Tuesday, May 17, 2011

8 Paper: Environmental Stress in Borrelia Burgdorferi

The things you find, just randomly surfing online...

So, this is someone's dissertation for their doctoral degree. In 2004.

RESPONSES TO ENVIRONMENTAL STRESS TRIGGERS DIFFERENTIAL EXPRESSION
AND CELLULAR DAMAGE IN BORRELIA BURGDORFERI

A Dissertation Submitted to the Graduate Faculty of the University of Georgia in Partial
Fulfillment of the Requirements for the Degree
DOCTOR OF PHISOLOPHY
ATHENS, GEORGIA
2004

Should I forgive the typo, on a dissertation?

Well, I will. Just this once, because I am interested in commenting on more of the content inside and think this is a minor oversight. For all I know, there's a minor typo somewhere in my own publications that will come back to haunt me...

First, this section on serological tests for Lyme disease:

"ELISA assays are the most widely available and commonly performed tests, and have replaced IFA which are both labor intensive and subjective in interpretation (54, 77, 176, 192).  However, both ELISA and IFA are prone to both false positives and false negatives.  False positives generally result from the cross reactivity of B. burgdorferi proteins with proteins of other infectious agents (spirochetal, bacterial, rickettsial, rocky mountain spotted fever, EBV) (54, 77, 176, 192)."

 Yes, it's important to know what you're infected with, but in this case, with the exception of EBV - everything there is a bacterial infection requiring antibiotic treatment. So patient history plus serology is more than likely going to nab this one for treatment.

Next, let's look at this section on antibiotic resistance:

"Antibiotic resistance in B. burgdorferi has been investigated in vivo, in vitro, as well as in clinical reports.  B. burgdorferi is resistant to aminoglycosides, ciprofloxacin, rifampin, most first generation cephalosporins and some clinical isolates are erythromycin resistant (40, 134, 136, 138, 154, 192, 199, 220, 293)."

See, that's a lot of different drugs to which it's resistant. Note, please, that aminoglycosides are the first drug mentioned there.

And then we look at which antibiotics affect Borrelia burgdorferi:

"In contrast, it is  sensitive to penicillin and penicillin derivatives along with some macrolides and second generation cephalosporins (9, 40, 134, 136, 138, 154, 199, 220, 273, 277, 310).  To effectively treat B. burgdorferi located in deep tissue, CNS, eye, and within tendons, higher doses are often required (9, 40, 199, 220, 273, 277, 310)."

Okay, I think you could have expected this... this statement is totally within the standard guidelines and on research done to date on these particular antibiotics in vitro.

But then there's this part of the paper:
"Treatment of disseminated and late Lyme disease is much more difficult.  The duration of treatment is longer, the response is often slower and treatment failure is higher due to the presence of B. burgdorferi in the CNS, eye, within tendons and deep tissue (192, 306).  For patients with neurological complications, intravenous treatment regimens can last many months and includes 2 grams daily of ceftriaxone or 20 million units per day of penicillin G in divided doses (192, 306, 309). "
Hm. Okay. This isn't something that's included in the guidelines. Fascinating. This sounds more like the treatment plan that many Lyme disease patients with persisting symptoms have been taking, and getting some flack for from some medical professionals.

So why? If this is good enough for a doctoral dissertation, why isn't it good enough for patients?

Did something happen in 2004 I don't know about? I'm pretty sure the guidelines for treatment at this point did not include this treatment recommendation.

So what are papers 192, 306, and 309?

192. Nocton, J. J., and A. C. Steere. 1995. Lyme disease. Adv. Intern. Med. 40:68-115
306. Wilson, M. E. 2002. Prevention of tick-borne diseases. Tick-Borne Diseases 86:219-238.
309. Wormser, G., R. Nadelman, J. Dattwyler, D. Dennis, E. Shapiro, A. C. Steere, T.
Rush, D. W. Rahn, P. K. Coyle, D. H. Persing, D. Fish, and B. J. Luft. 2000. Practice
guidelines for the treatment of Lyme disease. Clin. Infect. Dis. 31:S1-S14.

