A Critical Appraisal of "Chronic Lyme" in the NEJM

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The New England Journal has an article on the phenomenon known as chronic Lyme disease. Lyme disease, is a tick-borne infectious disease caused by an bacterium known as Borrelia burgdorferi carried by ticks in certain regions of the United States and Europe in which it is endemic. Here is the US map of cases below.
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It can result in a fever-like illness with a characteristic rash (although not in all cases) called erythema migrans, and if left untreated, can cause more serious problems like arthritis, and cardiovascular and neurological complications.

A small number of people and doctors have come to believe that in addition to these known presentations, Lyme disease can also cause a chronic syndrome after treatment with antibiotics has cleared the disease. The problem is this syndrome has all the hallmarks of being a quack diagnosis. While a small subset of patient may actually have such a syndrome, for a large number of diagnoses, there are a number of red flags indicating this diagnosis is inappropriately applied and treatment worthless. Here's an excerpt from the paper, see if you can spot them all:

The diagnosis of chronic Lyme disease and its treatment differsubstantively from the diagnosis and treatment of recognizedinfectious diseases. The diagnosis is often based solely onclinical judgment rather than on well-defined clinical criteriaand validated laboratory studies, and it is often made regardlessof whether patients have been in areas where Lyme disease isendemic.6,7 Although proponents of the chronic Lyme diseasediagnosis believe that patients are persistently infected withB. burgdorferi, they do not require objective clinical or laboratoryevidence of infection as a diagnostic criterion.5,8,9,10

Several lines of reasoning are used to provide support for thisdiagnostic rationale. One is the unproven and very improbableassumption that chronic B. burgdorferi infection can occur inthe absence of antibodies against B. burgdorferi in serum (Table 2).Negative results of serologic tests are often attributed toprevious antibiotic therapy or to the theory that chronic infectionwith B. burgdorferi suppresses humoral immune responses; neithertheory is well supported by scientific data.12,13,14 When physicianswho diagnose chronic Lyme disease obtain laboratory tests toprovide support for their diagnoses, they often rely heavilyon "Lyme specialty laboratories." Such laboratories may performunvalidated in-house tests that are not regulated by the Foodand Drug Administration, or they may perform standard serologictests interpreted with the use of criteria that are not evidence-based.11,12,15,16,17

Once the diagnosis of chronic Lyme disease is made, patientsare commonly treated for months to years with multiple antimicrobialagents, some of which are inactive in vitro against B. burgdorferi.2,5,18,19,20Antibiotics may be prescribed either simultaneously or sequentially,and they are often administered parenterally. Occasionally,these patients are treated with unconventional and highly dangerousmethods such as bismuth injections or deliberate inoculationof plasmodia to cause malaria.2,21,22 No other spirochetal infection,including the neurologic complications of tertiary syphilis,is managed in an analogous fashion.2,23 The duration of treatmentcommonly prescribed for chronic Lyme disease often far surpasseseven the conventional 6-month course of therapy successfullyused for most cases of tuberculosis.

This paper is written by eminent experts in infectious disease including Allen Steere - the discoverer of Lyme disease - they systematically evaluate the evidence for and against a chronic infection, or the advantage of current treatments for this disorder. The news gets worse.

Basically what we have here is the classic case of a made-up diagnosis used to explain the symptoms of patients who complain of a variety of non-specific and subjective complaints. Diagnostic testing is performed by labs of questionable legitimacy, and worse, long courses of potentially dangerous antibiotics are prescribed as a treatment. A majority patients being diagnosed with chronic lyme often lack any evidence of clinical borrelia infection, past or present, and have often received other diagnoses that they would rather avoid.

I've actually been contacted by people who feel as though they've been victimized by doctors convincing them of this diagnosis, and are now upset at the expense and side-effects of the prescribed treatment. While the authors acknowledge a "post-Lyme" syndrome does in fact exist, it represents a minority of cases of chronic Lyme, and further, long courses of antibiotics are completely ineffective in careful studies of the syndrome. Note "category 4" represents one of four categories of chronic Lyme patients, and are the ones that have had a previous clinically-documented infection and are likely to be the real thing.

