Hitting the target: Lyme or STARI?
Erythema migrans (EM) is a characteristic rash seen in patients with certain spirochete infections. The most common culprit in the United States, Borrelia burgdorferi, is spread by Ixodes scapularis ticks and causes Lyme disease (LD). B. burdorferi is endemic in the northeastern and north central parts of the United States; however, more than 90% of LD cases occur in the Northeast. (1) In contrast, patients in the southeastern United States can present with rashes similar to EM after being bitten by Amblyomma americanum ticks; these cases have been classified as Southern Tick-Associated Rash Illness (STARI). Clinicians should be able to recognize LD, (2) as LD left untreated can lead to long-term complications. This case report highlights the clinical difficulties in distinguishing STARI and Lyme disease in Louisiana.
A 3-year-old female with no history of recent travel presented to her family physician in July 2011 with a skin rash on the right side of her face consistent with erythema migrans (Figure 1). In addition to the rash, her umbilicus showed multiple erythematous papules arranged in a circular pattern with no other symptoms or findings (Figure 2). After consultation with a dermatologist, the patient was started on a course of cephalexin.
On the third day, the patient returned to her family physician complaining of a new onset of fever. Her antibiotics were switched from cephalexin to cefuroxime, in line with the recommendations of the Infectious Diseases Society of America, (3) and her blood was drawn for laboratory evaluation.
This sample was evaluated using the two-step approach (4) recommended by the CDC. (5) First, a specimen is sent for an enzyme immunoassay (EIA) or immunofluorescent assay (IFA). If the first test is positive, the specimen should be sent for Western blot to confirm the results. For a Western blot to be considered positive for Lyme disease, two IgM bands or five IgG bands should be present (Table 1). (6) If a patient remains symptomatic at 30 days, which was not the case with our patient, five IgG bands must be present to be considered a positive test.
The blood sample submitted for this patient on day three showed an EIA that was positive for Borrelia. A Western blot showed two IgG (p41, p45) antibodies and one IgM (p41) antibody; these antibody levels did not meet the CDC criteria for a positive Western blot and therefore, were classified as negative.
On day 51, the patient returned for a routine preschool physical, and a second blood sample was sent for Western blot and tested positive for Borrelia. It showed two IgG (p41, p45) antibodies and two IgM (p41, OspC). The p41 antibody corresponds to the flagella of Borrelia but is nonspecific; the OspC antibody corresponds to the outer surface protein C and is highly specific for B. burgdorferi. However, because this sample was not sent for an EIA, it could not be classified as positive based on the CDC two-step method; for without a quantitative EIA first, the chances of false positive with Western Blot are higher.
The patient lives in a wooded area in Evangeline Parish in central Louisiana and spent recent summer afternoons playing outdoors. Until her initial presentation, she had no significant medical history. By the fifth day, her rash had lightened substantially and fever had resolved. She completed her full course of antibiotics and recovered with no complications.
Lyme Disease (LD), caused by spirochetes in the Borrelia burgdorferi sensu lato complex, is transmitted by Ixodes spp. ticks and carried by competent reservoir hosts--field mice, squirrels, and other rodents such as wood and cotton rats. It is the most common vector-borne disease in the United States, with the vast majority of cases occurring in the northern United States (Figure 3). (7) More than 15,000 cases are reported in the United States per year and 30,000 cases were reported to the CDC in 2010. (8) While it is possible to contract LD in the southeastern United States, exposure and infection are less likely. Samples from tick populations in Alabama, Oklahoma, Texas, North Carolina, and Virginia have shown the prevalence of B. burgdorferi to be between 0 and 3%. While little data exists for the spirochete in Louisiana, Brian Leydet, a researcher in the department of pathobiological sciences at Louisiana State University's School of Veterinary Medicine, reported a prevalence similar to other southern states (personal communication, 2 August 2012). Few cases are reported to the CDC each year from Louisiana (Figure 4).