Wait. I'm really seeing this?

I need to go look at these papers and have a stiff drink.

Okay, paper 192 is http://www.ncbi.nlm.nih.gov/pubmed/7747659 on PubMed, but there is no option to view an abstract of it, or pay for full text access  through PubMed. Advances in Internal Medicine stopped publishing in 2001, so you'll have to get a hard copy elsewhere (Elsevier doesn't have it, either.)

On to the next paper... http://www.ncbi.nlm.nih.gov/pubmed/11982299 which one has to pay for access online, though there is a limited abstract.

And then 309, which is this http://www.ncbi.nlm.nih.gov/pubmed/10982743  Which is the IDSA Lyme disease guidelines for 2000.

And, well, they say about what I expected:

"Late neuroborreliosis affecting the CNS or peripheral nervous system. For patients with late neurological disease affecting the CNS or peripheral nervous system, treatment with ceftriaxone (2 g once a day iv for 2–4 weeks) is recommended (B-II).

Alternative parenteral therapy may include administration of cefotaxime (2 g iv every 8 h) (B-II) or iv penicillin G (18–24 million units daily, divided into doses given every 4 h for patients with normal renal function) (B-II). Response to treatment is usually slow and may be incomplete. However, unless relapse is shown by reliable objective measures, repeat treatment is not recommended. For children, a 14–28-day course of treatment with ceftriaxone (75–100 mg/kg/d in a single daily iv dose; maximum, 2 g) is recommended (B-II). An alternative is cefotaxime (150–200 mg/kg/d iv, divided into 3 or 4 doses; maximum, 6 g/d) (B-II). Another alternative is iv penicillin G (200,000–400,000 units/kg/d, divided into doses given every 4 h for those with normal renal function; maximum, 18–24 million units/d) (B-II)."

As has been said other places at other times: Why aren't these "reliable objective measures" spelled out in this document?

And how does one determine whether to dose out 2 weeks, 3 weeks, or 4 weeks of ceftriaxone? What's the objective measurement they use to decide between giving a patient 2 weeks versus 4 weeks of IV?

And the next section is...

"Chronic Lyme disease or post–Lyme disease syndrome..."

Yeah, well, let's not even go there right now. Most people reading along already know what that section says...

I suspect that the 2002 Wilson paper is what mentions long term treatment protocols in the dissertation I began writing about - but I'm going to have to look for it elsewhere and see if I can find access available for all my readers. For what it's worth, there is some mention of Sam Donta in the same publication, so perhaps this is where the extended IV protocol in bold came from?

At any rate,  getting back to reading  the 2000 guidelines (and I have yet to reread the 2006 ones), it appears that there weren't many studies back then on large numbers of patients with neuroborreliosis and late stage Lyme disease including encephalopathy. We're talking 7 patients for this one case series, 48 for another... small numbers.

And amid all that, there are studies like this which were conducted:

"From 1986 through 1991, 48 adult and pediatric patients with Lyme arthritis were randomly assigned to receive either doxycycline (100 mg orally twice a day) or amoxicillin and probenecid (500 mg of each 4 times a day), in each instance for 30 days [87]. Eighteen of the 20 evaluable patients treated with doxycycline and 16 of the 18 evaluable patients who completed the amoxicillin regimen had resolution of arthritis within 13 months after enrollment in the study. However, neuroborreliosis later developed in 5 patients, 4 of whom were treated with the amoxicillin/probenecid regimen.

The concomitant use of probenecid with amoxicillin may be inadvisable, because probenecid may impair penetration of b-lactam antibiotics into brain parenchyma [72, 88].

In retrospect, it was noted that all 5 patients reported subtle distal paresthesias or memory impairment at the time of enrollment. It was concluded that patients with Lyme arthritis can usually be treated successfully with oral antibiotics, but practitioners must be aware of subtle neurological symptoms that may require treatment with iv antibiotics."

Hope that test got a do-over, and they found out what was wrong with those 5 patients and they got the help they needed. Would you have included patients with that background in this study? I wouldn't have. Their symptoms match those of neuroborreliosis. Why weren't they excluded from the study earlier on?