Controlled treatment trials have been conducted only for patientswith category 4 disease. Data from three double-blind, randomized,placebo-controlled trials have shown that there is substantialrisk, with little or no benefit, associated with additionalantibiotic treatment for patients who have long-standing subjectivesymptoms after appropriate initial treatment for an episodeof Lyme disease.32,33,34

One of these trials enrolled 78 patients who were seropositivefor antibodies against B. burgdorferi at trial entry; a secondtrial enrolled 51 patients who were seronegative.32 All patientshad antecedent objective signs of Lyme disease, most often physician-diagnosederythema migrans. Patients were treated either with a 1-monthcourse of ceftriaxone administered intravenously, followed by2 months of doxycycline given orally, or with identical-appearingintravenous and then oral placebos. Patients were assessed atenrollment and 3 months after completion of treatment with theuse of the Medical Outcomes Study 36-item Short-Form GeneralHealth Survey (SF-36). There were no significant differencesin the scores between the patients in the antibiotic and placebogroups.

In a single-center trial conducted by Krupp et al., 55 patientswith severe fatigue (as measured by an 11-item questionnaire)after treatment of well-documented Lyme disease underwent randomizationto receive ceftriaxone or an identical-appearing placebo for28 days.33 The investigators reported a reduction in scoresfor fatigue severity in the ceftriaxone group that exceededthe reduction in the placebo group by 13 percentage points (i.e.,a reduction of 22% vs. 9%; P=0.01) but no significant improvementin cognitive function. There was no significant difference betweenthe groups with regard to the degree of improvement in reportedhealth status on the basis of the SF-36 score. Patients in theceftriaxone group were significantly more likely than thosein the placebo group to identify their treatment assignmentcorrectly at the end of therapy, raising a concern that maskingwas compromised and that a placebo effect may explain the greaterimprovement in scores for fatigue severity in the treated group.33

While most people probably think it's no big deal to receive treatment, and that it might not be a big deal to try, one has to understand that the types of antibiotics prescribed, and the methods of administration possess significant risks.

Antibiotic therapy can cause considerable harm to patients treatedfor chronic Lyme disease or post-Lyme disease symptoms.2Life-threatening anaphylaxis33 and biliary complications requiringcholecystectomy35 have occurred after ceftriaxone administration.Candidemia from infection of an intravenous catheter has resultedin death.36 In an unpublished study in which 37 patients underwentrandomization to receive 10 weeks of treatment with either ceftriaxoneor placebo, about one fifth of the patients had serious adverseevents, the majority of which were related to intravenous catheters.37In light of the risk of serious adverse events in their study,Krupp et al. concluded that "repeated courses of antibiotictreatment are not indicated for persistent symptoms followingLyme disease, including those related to fatigue and cognitivedysfunction."33

The authors then go on to describe that the basis for the persistent infection theory of post-Lyme syndrome is based on poorly designed and controlled studies that have failed to be subsequently replicated.

The news overall is therefore not good. There is a post-Lyme syndrome but a persistent infection with the causative agent of Lyme is not present and does not play a role. Further, there is no known effective treatment. This creates a terrible problem, because the doctors that would tell patients the correct scientific information have no hope to offer to patients who are suffering from these symptoms (which are real), and the patients will then likely find a great deal of misinformation online about the syndrome. Eventually, they will find a quack that will offer them false hope, whether or not they have legitimate post-Lyme syndrome, and prescribe a dangerous and expensive course of therapy that has been shown to be ineffective.

This is an important paper for guiding doctors who encounter patients who believe they have this syndrome, and for explaining why the current understanding and myths about "chronic lyme" are incorrect. To summarize, a post-Lyme syndrome does exist, but represents a minority of "chronic Lyme" diagnoses. Quack doctors are over-diagnosing people with this disorder to the detriment of their patients. Treatment with large doses of intravenous antibiotics is ineffective in any case.

1. Feder, Henry M., Jr., Johnson, Barbara J.B., O'Connell, Susan, Shapiro, Eugene D., Steere, Allen C., Wormser, Gary P., the Ad Hoc International Lyme Disease Group, A Critical Appraisal of "Chronic Lyme Disease" N Engl J Med 2007 357: 1422-1430

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Heh. I love how, in maps like this, the disease just mysteriously stops at the border...

I'm a second year medical student, and we just had a lecture on Borrelia burgdorferi last week where our professor made a point to express his skepticism about "chronic lyme disease" and mentioned that there was little evidence to support its relation to B. burgdorferi infections. Good post - in a way reading your blog is helping me study for our upcoming exam...or at least that's what I'm going to tell myself. :)

Good news! A lot of rumours about chronic Lyme are floating around tic-infested southern Sweden. I've had a hunch that it was actually woo. Looks like I was right.

