A Systematic Review of Borrelia burgdorferi Morphologic Variants Does Not Support a Role in Chronic Lyme Disease

Lyme disease, which is caused by the tick-borne spirochete Borrelia burgdorferi sensu lato, is by far the most common vector-borne infectious disease in the temperate northern hemisphere. Many aspects of the pathogenesis, clinical manifestations, appropriate treatment, and outcomes of Lyme disease are well-accepted by the mainstream medical and scientific communities. There is considerable controversy, at least in the public discourse, about “chronic Lyme disease.” This is a largely undefined term that is applied by a small minority of practicing clinicians to patients with a wide variety of presenting symptoms. Moreover, the diagnosis is not contingent upon laboratory evidence of B. burgdorferi infection. Most often such patients lack the objective clinical findings that are most closely associated with Lyme disease [1–10]. In contrast to authentic infection with B. burgdorferi, a diagnosis of chronic Lyme disease is often given to patients who either have alternative medical diagnoses or who have syndromes of prolonged, unexplained subjective complaints such as fatigue, pain, and/or cognitive dysfunction [11, 12]. Two central assumptions accompany this diagnosis: Such syndromes are caused by chronic, cryptic infection with B. burgdorferi; and B. burgdorferi assumes a fastidious biology in these infections that necessitates prolonged antibiotic therapy. Advocates for greater recognition of chronic Lyme disease have presented a number of arguments meant to validate the biological plausibility of this concept. Perhaps the most commonly voiced theory contends that morphologic variants of the B. burgdorferi spirochete, known variably in the medical literature and lay Internet content as “L-forms,” “cyst forms,” “spheroplasts,” “morphologic variants,” “propagules,” “round bodies,” and “cell wall–deficient forms,” are responsible for chronic Lyme disease [13–16]. In fact, articles about morphologic variants of B. burgdorferi constituted more than 10% of 176 publications submitted to contest practice guidelines for Lyme disease from the Infectious Diseases Society of America [17, 18]. In some cases, patients with a diagnosis of chronic Lyme disease have been treated with antibiotics believed to be selectively active against these morphologic forms, such as metronidazole and tinidazole [19, 20]. The terminology around morphologic variants of B. burgdorferi has proved confusing (Table ​(Table1).1). The commonly used terms “cyst” and “cystic” are often used colloquially to describe round morphologies of B. burgdorferi when seen microscopically. In microbiologically strict terms, there is no true encystment performed by this organism as is the case among a few bacterial genera, such as Azotobacter, Azospirillium, and Rhodospirillium. As this has become recognized, less specific descriptors such as “round bodies” have come into more common use regarding chronic Lyme disease. Table 1. Terminology That Has Been Used to Describe Morphologic Variants of Borrelia burgdorferi and Conventional Definitions of the Terms Used We have undertaken a systematic review of the medical and the scientific literature to evaluate whether these morphologic variants of B. burgdorferi play a role in human Lyme disease, whether they have been associated with illnesses compatible with “chronic Lyme disease,” and whether there is evidence to support antibiotic choices meant to eradicate these morphologic variants.