In contrast, in high-risk areas in the northeastern and north central United States, the prevalence is as high as 50%. Moreover, the ecology of Lyme Borrelia is far more complex in the Southeast United States when compared to the Northeast United States. Many studies have identified lizards as important hosts for immature I. scapularis, and while some lizard species have been shown to be competent reservoirs (Southeastern five-line Skinks, Green Anoles) for Lyme Borrelia, others seem to be refractory (Western Fence Lizard). Southern lizards have been found to carry Rickettsia and Anaplasma, as well as Borrelia; however, the true importance of lizards on the ecology of Lyme in the South still eludes researchers. (9-14) The Louisiana Department of Public Health reports the average number of serologically confirmed LD cases as four per year over the last 10 years. (15) LD presents with an early-localized stage consisting of the classic erythema migrans rash, as well as possible fever, chills, headache, lymphadenopathy, and muscle and joint aches. It is treated with doxycycline, amoxicillin, or cefuroxime depending on the age of the patient. (16) Left untreated, LD can progress to disseminated disease, leading to facial palsies, meningitis, chronic neurologic deficits, arthritis, and heart disease. It should be noted that the IDSA guidelines for management of LD were challenged by outside groups in 2006, but an independent expert panel reviewed the guidelines and found them scientifically sound in their entirety. (17)
It is unknown which organism causes STARI. In one report of a patient who developed an EM rash after traveling to Maryland and North Carolina, a novel spirochete was detected by PCR from both the patient and the tick still attached to his abdomen. (18) This spirochete was named Borrelia lonestari and has been isolated in other infected ticks. (19) However, another case series in Missouri failed to show B. lonestari in skin biopsies of 30 patients with STARI, questioning whether there are other possible etiologic agents. (20) B. lonstari is carried by Ambylomma americanum, also known as the lone star tick. The tick is endemic throughout the southeastern United States (Figure 5). (21) The lone star tick does not carry Lyme disease, and its saliva has been found to kill Borrelia. (22) Neither the Centers for Disease Control and Prevention (CDC) or the Louisiana Department of Public Health collect data on the incidence of STARI. Patients bitten by lone star ticks can develop an EM rash. (23) Occasionally, they will also develop systemic symptoms including fever, headache, fatigue, and muscle pains. No long-term chronic symptoms of STARI have been reported. (24) However, since STARI is not reportable and has no diagnostic serology, it is possible that we do not fully appreciate its long-term sequelae. It is unknown whether antibiotic therapy is useful in treating STARI, but some think it warranted. (25)
Distinguishing between Lyme disease and STARI is complex in some patients, and comprises the following four factors: (1) exposure geography, (2) clinical presentation, (3) laboratory results, and (4) long-term sequelae (Table 2). Wormer et al. (26) reported that differences exist between the acute clinical presentation of LD patients in New York and STARI patients in Missouri. The time of onset between tick bite and emergence of EM rash was shorter in STARI (six days) than in LD (10 days). Patients with STARI were less likely to become symptomatic (19%) than those with LD (76%). The STARI rash was more likely to be circular in shape. It was also more likely to have central clearing (76%) than the LD rash (22%). All patients were treated with doxycycline, and those with STARI recovered more rapidly and were less likely to report symptoms at a follow-up visit than those with LD.
Clinicians should be aware of the limitations of serologic testing for Lyme disease. In the first two weeks of infection, laboratory evaluation is too insensitive, and diagnosis should be based on clinical findings. (27) Since EIA, IFA, and Western blot measure the body's immunologic response to Borrelia, serology results depend on the timing of sample collection and administration of antibiotics. (28) In early-localized disease, antibiotic treatment may blunt or eliminate the antibody response. In early disseminated or late disseminated disease, patients will show serological reactivity and will often stay positive for months or years following infection, whether treated or untreated. In addition, not all patients with Lyme disease convert from IgM to IgG, particularly if they have been treated early in their disease course. Aguero-Rosenfeld (29) found that while the majority of patients (62%) had both IgG and IgM antibodies, up to 36% of patients with EM of short duration showed only IgM reactivity, with no IgG. In their study, the immunoblot reactivity was directly related to the duration of EM. The CDC criteria requires multiple IgM or IgG bands to be present due to the fact that isolated bands are associated with non-specific reactivity and are interpreted as false positives. In contrast, no diagnostic test exists for STARI. (30) In the case of our patient, she did not meet the technical definition of a positive test based on CDC criteria because her positive EIA and positive Western Blot were found on separate blood samples. This patient may represent a case of Lyme disease outside of its normal geographic distribution. However, this cannot be confirmed based on the patient's available laboratory testing and clinical presentation.
The Food and Drug Administration (FDA) has also approved an alternative test for LD, the C6 ELISA. One recent study found that the C6 ELISA showed greater sensitivity than the traditional two-step testing in early disease patients with EM and comparable sensitivity with late-stage patients with neurologic disease or arthritis. (31) The C6 ELISA showed slightly decreased specificity compared to the two-step testing. Currently, the FDA has approved the C6 ELISA for a first-tier test and is still studying its use as a standalone test.
