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Clinical Infection & Immunity

Review

Volume 8, Number 1, March 2023, pages 5-12

STARI: The Other Lyme Disease?

Lyme disease, or Lyme borreliosis, has become a major health problem in various countries [1, 2], and its global burden has extended into regions where it was not previously reported [3]. Lyme disease is a tick-borne disease caused by infection with spirochetes belonging to the genus Borrelia, primarily Borrelia burgdorferi in North America and Borrelia garinii or Borrelia afzelii in Asian and European countries [4, 5].

Southern tick-associated rash illness (STARI), also known as Master’s disease, is a condition described in southeastern and south-central United States, where classic Lyme disease is relatively rare. This makes STARI an important topic of investigation for researchers studying tick-borne diseases, as it is a unique and distinct clinical syndrome.

Amblyomma americanum, the lone star tick, was first suggested as a vector for Lyme disease in addition to the known Ixodes scapularis tick in the 1980s [6-9].

In 1984, a case report was published documenting a patient from New Jersey who developed an erythema migrans (EM) lesion, a common clinical manifestation associated with B. burgdorferi infection transmitted by the bite of the tick species Ixodes scapularis. The report showed that the attached tick was actually A. americanum [9]. This was further supported by a study in 1998 [10]. Case reports in the 1990s and 2000s continued to suggest a new tick vector associated with EM.

The identification of an a then-unculturable Borrelia species in Amblyomma americanum in 1996 led to further investigation, and in 2001, Borrelia lonestari DNA was found in A. americanum ticks in the southeastern US states [11, 12]. Borrelia lonestari was first isolated from culture in 2004, and identical DNA sequences were subsequently identified from a patient with an attached A. americanum tick [13].

STARI is of significant concern due to its lack of definitive diagnostic tests and potential to cause human illness. The aim of this review article is to provide valuable insights for clinicians, researchers, and public health officials working to address tick-borne diseases, particularly in regions where Lyme disease is rare. This paper provides a comprehensive overview of the current knowledge of STARI and its public health significance. It also highlights the current impasses, future directions, and the need for enhanced surveillance programs to raise the level of diagnostic suspicion for STARI and improve reporting.

This narrative review article was conducted using a comprehensive literature search of various databases including PubMed, Scopus, and Web of Science. The search was conducted using specific keywords related to the subject matter including “STARI”, “Southern tick-associated rash illness”, “tick-borne illness”, “Lyme disease”, and “vector-borne disease”. Inclusion criteria were set to include all relevant articles published in the English language from 1990 to 2022 that provided insight into the pathogenesis, epidemiology, clinical presentation, diagnosis, treatment, and prevention of STARI. Exclusion criteria included articles not relevant to the topic, non-English language articles, and articles published before 1990. Full-text articles that met the inclusion criteria were then reviewed in detail. Data were extracted from the articles and compiled into themes related to the purpose of the review.

A geographical distribution of the 20 named species called Borrelia burgdorferi sensu lato complex has been described [2, 5]. Three species are of medical importance as human pathogens, B. burgdorferi sensu stricto in North America and Western Europe, and Borrelia garinii and Borrelia afzelii in Eurasia [2, 14, 15]. Besides B. burgdorferi s.l., other more genetically distant Borrelia species are associated with relapsing fever and transmitted by hard ticks [5].

Lyme disease caused by B. burgdorferi sensu stricto is less common in the southeastern and south-central United States. Borrelia burgdorferi is mainly transmitted by ixodid ticks, possibly because Ixodes is a more efficient vector than Amblyomma americanum or Dermacentor [16]. A New Jersey study from 1978 to 1982 identified that a large proportion of ticks collected during Lyme disease season in the state were A. americanum [7, 8], suggesting it as a potential vector of Lyme disease in that area. In the southeast and Atlantic states, A. americanum has been reported as the most often reported tick attached to humans [17]. Further, geographic expansion of A. americanum has been occurring over the past few years [18]. Incidence of A. americanum tick-borne diseases is anticipated to increase in the coming years due to several factors, including high A. americanum population densities and expanding geographic distribution, aggressive biting habits in all active life stages, and ability to transmit a broad assortment of zoonotic infectious pathogens, such as Ehrlichia and Francisella tularensis [19-22].

