Probable Late Lyme Disease

A Variant Manifestation of Untreated Borrelia burgdorferi Infection

John N Aucott; Ari Seifter; Alison W Rebman


BMC Infect Dis. 2012;12(173) 

In This Article


Lyme disease, caused by infection with the tick-borne spirochete Borrelia burgdorferi, is the most common vector-borne disease in North America. In highly endemic regions of the United States, the annual incidence of infection may be as high as 1–3% with a cumulative prevalence as high as 7–15%.[1,2] In the majority of cases, the diagnosis of confirmed early Lyme disease is based on identification of the hallmark erythema migrans (EM) rash, which may occur in isolation or in conjunction with viral-like symptoms such as fever, malaise, fatigue, and generalized achiness.[3]

However, in up to 16% of early Lyme cases, patients do not present with a rash and the primary symptoms of their acute illness are viral-like.[4] Historically, surveillance criteria requiring a high degree of specificity have excluded patients with only viral-like or subjective patient-reported symptoms in case definitions for Lyme disease.[5] In 2008, however, the Centers for Disease Control (CDC) surveillance criteria for Lyme disease were modified to include patients with solely subjective symptoms and a positive confirmatory serology as probable Lyme disease.[6] Based on the revised surveillance case definition, more than 30,000 new confirmed or probable cases of Lyme disease were reported in 2009,[7] though studies have shown that the actual number of cases may exceed reported cases by a factor of 6 to 12 in endemic areas.[8,9]

If left untreated, Lyme disease may progress to later stages involving the musculoskeletal, neurologic, or cardiovascular systems. The diagnosis of these late stages of Lyme disease is based on clinical diagnosis with serologic confirmation using CDC surveillance criteria.[10] The CDC case definition for confirmed late Lyme disease relies on signs of specific organ damage such as inflammatory arthritis with synovitis and joint effusion, or objective neurologic disease, all confirmed by a positive IgG immunoblot (western blot) for antibodies to B. burgdorferi.[6] However, an initial longitudinal observation of untreated Lyme disease patients suggested that a significant number (18%) of late Lyme cases may only exhibit symptoms such as fatigue, arthralgias or myalgias, without development of classic physical signs of late Lyme arthritis or neurologic disease.[11] The patient phenotype of IgG seropositivity and musculoskeletal pain, fatigue, and/or cognitive dysfunction without signs of organ inflammation or dysfunction corresponds with a late manifestation of the current surveillance category of probable Lyme disease. When present, this phenotype can be termed "probable late Lyme disease".

The specific presentation of probable late Lyme disease, including untreated patients with a history of subjective symptoms and a positive IgG immunoblot, differs in two important ways from those meeting criteria for post-treatment Lyme disease syndrome (PTLDS), a disease category recently added to the Infectious Disease Society of America (IDSA) guidelines.[10] First, patients with probable late Lyme have no history of a prior physician diagnosis of objective findings consistent with early or late Lyme disease, a requirement for patients with PTLDS. Second, patients with probable late Lyme have not been previously treated with an antibiotic regimen recommended for Lyme disease, also a requirement for PTLDS. Since patients with probable late Lyme disease have serologic evidence of remote exposure to B. burgdorferi, they represent a distinct subset among patients with other chronic presentations that are often categorized as "medically unexplained" symptoms or syndromes such as chronic fatigue syndrome or fibromyalgia.

The existence of probable late Lyme disease, manifesting only as subjective symptoms with a concurrent positive IgG immunoblot serology, has remained controversial. This patient presentation was described in a recent review categorizing the spectrum of patients labelled as having "chronic Lyme disease".[12] The authors suggest that IgG seropositive patients with symptoms but no signs of illness have at most "equivocal evidence for infection with B. burgdorferi and that any benefit from treatment would be unlikely".[12] Patients with probable late Lyme disease share clinical phenotypes which overlap with patients who have PTLDS, fibromyalgia, chronic fatigue syndrome, and those whose symptoms remain medically unexplained after extensive medical evaluation. Thus, many have argued against serologic screening for Lyme disease among patients whose symptoms of fatigue, widespread pain, and subjective cognitive dysfunction exist in the absence of physical findings or laboratory abnormalities.[2,12]

Patients with probable late Lyme disease, or those untreated patients with a positive IgG serologic test for Lyme disease and otherwise unexplained symptoms, represent an interesting subset of patients who have not been clinically characterized in the modern Lyme disease literature. This article offers a description of a sample of such patients, within the context of the wider spectrum of late and chronic Lyme patients seen for evaluation in community-based clinical practice.