Lone Star tick sex and age relative to rash size and incubation time. F indicates adult female; M, adult male; and N, nymph.
Patient 6. Rash on back following an adult female Lone Star tick bite. The tick was saved and was placed on her near the rash at the 2-o'clock position for this photograph. Note the distinctive white dot on the tick's back. There were 4 smaller associated lesions. Histopathological findings were consistent with erythema migrans and apparent dermal spirochetes were seen with silver stains. She had many serology results consistent with a borreliosis.
Patient 14. Rash (9.5 cm in diameter) with a 13-day incubation time following a Lone Star nymph bite. Histopathological findings were consistent with erythema migrans and apparent dermal spirochetes were seen with silver stains.
Patient 2. Rash (6.0 cm in diameter) with a 7-day incubation time following an adult female Lone Star tick bite.
Patient 10. Annular rash (10 cm in diameter) with a 6-day incubation time following an adult male Lone Star tick bite. The tick midgut stained negative with H5332 immunofluorescent assay at 1:100 dilution.
Patient 11. Scanning magnification of peripheral rash biopsy specimen shows superficial and deep perivascular mononuclear cell infiltrates (hematoxylin-eosin).
Patient 12. Histopathological biopsy findings of Lone Star tick–associated erythema migrans from the peripheral rash margin shows a perivascular cuff of lymphocytes lined by plump reactive endothelial cells. These findings, while not specific, are typical of erythema migrans (hematoxylin-eosin, ×400).
Patient 5. Modified Dieterle silver stain of peripheral biopsy specimen of rash showing an apparent dermal spirochete. Reprinted with the permission of Missouri Medicine.26
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Masters E, Granter S, Duray P, Cordes P. Physician-Diagnosed Erythema Migrans and Erythema Migrans–like Rashes Following Lone Star Tick Bites. Arch Dermatol. 1998;134(8):955–960. doi:10.1001/archderm.134.8.955
To differentiate cases of physician-diagnosed erythema migrans and erythema migrans–like rashes associated with Lone Star tick (Amblyomma americanum) bites.
Retrospective case series.
Private primary care clinic in rural Missouri.
Seventeen patients with physician-diagnosed erythema migrans following a definite Lone Star tick bite at the rash site.
A biopsy was performed on all rash sites. All patients were treated with oral antibiotics.
Main Outcome Measures
Rash appearance, size, body location, multiple lesions, incubation time, associated symptoms, seasonal occurrence, histopathological features, tick stage and sex, patient age and sex, treatment response, growth in BSK II culture media, and serologic evaluation.
Rashes associated with Lone Star ticks were similar to erythema migrans vectored by other Ixodes ticks. Differences were noted in Lyme disease serology results, especially flagellin-based enzyme immunoassays, and failure to yield spirochetes in BSK II cultures. Lyme serology results were often negative, but were also frequently inconsistent with results of controls without Lyme disease.
Lone Star ticks are associated with rashes that are similar, if not identical, to erythema migrans associated with borrelial infection. The recent isolation and cultivation of Borrelia burgdorferi from ticks (including 1 Lone Star tick) from the farm of a patient included in this report has raised the possibility that Lone Star ticks are "bridge vectors" for human borrelial infection. Although further investigation is needed, these rashes may be secondary to spirochetal infection.
