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Clin Vaccine Immunol. Oct 2006; 13(10): 1170–1171.
PMCID: PMC1595329
Serologic Evaluation of Patients from Missouri with Erythema Migrans-Like Skin Lesions with the C6 Lyme Test
Mario T. Philipp,1* Edwin Masters,2 Gary P. Wormser,3 Wayne Hogrefe,4 and Dale Martin1
Tulane National Primate Research Center, Tulane University Health Sciences Center, Covington, Louisiana,1 Family Practice of Dr. Edwin Masters, Cape Girardeau, Missouri,2 Division of Infectious Diseases, Department of Medicine of New York Medical College, Valhalla, New York,3 Focus Diagnostics, Inc., Cypress, California4
*Corresponding author. Mailing address: Division of Bacteriology and Parasitology, Tulane National Primate Research Center, Tulane University Health Sciences Center, 18703 Three Rivers Road, Covington, LA 70433. Phone: (985) 871-6221. Fax: (985) 871-6390. E-mail: Philipp/at/tpc.tulane.edu.
Received June 26, 2006; Accepted July 27, 2006.
Southern tick-associated rash illness (STARI), also known as Masters disease, affects people predominantly in the Southeast and South Central United States. These patients exhibit skin lesions that resemble erythema migrans (EM), the characteristic skin lesion in early Lyme disease. The etiology of STARI remains unknown, and no serologic test is available to aid in its diagnosis. The C6 Lyme enzyme-linked immunosorbent assay was used to evaluate coded serum specimens from patients with STARI at two laboratory sites. The specimens tested at one site consisted of acute- and convalescent-phase samples that were obtained from nine STARI patients from Missouri and from one patient with documented Borrelia lonestari infection who acquired this infection in either North Carolina or Maryland. All of these samples were C6 negative. Seventy acute- or convalescent-phase specimens from 63 STARI patients from Missouri were C6 tested at the second site. All but one of these STARI specimens were also negative. In contrast, of nine acute- and nine convalescent-phase serum specimens obtained from culture-confirmed Lyme disease patients with EM from New York state, seven were C6 positive at the acute stage, and eight were positive at convalescence. The C6 test is negative in patients with STARI, providing further evidence that B. burgdorferi is not the etiologic agent of this disease.
In the United States, the majority of cases of Lyme borreliosis are reported from the Northeast, Mid-Atlantic, Midwest, and Far West regions of the country. The skin lesion known as erythema migrans (EM) is the disease's most common clinical sign; the spirochete Borrelia burgdorferi, the etiologic agent of Lyme disease, is often recovered from EM skin biopsy cultures.
EM-like skin lesions may also develop in patients from the Southeast and South Central United States, often preceded by the bites of Amblyomma americanum ticks (14). Skin biopsy cultures from such lesions have not yielded B. burgdorferi (21), and, moreover, the tick A. americanum has been shown in the laboratory to be an incompetent vector for this spirochete (5, 19). Therefore, B. burgdorferi is not thought to be the cause of the EM-like lesions in patients from the Southeast and South Central United States (14, 21). This condition is referred to either as southern tick-associated rash illness (STARI) or as Masters disease.
Clinically, Masters disease also differs from Lyme borreliosis, despite the fact that patients may present in both cases with, in addition to the EM-like sign, symptoms such as joint pain, fatigue, fever, chills, and headache. In a comparative prospective clinical evaluation of patients from Missouri and New York presenting with EM, the lesions in the Missouri cases were significantly smaller in size, more circular in shape, and more likely to have central clearing than those from patients in New York (22). In addition, Missouri case patients were less likely to be symptomatic or to have multiple skin lesions than were New York case patients, and they recovered more rapidly after antibiotic treatment (22). Thus, there are clear distinctions between the clinical presentations of Lyme and STARI patients (22).
The etiology of STARI has not been elucidated. In a single reported case, the EM-like lesion was caused by Borrelia lonestari, a spirochete known to infect A. americanum (3). However, in a recent microbiological evaluation of Missouri patients with EM, B. lonestari was not detected by PCR in any of 31 skin biopsy specimens collected from 30 Missouri patients (21). Thus, the etiology of STARI is unknown.
There is no serologic test available to aid in the diagnosis of STARI. Enzyme-linked immunosorbent assays (ELISAs) with B. burgdorferi whole-cell extracts as antigens have been used with Missouri EM patients, but with some exceptions, the overall outcome of such testing has been negative (14, 21). Detection of antibody to C6, a peptide that reproduces the sequence of the sixth invariable region (IR6) within the central domain of the VlsE protein of B. burgdorferi, is used currently for the serologic diagnosis of Lyme disease in humans (The C6 Lyme disease ELISA [Immunetics]) (1, 4, 9, 10, 12, 13, 15-18) and in canines (Canine SNAP 3Dx test [Heartwork Ag, E.C.A., Lyme Ab]; IDEXX [Lyme quantitative C6 antibody test]) (2, 6-8, 11). In view of the clinical similarity of STARI and EM and the likelihood that the B. burgdorferi antigen extracts used in whole-cell Lyme ELISA lacked VlsE—the linear plasmid lp28-1, which encodes VlsE, is lost after as few as five culture passages (20)—we reasoned that anti-C6 antibodies should be evaluated in the sera of patients from Missouri with EM-like lesions.
The C6 Lyme ELISA (Immunetics, Cambridge, MA) was used to evaluate coded serum specimens from patients with STARI. The test was used according to the manufacturer's instructions, and evaluations were conducted independently at two separate laboratory sites. The specimens tested at Focus Diagnostics, Inc. (FDI) consisted of acute- and convalescent-phase specimens from nine STARI patients from Missouri and from one patient who had a proven B. lonestari infection acquired in either North Carolina or Maryland. Seventy acute- or convalescent-phase specimens from 63 STARI patients from Missouri were tested at the Tulane National Primate Research Center (TNPRC).
All of the samples tested at FDI were C6 negative. All but one of the STARI specimens tested at TNPRC were also negative by this test. In contrast, of nine acute-phase and nine convalescent-phase serum specimens obtained from culture-confirmed Lyme disease patients with EM from New York State and tested at FDI, seven were C6 positive at the acute stage, and eight were positive at convalescence. Our results, which are summarized in Table Table1,1, show that the C6 test is negative in patients with STARI and provide further evidence that B. burgdorferi is not the etiologic agent of this disease.
TABLE 1.
TABLE 1.
C6 serology of STARI and Lyme disease patients
Acknowledgments
This study received financial support from NIH grant RR00164-41.
The secretarial assistance of Avery MacLean is gratefully acknowledged.
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