I underlined "subtle neurological symptoms" to make a point, by the way: The panelists are always mentioning that they need objective evidence of infection, yet here they are urging practitioners to be aware of subtle neurological symptoms. Which are subjective evidence.

So... what else can you look at as objective measurements other than serology? Because after the first two weeks of infection, CSF tests don't have good yields. And if your patient already had some antibiotics but they were undertreated, will they produce a robust ab response on tests? Can someone tell me?

Okay, here's another study from the 2000 guidelines:

"Patients with late Lyme disease associated with prominent neurological features also respond to antibiotic therapy. In trials conducted from 1987 through 1989, 27 adult patients with Lyme encephalopathy, polyneuropathy, or both were treated with iv ceftriaxone (2 g/d for 2 weeks) [93]. In addition to clinical signs and symptoms, outcome measures included CSF analyses and neuropsychological tests of memory. Response to therapy was usually gradual and did not begin until several months after treatment. When response was measured 6 months after treatment, 17 patients (63%) had uncomplicated improvement, 6 (22%) had improvement but then relapsed, and 4 (15%) had no change in their condition."

So right there, the study outcome was that 6 of 27 patients improved but relapsed, and 4 just didn't get any better.  In this study, 37% of the patients did not have "uncomplicated improvement". (What does that mean, "uncomplicated improvement"? Why not use the words "were cured"? )

No, in this study, 37% did not improve at all as far as we know. Some followup report here would be good.

Moving on to another study from the 2000 guidelines (are you bored yet?):

"In 1987, a case series of 7 patients with Lyme arthritis or chronic neuroborreliosis, who were refractory to oral or iv penicillin therapy were then treated with iv ceftriaxone (2 or 4 g/d for 2 weeks) [83]. All 5 patients who had arthritis responded to ceftriaxone therapy, and for 5 of the 6 patients with limb paresthesias, a reduction in symptoms and improvement of nerve conduction study findings were noted."

So here, again, "reduction in symptoms" and "improvement of nerve conduction study findings were noted"... but I'm not seeing the phrase, "resolution of symptoms". Is this the most patients can hope for with these conditions?

I'm hoping I missed something, and just need to find the original case series paper and read it. But I see this as 5-6 people out of 7 did not have resolution of their symptoms. How else can I read it?

More from the 2000 guidelines:

"In a follow-up study, 23 patients with Lyme arthritis or late neuroborreliosis were randomly assigned to receive penicillin (20 million units per day iv for 10 days) or ceftriaxone (4 g/d iv for 14 days) [84]. Of the 13 patients who received ceftriaxone none had objective evidence of persistent disease after treatment, although 3 had mild arthralgias and 1 complained of fatigue and memory difficulty. In contrast, 5 of the 10 patients who received iv penicillin continued to have fatigue, memory deficit, or recurrent oligoarthritis. For 4 of these 5 patients, symptoms resolved after repeat treatment with ceftriaxone."

Better outcome. Good. I'm glad they figured out ceftriaxone worked better than penicillin.

Still, what happens if ceftriaxone didn't work? Do you try another antibiotic or say, "that's it"? I'm wondering what happened to that fifth person and how they're doing today. And I do wonder what happened to those 3 patients with mild arthalgias and 1 with fatigue and memory problems... were they followed up later on? Did their symptoms resolve or continue? Do they know what caused them? Unanswered questions.

And also:

"In a subsequent study, 31 patients with Lyme arthritis or chronic neuroborreliosis were randomly assigned to receive 2 or 4 g/d of ceftriaxone for 2 weeks [84]. After treatment, 3 of the 31 patients had persistent encephalopathy, 2 had persistent neuropathy, and 3 had no diminishment of their arthritis. The overall frequency of persistent symptoms among patients was 13%, which was similar in both treatment groups."