THE ROLE of the Lone Star tick (Amblyomma americanum) in the transmission of Lyme disease, erythema migrans, or Lymelike illness has been controversial since first reported in 1984.1 The recent isolation of Borrelia burgdorferi sensu lato from ticks, including a Lone Star tick, collected at the Missouri farm of a patient with a physician-diagnosed erythema migrans rash following a witnessed Lone Star tick bite raises the possibility that the Lone Star tick may act as a "bridge vector" much like Ixodes pacificus in the western United States.2 Recently, 14 cases of erythema migrans–like rashes were reported in North Carolina where a tick survey implicated Lone Star ticks as the likely vector since they accounted for 95% of the human tick bites. Borrelia burgdorferi were cultured from 1 local white-footed mouse. Two of the 14 patients accurately described a Lone Star tick bite as preceding their rash. In 1 case, the Lone Star tick was positively identified. The study results argued against a B31 B burgdorferi–like cause.3 In one study of suspected early Lyme disease in Missouri, several patients with erythema migrans–like rashes accurately described the adult female Lone Star tick as the one that bit them.4 A Lone Star nymph that did stain positive to H5332 immunofluorescent assay after being removed from a human has been previously reported.5 The increasing heterogeneity of B burgdorferi in North America may relate to the possibility that strain variants may have adapted to the Lone Star tick.6-9 Additionally, the identification of Borrelia lonestari in Lone Star ticks10 and the findings of other researchers of spirochetes consistent with B burgdorferi or Borrelia DNA in Lone Star ticks8,11-15 have warranted a closer look at Lone Star ticks as a possible vector of a borreliosis. The exact cause of physician-diagnosed erythema migrans in the South, including Missouri, is currently being investigated. To our knowledge, this is the first published series of physician-diagnosed erythema migrans rashes associated with definite Lone Star tick bites.
Seventeen patients who presented to a primary care clinic in Cape Girardeau, Mo, from May 6, 1990, to September 15, 1993, with rashes similar, if not identical, to erythema migrans and documented Lone Star tick (Amblyomma americanum) bites were studied. For inclusion in this study, positive identification of the arthropod as a Lone Star tick required confirmation of the distinctive white dot on the back of the adult female. Witnessed nymph tick bites were excluded unless the tick was saved for definitive identification. Some patients have been subjects of other studies. Five patients (patients 3, 5, 6, 8, and 9) were enrolled in a double-blind, randomized controlled trial comparing azithromycin with amoxicillin in the treatment of erythema migrans.16 Remarkably, these patients were not distinguishable in this study from patients in accepted Lyme disease endemic areas. Six patients (patients 1, 3, 4, 5, 7, and 9) were in a Centers for Disease Control and Prevention (CDC) retrospective study of Missouri patients with suspected early Lyme disease.4 Fourteen of the rashes had biopsy specimens of the peripheral margins available for study. All biopsy specimens were formalin fixed and paraffin embedded by standard techniques. Sections were also stained using a modified Dieterle silver stain to identify spirochetes. This stain was performed as previously described.17
The clinical data are summarized in Table 1. Seventeen patients, 9 male and 8 female, were studied. Their ages ranged from 12 to 69 years (median, 33 years).
All rashes were measured and photographed. They had a median incubation time of 7 days, with a range from 2 to 15 days. The relationships among the tick sizes and sex, incubation times, and rash diameters are illustrated in Figure 1. The nymph tick bites were associated with rash incubation times ranging from 3 to 14 days; 3 of 4 had incubation times of 11 days or longer. Rash location included the back (10 cases), anterior thorax or abdomen (4 cases), groin (2 cases), and leg (1 case). The median rash diameter was 7.5 cm, with the largest being 15 cm (range, 2.5-15 cm). All rashes were similar to, and often indistinguishable from, erythema migrans in patients from areas with endemic Lyme disease. Examples of rashes are shown in Figure 2, Figure 3, Figure 4, and Figure 5. Fourteen of the 17 rashes had central clearing. Sixteen of these rashes were solitary erythemas. Patient 6 had multiple lesions. This is consistent with the experience at the study site clinic in which approximately 15% of cases show multiple lesions. None was significantly pruritic or painful. Five patients (patients 1, 6, 9, 13, and 14) had mild associated flulike constitutional symptoms. The rashes occurred from April 18 to September 5 (median, May 31) during the years 1990 to 1993. There was no correlation between tick stage or sex and rash diameter or incubation time. Nymph-associated rash incubation time ranged from 3 to 14 days and adult female–associated rash incubation time ranged from 2 to 15 days. Most patients have been followed up since, and although many have had additional tick bites, none has developed an erythema migrans–like rash.
