A Critical Appraisal of “Chronic Lyme” in the NEJM

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.

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 differ substantively from the diagnosis and treatment of recognized infectious diseases. The diagnosis is often based solely on clinical judgment rather than on well-defined clinical criteria and validated laboratory studies, and it is often made regardless of whether patients have been in areas where Lyme disease is endemic.^6,7 Although proponents of the chronic Lyme disease diagnosis believe that patients are persistently infected with B. burgdorferi, they do not require objective clinical or laboratory evidence of infection as a diagnostic criterion.^5,8,9,10

Several lines of reasoning are used to provide support for this diagnostic rationale. One is the unproven and very improbable assumption that chronic B. burgdorferi infection can occur in the absence of antibodies against B. burgdorferi in serum (Table 2). Negative results of serologic tests are often attributed to previous antibiotic therapy or to the theory that chronic infection with B. burgdorferi suppresses humoral immune responses; neither theory is well supported by scientific data.^12,13,14 When physicians who diagnose chronic Lyme disease obtain laboratory tests to provide support for their diagnoses, they often rely heavily on “Lyme specialty laboratories.” Such laboratories may perform unvalidated in-house tests that are not regulated by the Food and Drug Administration, or they may perform standard serologic tests 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, patients are commonly treated for months to years with multiple antimicrobial agents, some of which are inactive in vitro against B. burgdorferi.^2,5,18,19,20 Antibiotics may be prescribed either simultaneously or sequentially, and they are often administered parenterally. Occasionally, these patients are treated with unconventional and highly dangerous methods such as bismuth injections or deliberate inoculation of 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 treatment commonly prescribed for chronic Lyme disease often far surpasses even the conventional 6-month course of therapy successfully used 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 patients with category 4 disease. Data from three double-blind, randomized, placebo-controlled trials have shown that there is substantial risk, with little or no benefit, associated with additional antibiotic treatment for patients who have long-standing subjective symptoms after appropriate initial treatment for an episode of Lyme disease.^32,33,34

One of these trials enrolled 78 patients who were seropositive for antibodies against B. burgdorferi at trial entry; a second trial enrolled 51 patients who were seronegative.³² All patients had antecedent objective signs of Lyme disease, most often physician-diagnosed erythema migrans. Patients were treated either with a 1-month course of ceftriaxone administered intravenously, followed by 2 months of doxycycline given orally, or with identical-appearing intravenous and then oral placebos. Patients were assessed at enrollment and 3 months after completion of treatment with the use of the Medical Outcomes Study 36-item Short-Form General Health Survey (SF-36). There were no significant differences in the scores between the patients in the antibiotic and placebo groups.

In a single-center trial conducted by Krupp et al., 55 patients with severe fatigue (as measured by an 11-item questionnaire) after treatment of well-documented Lyme disease underwent randomization to receive ceftriaxone or an identical-appearing placebo for 28 days.³³ The investigators reported a reduction in scores for fatigue severity in the ceftriaxone group that exceeded the reduction in the placebo group by 13 percentage points (i.e., a reduction of 22% vs. 9%; P=0.01) but no significant improvement in cognitive function. There was no significant difference between the groups with regard to the degree of improvement in reported health status on the basis of the SF-36 score. Patients in the ceftriaxone group were significantly more likely than those in the placebo group to identify their treatment assignment correctly at the end of therapy, raising a concern that masking was compromised and that a placebo effect may explain the greater improvement 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 treated for chronic Lyme disease or post-Lyme disease symptoms.² Life-threatening anaphylaxis³³ and biliary complications requiring cholecystectomy³⁵ have occurred after ceftriaxone administration. Candidemia from infection of an intravenous catheter has resulted in death.³⁶ In an unpublished study in which 37 patients underwent randomization to receive 10 weeks of treatment with either ceftriaxone or placebo, about one fifth of the patients had serious adverse events, the majority of which were related to intravenous catheters.³⁷ In light of the risk of serious adverse events in their study, Krupp et al. concluded that “repeated courses of antibiotic treatment are not indicated for persistent symptoms following Lyme disease, including those related to fatigue and cognitive dysfunction.”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