And... and... oh, here's one with more people, and it's randomized:

"In an open-label, randomized, multicenter study, 143 evaluable patients with manifestations of late Lyme disease, primarily Lyme arthritis, were treated with iv ceftriaxone (2 g/d for either 2 or 4 weeks) [85]. In 76% of those treated for 2 weeks and 70% of those treated for 4 weeks, symptoms resolved after treatment (the P value was not significant). The most common persistent symptoms were arthralgia, pain, weakness, malaise, and fatigue."

Okay, so 76% of patients treated for 2 weeks and 70% of those treated for 4 weeks, symptoms resolved. Now what about the other 24% and 30% respectively? Their symptoms must not have resolved?

Now I can't keep going on with posting all of these, it's getting tedious - there are more examples of the work they were doing in the guidelines and you can check them out for yourself.

Let's review the treatment recommendation for Late stage Lyme neuroborreliosis, shall we?

"Late neuroborreliosis affecting the CNS or the peripheral nervous system. For patients with late neurological disease affecting the CNS or peripheral nervous system, treatment with ceftriaxone (2 g once a day iv for 2–4 weeks) is recommended (tables 3 and 4) (B-II). Alternative parenteral therapy may include administration of cefotaxime (B-II) or penicillin G (BII). Response to treatment is usually slow and may be incomplete. However, unless relapse is shown by reliable objective measures, repeat treatment is not recommended. For children, treatment with ceftriaxone is recommended (tables 3 and 4) (BII). Cefotaxime or penicillin G administered iv are alternatives (B-II)."

So this is the recommendation for 2000.

I really need to take a look at the guidelines for 2006 and compare them.

But just looking at the 2000 guidelines as their own sort of universe, what is puzzling me is why they are recommending treatment guidelines which don't lead to resolution of symptoms for everyone. At least a greater number of people?

If the reason these other cases failed - and with the bigger studies, we're looking at 24-37% of patients did not have resolution of their symptoms - was because they had this particular human leukocyte antigen–DR4 specificity and antibody reactivity with OspA of the spirochete... that isn't stated for ANY of these studies.

It is stated for one study they mentioned later on with 16 patients though - but it's the only one mentioned where they tested for this marker. One study. Sixteen people.

I'm hoping when I look at the next set of guidelines, it will be data rich. Right now, I'm just reeling a bit from this, and wondering if the author of the dissertation saw these results and wondered about them, too.

How do you tell the difference between late stage Lyme disease that relapsed or continued versus what they are calling PLDS?

Getting back to the dissertation (remember the dissertation I first began writing about? It's okay if you don't - I almost forgot it myself):

I found this bit of microbiology trivia for those interested:

"Finally, in contrast to most bacteria, B. burgdorferi phospholipids, lipoproteins and glycolipids contain unsaturated fatty acids, such as linoleic, linolenic, and arachidonic acids, which are derived from the host (35, 38, 121, 171)."

The damned things are just parasites, really.

8 comments:

  1. I just skimmed the Wilson article - I can't see any mention of long term treatment - it mainly focusses on prevention. Great blog, by the way - nice to see a critical appraisal of the evidence!

    ReplyDelete
  2. Mark,

    Thank you for reading the Wilson article - I have yet to check it out for myself. I have limited online access to some journals, but it's not all-inclusive. I need an Athens account.

    I'm wondering where the author got this long-term antibiotic treatment information from - I'm going to have to get a hold of that first paper offline somehow and see what it has to say.

    Thank you for the compliment. How did you hear about this blog?

    ReplyDelete
  3. Mark,

    I'm kinda curious - what made you interested in reading about Lyme disease and posts here on it?

    ReplyDelete
  4. Hi! My finance has chronic Lyme (contracted either at birth, or at least >a decade ago), so we have a strong interest in figuring out what's really going on with Lyme.

    I have no background in biology or medicine, but I am a scientist, so I'm trying to play catch-up so that we can make educated decisions on treatment, and separate the wheat from the chaff when it comes to the various alternatives available.

    I think I found a link to your blog from a collection of Lyme blogs listed on facebook.

    ReplyDelete
  5. Mark,

    Hi. I'm sorry to hear that your fiance has been ill with Lyme disease. You are good for being supportive and trying to figure out what the best course of action is to help her.