Other species of Amblyomma, such as A. testudinarium, have been found to be infected with Borrelia burgdorferi sensu lato in Eastern China [23]. Recently, new Borrelia species, intermediate between Lyme disease and relapsing fever groups, were reported in two Amblyomma tick species in French Guiana, A. longirostre and A. geayi, which feed on neotropical mammals and bird species [24], including migratory species moving to North America.

B. burgdorferi s.l. have been found present in ticks of the genus Dermacentor collected from horses in other parts of America, such as Brazil [25]. Genetic analysis has shown that B. burgdorferi now comprises three subpopulations that are geographically separated. One major B. burgdorferi population in the West transmitted by Ixodes pacificus in California, and North Eastern/Upper Midwestern populations transmitted by I. scapularis [26].

A case of B. burgdorferi s.s. transmitted by Amblyomma in Brazil was reported in the context of an inflammatory condition named Baggio-Yoshinari syndrome [27]. This syndrome appears to have higher morbidity compared to Lyme disease, as symptoms tend to recur, requiring prolonged treatment [28]. It is argued that genetic and morphological changes in the spirochete probably affected important molecular interactions between Borrelia burgdorferi and the host [27].

A Lyme disease-like illness, STARI, develops following the bite of the lone star tick, Amblyomma americanum. Although the etiological agent of STARI has not been definitively identified, several lines of evidence suggest that it could be a new species of Borrelia, and that it could be transmitted by the lone star tick, causing this illness. Such spirochete has been named Borrelia lonestari [29]. Phylogenetic analysis of amplified DNA sequences from B. lonestari has shown that it differs from all borrelial species known to cause Lyme disease. It is genetically related to the relapsing fever Borrelia miyamotoi sp from Japan, as well as to an unnamed Borrelia species isolated from dogs in Florida [11, 12].

Since the first culture isolation of Borrelia lonestari, it appears that there are some differences with B. burgdorferi, which may pose important impasses in the use of serological tests currently available for known species of Borrelia [13]. Cultured organisms are critical for the development of accurate human diagnostic assays that would allow epidemiological studies and infection confirmation in the clinical setting.

A. americanum geographical distribution ranges from central Texas and Oklahoma eastward across the southern states, up to Maine in the Atlantic coast [29]. Infection of A. americanum with B. lonestari was first reported in 1996 [11, 12] and has been reported to be present throughout the geographical range of the lone star tick (Fig. 1) [13, 30-34].

Click for large image

Figure 1. B. lonestari infected-lone star tick [13, 31, 33, 34].

A major study examined ticks collected from eight eastern states to evaluate the epidemiology of B. lonestari, B. burgdorferi, and their tick hosts from genera that included Amblyomma, Ixodes, and Dermacentor [33]. Out of 300 individual or small pool samples, Borrelia DNA was detected in approximately 10% of the A. americanum and I. scapularis ticks tested. Positive samples for B. lonestari were detected in 5.3% of Amblyommma ticks collected from Kentucky and in 1.3% from Virginia. Interestingly, B. lonestari was also found in Ixodes scapularis, the Lyme disease vector, in 1.8% from Massachusetts and 3.2% from New York, but none was present in any of the Dermacentor samples. B. lonestari was not detected in ticks from Pennsylvania, Maryland, New Jersey, or North Carolina [33].

The white-footed mouse is considered the most competent reservoir host for B. burgdorferi in the northeastern United States [2]. Several other rodents and birds serve as reservoirs as well [2, 35]. Small rodents, and even bats have also been identified as reservoirs for new species of Borrelia in South America [36-38].

Although the white-tailed deer serve as hosts for adult ticks, they do not become infected with B. burgdorferi. A most impressive finding is that B. lonestari has been found infecting 8.7% of white-tailed deer in eight southern states (AR, FL, GA, KY, LA, MS, NC, and SC) [31] (Fig. 2) [13]. The role of the white-tailed deer as a reservoir host for B. lonestari is unclear. These animals are able to mount an antibody response following B. burgdorferi infection but are unable to infect ticks with B. burgdorferi and thus do not serve as a reservoir [31]. Genomic analysis places B. lonestari genetically close to Borrelia theileri, the agent of bovine borreliosis [13, 39].

Click for large image

Figure 2. B. lonestari detected from ticks collected from white-tailed deer [13, 31].

