PLEASE, may we understand persistent symptoms attributable to Lyme disease?
There are few diseases that have created divisions between the medical establishment and some patients, or that have engaged political interest, as much as chronic Lyme disease has. In their recent NEJM article, Berende et al have provided evidence to guide the major controversy regarding the potential benefit of longer-term antibiotic therapy for Lyme disease, through a rigorous, randomized clinical trial, called Persistent Lyme Empiric Antibiotic Study Europe (PLEASE). In this double-blind, randomized, placebo-controlled study, patients were included with persistent symptoms attributed to Lyme disease, either temporally related to proven Lyme disease or accompanied by a positive B.burgdorferi IgG/IgM immunoblot. All patients received open-label ceftriaxone (2 weeks) followed by randomized blinded oral follow-up treatment of 12 weeks with doxycycline, clarithromycin with hydroxychloroquine, or placebo. The primary outcome was health related quality of life at End of Treatment (14 weeks), assessed using the RAND SF-36 physical component summary score.
Although all the groups showed significant improvement over time (p=0.001), there was no statistically significant difference across treatment arms (p=0.69). It is possible that the initial two week therapy with ceftriaxone administered to all groups accounted for some of the improvement observed in all groups. What this study does strongly suggest is that longer term antimicrobial therapy is not an efficacious approach to treating persistent symptoms attributed to Lyme. Unfortunately, despite the improvement over time, the patients still had a health related quality of life which was worse than that expected in the general population.
An interesting aspect of the study is that about 1200 patients had to be screened for recruiting the 284 study participants. One of the most important causes for excluding potential participants was negative serology combined with unproven or temporally unrelated Lyme disease. This highlights the constellation of possible diagnoses, aside from Lyme disease, that can give rise to these symptoms.
In an accompanying editorial, Melia and Auwaerter propose that it is time to abandon the longer term antibiotic therapy strategy to treat long-standing symptoms ascribed to Lyme disease. In this editorial they also point out that over two-thirds (185 of 281) of the participating patients did not present with obvious clinical manifestations suggestive of Lyme disease (i.e. temporally related symptomatic Lyme disease or erythema migrans); they were diagnosed with the the disease based on B. burgdorferi IgG or IgM antibodies confirmed on immunoblot.
The protean presentation of Lyme disease makes it a difficult diagnosis, and often, a difficult condition to live with. Patients with chronic, debilitating symptoms which they ascribe to long standing Lyme disease, thus, feel betrayed when evidence based medicine does not support their diagnosis. This uncertainty, combined with the devitalizing course of the disease, makes for a counter-narrative to the evidence.
NEJM Deputy Editor Dr. Lindsey R. Baden notes, “It is important that rigorous evidence guide medical practice as all medications including antimicrobials have side effects, including engendering antimicrobial resistant organisms. Furthermore, using ineffective treatments means that effective treatments are not pursued and developed. Well done trials, such as this one, provide important evidence to guide the community to focus efforts in other directions to try and provide relief to these patients.”
This study by Berende et al provides convincing evidence against longer term use of antibiotics. Though the human side of the story is immensely disheartening, there needs to be a closer scrutiny into the etiology of the symptoms that are being attributed to Lyme disease.
On one side of the schism stands the evidence, which grows stronger by the day, that persistent symptoms attributed to Lyme disease are not amenable to longer antibiotic therapy; and on the other, there is a multitude of patients suffering from debiliating neurologic, cognitive, musculoskeletal or even multisystemic symptoms. Standing witness at the tug of war between these two sides, we still do not have an answer. We know that longer term antibiotics do not work; but we do not know what works, or sometimes, even what causes these devastating collection of symptoms.
Don’t miss the NEJM Quick Take video summary on this study:
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Bhavna Seth is a Resident in Internal Medicine at Boston University Medical Center.