    I've been in the same position your fiance has been in - and have only gotten part of my brain back since I was treated with Mepron and a macrolide (Azithomycin usually, sometimes Clarithromycin) for a coinfection, Babesia.

    I suspect that for me, what is left is either Lyme-related and/or general damage from infection - I'm just not sure yet.

    Since treating for Babesia (which was a positive smear), fatigue has been far more pronounced lately and pain less intense late at night. A relief, because it means more sleep (well, except a night like tonight, where I am responding to you during your European Friday morning).

    (Disclaimer: I am not a doctor, so anything that follows is informational and not medical advice.)

    If she hasn't been evaluated for any coinfections, I highly recommend that she look into it based on which coinfections would have been likely to be present in the area she grew up in. Also, I wouldn't dismiss the possibility she might have been reinfected since then if she has had any symptom exacerbation - look for new serological responses on tests.

    So you are pretty sure she has been sick from a tick bite many years ago or from congenital infection? The former is far more common than the latter.

    Alongside doing what sleuthing you are doing, I recommend making sure any differential diagnoses are looked at and handled - just in case her symptoms are due to something other than tickborne illnesses. Sometimes you can have more than one problem concurrently, too.

    (more)

    ReplyDelete
  6. Regarding doing the scientific research for Lyme disease and reading what's currently out there:

    I get the impression I am one of a small handful of people who has been infected who has worked in the sciences and who has actually gotten sick with Lyme disease (Borreliosis) who also has had persistent symptoms. My luck?

    Most of what I have come across online in terms of Lyme disease patient information has been about finding a treating doctor, taking antibiotics longer term than is standard, complaining about symptoms and symptomatic relief, and herbal and some unusual alternative treatments.

    Occasionally some online support groups will post something about scientific abstracts and research on chronic Lyme and its treatment - most US sites do not do this as much as the Canadian Lyme Disease web site or Lymenet Europe.

    Overall, Lyme patient blogs are low on the science factor and high on the alternative side; many are about patients' experiences with Lyme in terms of how it affects them socially, emotionally, and physically.

    There is a need for that and when I was at my absolute sickest, I couldn't read what I can read now. I was too sick. Being so sick I couldn't understand most of what I read unless it was short and simple was depressing, so emotional support was more what I needed in the early days of my illness.

    I don't need emotional support as much now - what I want now is to get my life back. The fatigue has been relentless, and pain ongoing. Even if I went to sleep for 10 hours, I won't feel much better than if I'd slept for 6.

    But I digress... I wanted to read someone else's blog like this one, and there isn't one - or at least I couldn't find any. So I ended up writing one.

    I'm hoping others will do the same, and just start writing about the research they find and what they think of it. I'm hoping they'll also find more scientific justification for the things they try and the risks they take, and share the process with others going down the same path.

    In general, I've ended up poking around at all kinds of web sites online: LLMDs, the IDSA, pubmed, oxford journals, Lymenet Europe, CanLyme, Lymeinfo, and also read some journals and books offline. Between all of these and my own experience, I've ended up reading, researching, and writing this blog as I go... Consider this blog somewhat of a reflection of my trying to understand the controversy over the diagnosis, treatment, and naming of chronic Lyme disease.

    I've read sites like science-based medicine and science blogs, and there are people there who I would gladly discuss any of a number of topics with - but as yet, chronic Lyme disease is not one I'd pick.

    I've seen other patients attempt to discuss their condition on such blogs, only to get insulted and leave. Which is not what is needed - what is needed is more open discussion about this disease as it is so common now, and to talk about research findings and what research needs to be done next.

    I want to go back on these blogs to discuss it, and perhaps sometime in the future I will once someone posts something new about it and I am confident I have the right citations at hand.

    At any rate, I am a skeptical person and sometimes I look at my own condition and wonder if more antibiotics are what is needed now, or if it's something else that is needed. I am not back to my normal self.

    I'm not always sure what's next. I'm trying to come up with an intelligent map to help me decide what to investigate next and what an endpoint is for trying particular treatments. I've learned since this medical rollercoaster began that I'm usually better off asking questions and doing my own research on whatever is suggested before jumping in with both feet.

