Toward a more complete appreciation of the clinical spectrum of Borrelia burgdorferi infection: early lyme disease without erythema migrans

Abstract

In the majority of cases of Lyme disease, the extant stereotypic and stratified schema (1) delineates the clinical spectrum: early localized disease (erythema migrans with its associated signs and symptoms), early disseminated disease (multiple erythema migrans, carditis, peripheral and cranial neuropathies with/without meningitis), and late disease (arthritis and central neurologic dysfunction; the latter also called tertiary neuroborreliosis). However, there is more to the interaction between Borrelia burgdorferi and humans. After the infection is treated and cured, some patients experience a post–Lyme disease syndrome characterized by fatigue, cognitive dysfunction, sleep disorder, and fibromyalgia (2-4). At the other end of the infection timeline, an oftenasked question has been “Does B. burgdorferi cause a nonspecific viral illness–type syndrome without erythema migrans, which would otherwise be ascribed to a ‘summer virus’—a minimally symptomatic infection that, at least in the short term, resolves spontaneously?” Such subclinical or asymptomatic infection can occur with other tick-borne infections (5), such as Babesia microti (6) and the human granulocytic Ehrlichia (7), both of which can cause self-limited infections. However, what about B. burgdorferi? In such cases, seroconversion may be the only persisting proof of the preceding infection. In a study of an area newly endemic for Lyme disease, O’Connor and colleagues found evidence of transient infection: asymptomatic seroconversion and transient spirochetemia documented by polymerase chain reaction (8). Feder and colleagues reported on a small number of children with early Lyme disease without erythema migrans (9). In this issue of the Journal, Steere and colleagues (10) are to be commended for seizing the unique opportunity provided by a prospective Lyme disease vaccine trial conducted in states endemic for the disease, collecting clinical information and sequential serum samples to study the recent acquisition of B. burgdorferi infection without erythema migrans. Using seroconversion as proof of infection, the authors identified 63 subjects who had systemic symptoms with immunoglobulin (Ig) M or IgG seroconversion from the total trial sample of 10,936 people. In their description of 28 subjects from the same vaccine trial who had asymptomatic seroconversion (11), Wormser et al. suggested that seroconversion was an imperfect marker of subclinical infection. Despite these caveats, including the possibility that some B. burgdorferi may be noninvasive and incapable of causing even skin inflammation, much less a systemic disorder (12), the subjects described in the report by Steere et al. should be acknowledged as having Lyme disease. Of these 63 vaccine recipients, 42 who had apparent early infection with B. burgdorferi sans erythema migrans experienced nonspecific symptoms that were no different from the symptoms of patients with classic early Lyme disease accompanied by erythema migrans. These patients did not have upper respiratory or gastrointestinal tract symptoms, but rather they had “nonspecific viral symptoms,” a term that I prefer to “influenza-like” or “flu-like” symptoms (13). As in patients with erythema migrans, coinfection with either of the other two documented Ixodes scapularis–transmitted infections, B. microti or the human granulocytic Ehrlichia, resulted in more severe symptoms. There was no evidence that vaccination altered the features of these patients’ condition. Previous concerns that vaccination might worsen early Lyme disease or prevent erythema migrans so that the B. burgdorferi infection would present with later features were ill founded (14) and are now moot, as the vaccine has been withdrawn from the market by its manufacturer owing to poor sales. In this short-term study, the long-term prognosis of early Lyme disease without erythema migrans cannot be determined fully, but there is no reason to doubt that some of these patients might progress to later features of Lyme disease. There are many patients who present with seventh nerve palsy or arthritis, and some who present with aseptic meningitis or tertiary neuroborreliosis, who have no memory of a rash compatible with erythema migrans; these patients presumably had early Lyme disease Am J Med. ;114:74 –75. From the Division of Rheumatology and Connective Tissue Research, Department of Medicine; Department of Pediatrics; Department of Molecular Genetics and Microbiology; and the Lyme Disease Center; University of Medicine and Dentistry of New Jersey—Robert Wood Johnson Medical School, New Brunswick, New Jersey. Requests for reprints should be addressed to Leonard H. Sigal, MD, Division of Rheumatology and Connective Tissue Research, Department of Medicine, University of Medicine and Dentistry of New Jersey—Robert Wood Johnson Medical School, P.O. Box 19, MEB484, New Brunswick, New Jersey 08903-0019, or sigallh@umdnj.edu.