with joint tenderness, and 1 each with joint swelling, nuchal rigidity, and facial nerve palsy. No patient had new electrocardiogram evidence of atrioventricular block. Liver function assays were abnormally elevated in 37% of patients. Thirty-four percent of patients were seropositive by enzyme-linked immunosorbent assay at presentation. Most others rapidly seroconverted so that 69 of 78 evaluable patients (88%) were seropositive at some point during the first month after diagnosis.
CONCLUSIONS:
We describe the largest group of culture-positive patients with EM from the United States to date. Although systemic symptoms were present in most patients, objective evidence of advanced disease was uncommon. Our patients with culture-confirmed EM were less sick than those described in the days before culture confirmation was possible. The ability to isolate B burgdorferi from lesional skin of large numbers of patients with EM should make culture-positive patients the standard by which to define manifestations of early Lyme borreliosis associated with this rash. Microbiologic documentation of Lyme borreliosis will help delineate the manifestations of this illness, and should form the framework for research directed at pathophysiology, diagnosis, treatment, and prevention.
Here are a few more:

http://www.ncbi.nlm.nih.gov/pubmed/12893393

Am J Med. 2003 Aug 1;115(2):91-6.
Long-term follow-up of patients with culture-confirmed Lyme disease.
Nowakowski J1, Nadelman RB, Sell R, McKenna D, Cavaliere LF, Holmgren D, Gaidici A, Wormser GP.
Abstract
PURPOSE:
To determine the long-term outcome of patients with culture-confirmed Lyme disease.
METHODS:
We analyzed data collected prospectively on adult patients from a highly endemic area in New York State who were diagnosed with early Lyme disease between 1991 and 1994. Patients with culture-confirmed erythema migrans were evaluated at baseline, 7 to 10 days, 21 to 28 days, 3 months, 6 months, 1 year, and annually thereafter. All patients were treated with antibiotics at the time of diagnosis.
RESULTS:
We evaluated 96 cases on 709 separate occasions (median, eight evaluations per case). The erythema migrans rash resolved within 3 weeks in all of the 94 evaluable cases, none of whom developed an objective extracutaneous manifestation of Lyme disease. Of the 81 cases who were followed for >/=1 year, all but 8 (10%) were asymptomatic at their last visit, a mean (+/- SD) of 5.6 +/- 2.6 years into follow-up, and only 3 (4%) were symptomatic at every follow-up visit. Intercurrent tick bites were reported by 45 cases (47%), and 14 (15%) developed a second episode of erythema migrans. Four other cases who were asymptomatic seroconverted between years 2 and 5.
CONCLUSION:
The long-term outcome of patients with erythema migrans after antibiotic therapy was excellent, but patients from a highly endemic area in New York State remained at high risk of re-exposure to ticks and reinfection. Subjective symptoms during follow-up evaluations tended to be mild to moderate, intermittent, and associated with more symptomatic illness at the time of initial diagnosis.
http://www.ncbi.nlm.nih.gov/pubmed/25470117

Long-Term Assessment of Fibromyalgia in Patients with Culture-Confirmed Lyme Disease.
Wormser GP, Weitzner E, McKenna D, Nadelman RB, Scavarda C, Farber S, Prakash P, Ash J, Nowakowski J.
Arthritis Rheumatol. 2014 Dec 2. doi: 10.1002/art.38972. [Epub ahead of print]
PMID: 25470117

duncan
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Re: Hunting the Elusive PTLDS Patient

Post by duncan » Sun 20 Sep 2015 23:32

Do you think insurance concerns find these "studies" interesting? Or agencies in nations which offer state-run medicine and/or disability programs?

RitaA
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Re: Hunting the Elusive PTLDS Patient

Post by RitaA » Mon 21 Sep 2015 19:20

duncan wrote:Do you think insurance concerns find these "studies" interesting? Or agencies in nations which offer state-run medicine and/or disability programs?
I have no doubt that insurance companies and governments worldwide are paying close attention, and that the take-away message for most is that Lyme disease patients who remain unwell after IDSA-recommended treatment are experiencing health issues that are (for the most part) unrelated to the original infection.

If a person in Canada is deemed (by a doctor, and in most cases a specialist) too unwell to work, a private insurer and/or a government agency will more than likely provide a financial safety net regardless of the diagnosis (i.e. ALS, PD, CFS/ME, fibromyalgia, psychiatric illness). As far as I can tell, no government or insurance company benefits when they have to cover disability payments of one kind or another.

Although Canada does supposedly have universal health care, it isn't as "universal" as some might think, so the issue of private insurers really is relevant:

https://en.wikipedia.org/wiki/Health_care_in_Canada
Health care in Canada is delivered through a publicly funded health care system, which is mostly free at the point of use and has most services provided by private entities.[1] It is guided by the provisions of the Canada Health Act of 1984.[2] The government assures the quality of care through federal standards. The government does not participate in day-to-day care or collect any information about an individual's health, which remains confidential between a person and his or her physician.[3] Canada's provincially based Medicare systems are cost-effective partly because of their administrative simplicity. In each province, each doctor handles the insurance claim against the provincial insurer. There is no need for the person who accesses health care to be involved in billing and reclaim. Private health expenditure accounts for 30% of health care financing.[4] The Canada Health Act does not cover prescription drugs, home care or long-term care, prescription glasses or dental care, which means most Canadians pay out-of-pocket for these services or rely on private insurance.[3] Provinces provide partial coverage for some of these items for vulnerable populations (children, those living in poverty and seniors).[3] Limited coverage is provided for mental health care.

[snip]

Canada is the only country with a universal healthcare system that does not include coverage of prescription medication
In other words, it is in the best interests of countries like Canada for patients to be diagnosed and treated as soon as humanly possible to prevent or lessen the negative long-term effects of any illness/disease. Lyme disease patient advocates in Canada often raise the very valid point that early diagnosis and effective treatment of Lyme disease would save the government (i.e. taxpayers) money in the long run. One would think that insurance companies paying for prescription medications and disability benefits (whether short or long term) anywhere in the world would also want their insured clients to be diagnosed and treated in a timely manner.
Last edited by RitaA on Mon 21 Sep 2015 19:25, edited 1 time in total.

RitaA
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Re: Hunting the Elusive PTLDS Patient

Post by RitaA » Mon 21 Sep 2015 19:21

Here are the very short extracts that I promised in an earlier post:

Correspondence -- Lyme Disease Comparators by Joan Crawford:
This study tells us nothing about the outcome for patients whose disease was missed or misdiagnosed resulting in months, years or even decades of disease progression before treatment commencement. This is perhaps the more common presentation in the community, and it may well be this distinctly different group of patients whose health outcomes are bleaker.
Correspondence -- Reply to Crawford by Gary P. Wormser et al:
We do agree with Ms. Crawford that our study does not provide data on the outcome of Lyme disease patients with a delayed diagnosis, a topic that deserves further investigation.
Correspondence -- Study Design Questions Regarding Long-Term Assessment of Health-Related Quality of Life in Patients With Culture-Confirmed Early Lyme Disease by Rosalie Greenberg:
A second concern relates to the study design and the distinction between clinical and statistical significance. This research was not designed (or powered) a priori to detect differences in functional outcomes. Rather, this question was added as a post hoc, secondary analysis 10-20 years after study enrollment.
Correspondence – Reply to Greenberg by Gary P. Wormser et al:
We do agree with Ms. Greenberg on the desirability of additional studies on the long-term outcome of both early and later manifestations of Lyme disease.

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