    Not sure what else to write here and I need to get some sleep. I'll probably check comments in 6 hours or so from when my comment is posted. Thanks for writing back.

    ReplyDelete
  7. Thanks, um, Camp?, for a detailed reply! [how should we address you?]

    Things are made slightly tricky in our case because my other-half-to-be spent significant time in both North America and Europe, never had the Erythema Migran rash, and is seronegative for Lyme and all co-infections (so far). Diagnosis was confirmed on the extensive overlap of symptoms, and eventually by PCR. She does, however, remember a number of tick bites and her mother also has/had Lyme (and is seropositive). There are also some instances of illness and behaviour in childhood that *could* in retrospect indicate early infection, but it's hard to say.

    Treatment with various antibiotics (IV and oral) has helped alleviate some symptoms (especially heart and neurological), but fatigue (such that she cannot work or do any extended activity) is the real problem.

    I hope that gives you some idea of the background here - I would rather not put too many details in this open forum. I'm sure you understand, having done a great job of obfuscating your identify ;-)

    I agree there is a real need for a critical approach - whilst not having medical training, my blood boils at the pseudo-scientific nonsense that is passed as treatment (e.g. Rife machines, homoeopathy). Whilst an open mind is needed, an open mind backed by some systematic approach and evidence is paramount!

    The lack of detailed evidence-based literature for chronic/late lyme also has a tendency to make everyone focus on the few resources available - for example the Burrascano book is a wonderful resource, but it's tempting to refer to it as a treatment manual, rather than digging to the bottom of each statement or suggestion. Of course this is a more global problem - there are so many information sources these days, that digging back to the primary in each case is nigh on impossible.

    In any case, I hope you managed to get a good (pain free) night's sleep!

    ReplyDelete
  8. Mark,

    Thanks for your quick reply. You can call me "CO" for short.

    Yes, I have some idea of her background now, thank you. If you wish, you can email me at CampOther at gmail dot com. I respond to private email there, though I do not check it all the time.

    Regarding alternative treatments: After a while, some people simply cannot tolerate antibiotics or develop allergies to them so using them does not remain an option. In such situations, I don't hold it against anyone for trying alternative treatments - however, I do think there are good and bad ways to go about assessing their worth and making decisions as to which ones to try and how to go about it.

    We're at the medical crossroads here, historically speaking. As time goes on, the issue of antibiotic resistance is more prominent, and new antibiotics need to be developed and tested. In the meantime, when they fail, something else will need to take their place. Some herbs should be tested for their antimicrobial properties, and some are effective - artemisinin is used to treat malaria in a number of countries, though in SE Asia, there is a strain of malaria which is resistant to it. So I won't throw all alternative medicine out the window - and it would be good to investigate treatments with potential.

    I wouldn't begrudge anyone alternative means for reducing pain, either - hot tubs, saunas, massages, acupuncture, TENS units, etc. because you have to have some quality of life and these things are pretty low risk and the costs can be contained - plus when it comes to hot tubs and saunas, if you install one, others will enjoy them, too. So more than one person can benefit, if you invest in some of these items.

    But I wouldn't go around expecting them to cure you. Help symptoms, yes.

    After suffering with my own symptoms long enough, I've seen alternative treatments come and go, and some stay that new patients try. I've heard of so many people not getting well on Rife and the cost of one machine is so high it's absurd. Not to mention the explanation behind how it is supposed to work and the risks listed on its use are high. (Somewhere there is a disclaimer on a rife book that needs to be shared, but it includes a warning about electrocution and death.)

    There are a lot of protocols out there, but at what point are they at least based on testable hypotheses and what is known about Lyme disease bacteria - versus speculation and projections of what in vivo behavior is based on in vitro data? Good question. The answer of which one has to take a lot of time reading and evaluating to make the determination - something which most patients neither feel well enough to do nor necessarily want to do. And with other conditions, it's clearer cut what to do - though that's not always the case.

    I got some sleep. I could use more, though.

    ReplyDelete

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