Ten of the 17 case patients had Lyme serology results inconsistent with test-negative non-Lyme (uninfected) controls. (Control subjects were randomly selected from consenting office patients and emergency department patients having blood drawn for other purposes and volunteers with no history compatible with a borreliosis.) Eight Lyme serology results from the 17 case patients had results suggestive of a borreliosis. Frozen serum samples were available on 3 patients and underwent multiple serologic evaluations. Extensive testing for other diseases and causes of possible cross-reactivity were negative with 1 exception: patient 7 tested positive for Coxiella burnetii (cause of Q fever). All tested patients had negative test results for rheumatoid factor, antinuclear antibody, and syphilis serology. Patients 3, 5, and 7 did not have Western immunoblots. Patient 8 had multiple negative enzyme-linked immunoabsorbent assays (ELISAs). Patient 16 did not return after his initial visit when the biopsy was done and was unavailable for follow-up. Patient 9 seroconverted in the treatment study.16 A CDC whole-cell sonicated ELISA on patient 9 was also strongly positive at 3.176 (positive >1.0). Results of serologic evaluations in patients 5, 6, and 7 are presented in Table 2. Additionally, 13 months after the tick bite, patient 6 (Figure 2) had a Western immunoblot with IgM of 59 and IgG of 20, 34, 38, 39, 41, 50, 60, 63, and 75 kd. Patient 6 was also the only patient in this series with multiple lesions (5) and associated constitutional symptoms. She also had the most positive results of Lyme tests, including a positive biopsy result. Results of Lyme Western blots are presented in Table 3. These data show the unusually high frequency of 4 or more IgG Western blot bands, B burgdorferi– associated bands, and positive ELISAs, all of which are inconsistent with published data on non-Lyme controls.18-21 Six patients (patients 3, 5, 6, 7, 8, and 10) were enrolled in a national erythema migrans treatment study, but patient 3 dropped out of the study. Test results of patient 8 were all negative, whereas the other 4 patients had 1 or more positive Lyme ELISAs.16
Biopsies were performed on all 17 rashes at the peripheral margin and cultured in BSK II medium with negative results. All 14 rashes with biopsy specimens for histopathological evaluation revealed findings consistent with erythema migrans (Figure 6 and Figure 7). Six of 11 biopsy specimens examined with the modified Dieterle method17 showed silver-positive structures consistent with dermal spirochetes (Figure 8).
In a separate tick survey, Lone Star ticks containing Borrelia -appearing spirochetes variably reactive to H5332 were found in the counties of 16 case patients.22 One patient was bitten in a county in Southern Illinois where ticks have not yet been examined. Ticks (2 nymphs and 3 adult males) from 5 study patients were examined with midgut smears and stained negative to H5332 immunofluorescent assay at 1:100 dilution.
All 17 patients were treated early and aggressively with oral antibiotics. The most common regimens were amoxicillin or doxycycline for 20 or more days. No sequelae or symptoms indicative of treatment failure were found in this small group.
Our study shows that Lone Star ticks are associated with rashes similar to, or even indistinguishable from, erythema migrans rashes associated with Lyme disease in CDC-accepted endemic areas. Photographs of Missouri physician-diagnosed erythema migrans rashes have been published.23-26 A few points regarding the rashes we evaluated deserve mentioning. It is not surprising that most of the rashes in this study were on the back since 10 of the 17 ticks were adults: this location would allow the larger adult tick to go unnoticed for a longer time and better transmit possible pathogens or antigens. Positive identification of the distinctive white dot on the back of the adult female tick was required for inclusion in this study; however, nymphal and adult male forms had to be saved for definitive identification. This study has an obvious selection bias for patients bitten by adult female forms. Therefore, it is not surprising that only 4 of 17 study cases presented here involved nymphal ticks, whereas our experience in dealing with physician-diagnosed erythema migrans during the past decade in Missouri indicates that the majority of these rashes are associated with nymphal ticks.