For clinicians who practice in a Lyme endemic area, the CDC states that an EM rash is sufficient enough for a Lyme diagnosis in the absence of laboratory confirmation if the patient had known exposure. Under this definition, a history of tick bite is not required, but the patient must have been in wooded, brushy, or grassy areas within the past 30 days in a county in which Lyme disease is endemic. A county is considered endemic if it has had two confirmed cases within it or if local tick populations are known to be infected B. burgdorferi. This definition does not apply to our patient because less than two confirmed cases were reported in the patient's parish since 1998.
Other studies have shown that some patients presenting with EM in the southern United States, though given a diagnosis of STARI, will actually test positive for Borrelia. For instance, Felz et al. (32) performed a prospective case series on 23 patients in Georgia and South Carolina--where B. burgdorferi has been frequently isolated from ticks and mammals --with EM rashes and recent history of tick exposure. Of these patients, 30% showed evidence of B. burgdorferi infection: two were positive via the CDC two-step method, and five were positive for B. burgdorferi flagellin DNA sequences by polymerase chain reaction of skin biopsies. Additionally, Oliver et al. (33) isolated Borrelia burgdorferi sensu lato complex spirochetes from ticks in Missouri, suggesting these organisms may already be present in more southern areas. Others have noted that the A. americanum and I. scapularis ticks have increasingly been reported in the same geographic locations. (34,35) It is currently unclear why the incidence of LD is not higher in the southern United States if the spirochete and its tick vector are both present. One possible explanation is that while adult I. scapularis ticks are found in robust numbers, the nymphs, which are more likely to go undetected, are less commonly encountered in southern states.
Overall, it has become increasingly difficult for clinicians to discern the etiology of EM rashes in the South and to treat these patients. In the case of our patient, we decided to treat for LD because the consequences of missing the diagnosis and subsequent development of long-term complications outweighed the risk of treatment and its side effects. Further research into the prevalence of Borrelia in Louisiana, as well as the causative organisms, laboratory testing, and proper treatment of STARI, is warranted.
The authors would like to thank David Mushatt, MD, MPH & TM and Dr. Christina Nelson, MD, MPH for all of their guidance.
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(7.) Evans, Janine. Lyme Disease: Clinical Research Perspectives. Yale University Podcast. Yale Peabody Museum Biodiversity and Global Change Day sponsored by NIH. Accessed 15 June 2012.
(8.) Louisiana Office of Public Health--Infectious Disease Epidemiology Section. Lyme Disease: Lyme Annual Report 2010. http://new.dhh.louisiana.gov/assets/oph/Center-PHCH/ Center-CH/infectious-epi/Annuals/LaIDAnnual_Lyme.pdf Accessed 15 June 2012.
(9.) Levin M, Levine JF, Yang S, Howard P, Apperson CS. Reservoir competence of the southeastern five-lined skink (Eumeces inexpectatus) and the green anole (Anolis carolinensis) for Borrelia burgdorferi. Am J Trop Med Hyg. 1996 Jan;54(1):92-7.
(10.) Blake, Paul. Georgia Epidemiology Report. Tick Bites and Erythema Migrans in Georgia: It Might NOT be Lyme Disease! Epidemiology Report. Division of Public Health, Georgia 2001.
(11.) Goddard J, Sumner JW, Nicholson WL, Paddock CD, Shen J, Piesman J. Survey of ticks collected in Mississippi for Rickettsia, Ehrlichia, and Borrelia species. J Vector Ecol. 2003 Dec;28(2):184-9.
(12.) Goddard, J. A ten-year study of tick biting in Mississippi: implications for human disease transmission. J. Agromedicine 2002;8(2):25-32.
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(14.) Tijsse-Klasen, E; et al. Role of sand lizards in the ecology of Lyme and other tick-borne disease in the Netherlands. Parasites & Vectors. May 2010; 14;3:42.
(15.) Louisiana Office of Public Health--Infectious Disease Epidemiology Section. Lyme Disease: Lyme Annual Report 2010. http://new.dhh.louisiana.gov/assets/oph/Center-PHCH/ Center-CH/infectious-epi/Annuals/LaIDAnnual_Lyme.pdf Accessed 15 June 2012.
(16.) Wormser 2006.
(17.) Lantos PM, Charini WA, Medoff G, Moro MH, Mushatt DM, Parsonnet J, Sanders JW, Baker CJ. Final report of the Lyme disease review panel of the Infectious Diseases Society of America. Clin Infect Dis. 2010 Jul 1;51(1):1-5.