Unfortunately the NEJM article is a classic denialist campaign that does little to help those actually suffering from this debilitating disease or society at large. One aspect is that they never covered the "dozens" of different types of lyme disease already documented, all of which potentially will respond differently to various treatments. Another flaw in their analysis is the numerous documented co-infections that are carried by the vast majority of lyme infected ticks. Other conveniently overlooked facts are; patients genetic disposition to expel toxins (Dr-2,DR-4, etc.), Vectors other than tic such as: fleas, cat scratch, sexual transmission and breast feeding.
Yes, over use of antibiotics can be wasteful, dangerous and ineffective, although their are numerous confirmations to the contrary (ask G.W Bush). But this article comes to the erroneous conclusion that the Dr's clinical analysis, the hallmark of western diagnosis, should be dismissed. And does nothing to further "true" analytical investigation for those suffering a horrible disease. But the article certainly coincided with the agenda of many of the author's clients; insurance companies. BTW, the Dr. who actually discovered what we now call Lyme Disease, was from Breslau Germany and has been dead about 100 years.

I happened to stumble onto this page and have to say that I happen to be one of those patients with a 20 year diagnosis of what I consider a waste-paper-basket diagnosis of CFS. I come from a Lyme endemic area in the north-east, have a history of EM rashes (but never went to the doctor for them at the time).

In 2004, I was diagnosed with chronic Lyme disease and to be honest, I was sceptical.

To my surprise, having stuck with the treatment of long-term antibiotics I have gone from having virtually no life due to constant flu-like feeling, fevers, profound fatigue, balance problems, etc etc etc (yep, one of those heart-sink patients with 100 symptoms) to being quite well again and able to work and contribute to society.

It would serve you well to look into and also listen to the "other camp" in this "war", ILADS.org.

Your critique of the NEJM article is excellent. However, there are a few additional points that should be considered. First, the clinical trials of Klempner et al., which were referenced in the NEJM review, did in fact show that the enrolled patients indeed suffered from significant pain and had real health deficits. Thus, although there is no evidence to indicate that their condition is due to a persistent Borrelia infection, other possibilities must be considered since these patients obviously are in need of appropriate treatment and care. Since Borrelia share cell surface structures homologous to human nerve, muscle, heart, and thyroid tissue, there is the possibility that symptoms experienced might be due to an autoimmune reaction in some individuals, depending on their genetic background. This is now being examined by some investigators and preliminary data indicate this is a real possibility in some but not all patients. Second, relief might be provided by treating symtomatically. In this context, the results of a small clinical trial indicate that treatment with Lyrica -- a drug approved by the FDA for treating fibromyalgia with symptoms similar to chronic Lyme disease- resulted in significant relief of pain in 9 of 10 patients with chronic Lyme disease (Dermatology 211:123, 2005). Third, aside from the well-known antiinflammatory effects of some antibiotics (e.g. tetracyclines), some antibiotics -- in particular ceftriaxone which is commonly used to treat chronic Lyme disease-- is know to have profound neuroprotective properties (Nature 433:73,2005). These phramacological effects, rather than the elimination of a persisting infection, could account for the short-term benefits observed in some patients given extended antibiotic therapy for chronic Lyme disease. If that is the case, other drugs besides antibiotics might be used with advantage to offer the same or better relief. In brief, the time is long past due to consider alternate more rational approaches for treating conditions such as chronic Lyme disease, fibromyalgia, and chronic fatigue syndrome which conceivably could share a common element.

By LymeResearcher (not verified) on 27 May 2008 #permalink

My Mother almost died in the state of MA with Lymes Disease she still cannot sleep for days and her memory has been so impaired at times she cannot remember five minutes ago....she still needs help yet the best hospitals in the world here in MA are having a war amongst Dr.s Insurance Companies, and Pharmaceutical Companies there is only one Lyme Disease Specialist I can find and he is so overwhelmed that it has been months and we still do not have a appointment...It is appalling that the Dr.s who know this to be such a serious issue are losing there license to practice medical care....Why does every hospital hand out to every patient that enters the hospital pain killers for there pain (Vicadan, Perks, etc,) yet have a serious problem with giving a antibiotic that may save a persons life not ruin it like the opiate family in this country?????

Lymes Disease is much more real and more scientific than given the thought here, we need people who listen to our problems and prescribe antibiotics we are not looking for drugs...we want to get better and function on our normal routine...for those of you reading these things in books well you better start looking and listening to what your patients are telling you because it is real and long term antibiotics are helping although may not cure the bacteria that is supposedly already gone which changes and produces toxins in the body that can cause just as great damage as the disease itself....you really need to do more studies....Good Luck

By Henrietta (not verified) on 07 Jun 2009 #permalink