The summer peak incidence, histological findings, treatment response, rash diameter, incubation time, patient age and sex, frequency of multiple lesions, and signs and symptoms were similar to that associated with Lyme disease reported nationally. Notably different was the inability to culture spirochetes in BSK II media. We did not necessarily expect good culture results with a medium designed for spirochetes from other Ixodes ticks. If the rashes we encountered are indeed associated with borrelial infection, the BSK II media may not be satisfactory for isolation of potential spirochetes associated with the Lone Star tick. It has been shown that that BSK II culture media can select for specific genotypes of B burgdorferi.27
Lyme serology testing argues against a B31 B burgdorferi cause. However, the serology results are also inconsistent with a test-negative, uninfected control population.18-21,26 We know that different strain variants can have different test results28,29 and that B burgdorferi sensu lato in Europe can test negative with culture-proven disseminated disease.30 With more B burgdorferi sensu lato being cultured in the South (eg, the farm of patient 12),2 this possibility needs to be explored. In 3 patients in our study there was a dramatic and unexplained difference in ELISA testing of Missouri patients using whole-cell sonicated antigens and flagellar antigens. This was observed in a serologic study by the CDC.4 Previously, the CDC whole-cell sonicated and flagellar ELISAs were highly concordant, but not in Missouri patients. The whole-cell sonicated ELISA tested positive in approximately 45% of Missouri patients with erythema migrans, but tested negative in 37 (96%) of 38 Missouri control subjects, whereas the flagellar ELISA was almost always negative. The discordant results were such that the odds of this occurring by chance were 1 in 25 million. These results are consistent with the possibility of a related Borrelia that frequently cross-reacts with the whole-cell sonicated ELISA, but rarely with flagellar ELISA.4,18,26 Similarly, Missouri Western blot results are usually negative by the strict criteria of Dressler et al31 adopted by the CDC where neither outer surface protein A (31 kd) nor outer surface protein B (34 kd) are counted.31 The results are also inconsistent with test-negative non-Lyme controls.18-21,26
The treatment of patients with erythema migrans and erythema migrans–like rashes outside CDC-accepted endemic areas of Lyme disease is controversial. We believe, given the likelihood of a borrelial etiology, that these rashes should be treated with antibiotics as would an erythema migrans rash in an accepted endemic area. This is also the view of others.3,4 No sequelae or symptoms indicative of treatment failure were found in this small group, which is similar to observations of others.32 Nationally, the erythema migrans treatment failure rate has been variously reported at between 5% and 10%.23 Until a borrelial cause is either proven or refuted for these cases, proper treatment and follow-up will be controversial.
In conclusion, we have presented evidence that rashes visibly similar or indistinguishable from other Ixodes tick–vectored Lyme erythema migrans can be associated with Lone Star tick bites. Collateral evidence suggests the possibility that Borreli a play a pathogenic role in these patients. If proven, the clinical and epidemiological implications of a Lone Star–vectored borreliosis are great, especially in view of the prevalence of the tick in the South and south central United States, as well as evidence that it is becoming more widespread. For example, the increase in prevalence of the Lone Star tick from 2 New York counties in the 1970s to 46 of the 62 New York counties today has been documented.33 Also, there is the possibility in areas where there are both Ixodes scapularis (Ixodes dammini)34 and Lone Star (Amblyomma americanum) ticks that frequently bite humans (eg, New Jersey), that a Lone Star–vectored borreliosis could result in physician-diagnosed or -suspected Lyme disease that could often be seronegative. Clearly, the pathogenic role of Borrelia in these patients needs further investigation.
Accepted for publication May 6, 1998.
We thank Group Health Foundation of St Louis and the Lyme Disease Institute for financial support of our effort to study physician-diagnosed erythema migrans rashes in Missouri.
This article is an expansion of an abstract presented at the VI International Conference on Lyme Borreliosis in Bologna, Italy, June 19-22, 1994.
We acknowledge the assistance of Paul Spence, MD, Patrick Downey, MD, Rod Crist, MD, Charles Crist, MD, and David Catron, MD, for referring patients and supporting the study; Don Miles, PhD, for technical and microbiological assistance; Pam Burton, Bonnie Holmes, and Jackie Masters for secretarial and data collection work; Charles Darby for computer data expertise; and Brent Voszler, MD, for reviewing the manuscript.
Reprints: Edwin Masters, MD, Regional Primary Care, 69 Doctors Park, Cape Girardeau, MO 63703.
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