(18.) James AM, Liveris D, Wormser GP, et al. Borrelia lonestari infection after a bite by an Amblyomma americanum tick. J Infect Dis 2001;183:1810 -1814
(19.) Varela, A.S. et al. First culture isolation of Borrelia lonestari, putative agent of southern tick-associated rash illness. J. Clin. Microbiol. 2004; 42:1163-1169.
(20.) Wormser 2005.
(21.) Centers for Disease Control and Prevention. CDC-Distribution --STARI. http://www.cdc.gov/stari/geo/index.html. Accessed 20 July 2012.
(22.) Zeidner N, Ullmann A, Sackal C, Dolan M, Dietrich G, Piesman J, Champagne D. A borreliacidal factor in Amblyomma americanum saliva is associated with phospholipase A2 activity. Exp Parasitol. 2009;121(4):370-5.
(23.) Blanton L, Keith B, Brzezinski W. Southern tick-associated rash illness: Erythema migrans is not always Lyme disease. South Med J. 2008;101(7):759-760.
(24.) Blanton 2008.
(25.) Masters EJ. Lyme-like illness currently deserves Lyme-like treatment. Clin Infect Dis 2006; 42:580 -1; author reply 581-2.
(26.) Wormser G, Masters E, Liveris D, et al. Microbiologic evaluation of patients from Missouri with erythema migrans. Clin Infect Dis 2005;40:423-428.
(27.) Wormser 2006.
(28.) Centers for Disease Control and Prevention. CDC. Lyme Disease. CDC--Lyme Disease. http://www.cdc.gov/lyme/. November 15, 2011. Accessed 22 July 2012.
(29.) Aguero-Rosenfeld ME, Nowakowski J, McKenna DF, Carbonaro CF, and Wormser GP. Serodiagnosis in early Lyme disease. J Clin Microbiol. 1993 December; 31(12): 3090-3095.
(30.) Centers for Disease Control and Prevention. CDC-Distribution --STARI. http://www.cdc.gov/stari/geo/symptoms. November 15, 2011. Accessed 22 July, 2012.
(31.) Wormser GP, Schriefer M, Aguero-Rosenfeld ME, Levin A, Steere AC, Nadelman RB, Nowakowski J, Marques A, Johnson BJ, Dumler JS. Single-tier testing with the C6 peptide ELISA kit compared with two-tier testing for Lyme disease. Diagn Microbiol Infect Dis. 2013 Jan;75(1):9-15.
(32.) Felz MW, Chandler FW Jr, Oliver JH Jr, Rahn DW, Schriefer ME. Solitary erythema migrans in Georgia and South Carolina. Arch Dermatol. 1999 Nov;135(11):1317-26.
(33.) Oliver JH Jr, Kollars TM Jr, Chandler FW Jr, et al. First isolation and cultivation of Borrelia burgdorferi sensu lato from Missouri. J Clin Microbiol. 1998;36:1-5.
(34.) Masters EJ, Grigery CN, Masters RW. STARI, or Masters Disease: Lone Star Tick-Vectored Lyme-like Illness. Infect Dis Clin N Am. 2008; 22:361-376.
(35.) Paddock CD, Yabsley MJ. Ecological Havoc, the Rise of White-Tailed Deer, and the Emergence of Amblyomma americanum Associated Zoonoses in the United States. CTMI. 2007; 315:289-324.
Mr. Goldstein and Ms. Black are with the Tulane University School of Medicine in New Orleans. Mr. Leydet Jr. and Dr. Vidrine are with the Louisiana State University School of Veterinary Medicine in Baton Rouge.
Table 1: Positive Western immunoblot markers in Lyme Disease. IgM IgG 18 kDa 21 kDa (OspC) 24 kDa (OspC) 28 kDa 30 kDa 39 kDa (BmpA) 39 kDa (BmpA) 41 kDa Fla 41 kDa (Fla) 45 kDa 58 kDa (not GroEL) 66 kDa 93 kDa Table 2: Characteristics of Lyme and STARI Disease Most Common Geographic EM Borrelia Long-Term Distribution in US Rash Serology Sequelae Lyme Northeast and North Central + + + or - STARI Southeast + - -
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|Title Annotation:||Lyme disease and Southern Tick-Associated Rash Illness|
|Author:||Goldstein, Ian M.; Black, Marissa A.; Leydet, Brian, Jr.; Vidrine, Steven B.|
|Publication:||The Journal of the Louisiana State Medical Society|
|Article Type:||Clinical report|
|Date:||Mar 1, 2013|
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