Feeding of the lone star tick on white-tailed deer occurs during all three parasitic stages of its life cycle. This is important in the natural history of Ehrlichia chaffeensis in the southeastern United States. Since white-tailed deer naturally can be infected with multiple, antigenically similar pathogens like Ehrlichia and Anaplasma, as well as with B. lonestari and B. burgdorferi, the potential for serological cross-reaction exists. This should be considered when planning and interpreting serological surveys.

Important evidence from a clinical case reported in 2001 for linking A. americanum tick vectors with causing B. lonestari in humans was observed when analyzing DNA sequences in a patient with EM with an attached A. americanum tick. DNA from B. lonestari found in the skin of the patient was identical to that found in the tick that was attached to it [29].

The initial stage of Lyme disease is characterized by a skin lesion known as EM. This term was first mentioned in Europe in 1909, and was sometimes associated with a tick bite [40]. An early disseminated infection may follow if antibiotic treatment is not initiated promptly. Lyme disease manifestations are mainly due to an excessive inflammatory response in the human host, as the spirochete is not well adapted to humans and is maintained in nature as a zoonosis [14]. Inflammatory manifestations include neurological abnormalities, carditis, and arthritis.

The clinical presentation of STARI resembles Lyme disease, as patients develop a bullseye, or expanding circular lesion at the site of the tick-bite similar to EM [41]. The lone star tick is known to cause rashes that are similar, and sometimes indistinguishable, to EM associated Lyme disease. In regions that the Centers for Disease Control and Prevention (CDC) recognizes as endemic for both STARI and Lyme disease, these rashes can be a diagnostic and management challenge [10].

STARI patients are more likely to have recognized tick bites, shorter time from tick bite to the onset of the skin lesion, and less frequent constitutional symptoms (particularly less regional lymphadenopathy and less tender/pruritic rashes) [42]. Patients with STARI may be less likely to develop neck stiffness, arthralgia, and regional lymphadenopathy than patients with Lyme disease. Constitutional symptoms such as generalized fatigue, headache, and fever may also be present just as in Lyme disease though in less severity [10, 43].

STARI lesions have a more homogeneous skin lesion with a circular shape, a prominent punctum, and raised, irregular borders. Compared to early Lyme disease lesions, the STARI rashes are typically less tender, smaller (with a mean diameter of 4.5 cm compared to 7.1 cm in early Lyme disease), and occur more frequently on the trunk. STARI lesions have increased central clearing and are less uniform in color and pattern than those in Lyme disease. In Lyme disease, the lesion has a target appearance in which a darker center is surrounded by clearing, which is then surrounded by an erythematous border. However, if clearing is present in Lyme disease cases, it often spares the exact center of the lesion [41, 42, 44, 45].

Since the clinical presentation of STARI could resemble Lyme disease, and because the distribution of A. americanum and Ixodes scapularis have been sympatric for years, it is possible that unrecognized cases of STARI may exist among cases of presumptive Lyme disease [11, 34, 46, 47]. Metabolic profiling has been shown to be a powerful tool for distinguishing between early Lyme disease and STARI. Researchers identified a metabolic biosignature to distinguish between early Lyme disease and STARI. This biosignature has been shown to be effective in objectively differentiating between the two conditions with an accuracy of 89-92%, depending on the statistical model used [46]. In contrast, the existing diagnostic algorithm for Lyme disease is a two-tiered serological approach that utilizes an enzyme-linked immunoassay or immunofluorescence assay as a first-tier test followed by IgM and IgG immunoblotting as the second-tier test. In this study, all STARI samples were negative by two-tiered testing, while early Lyme disease samples were only 44% positive. However, when the metabolic biosignature was used for classification modeling, diagnostic accuracy for STARI and early Lyme disease significantly increased. This highlights the potential of metabolic profiling as a powerful and objective approach to distinguish between these two conditions [46].

Currently, the diagnosis of STARI is based solely on clinical features, as there is no approved diagnostic modality for the disease attributed to B. lonestari and transmitted by Amblyomma ticks [45]. While more sophisticated molecular techniques have failed to detect this pathogen in a multitude of human samples, B. burgdorferi and relapsing fever Borrelia have been found in ticks and humans throughout the southern USA. This raises the possibility that “STARI” may be a misdiagnosis of a variant of Lyme disease and/or relapsing fever due to these organisms [48-50]. Additionally, deer and birds are known to be important hosts for various tick species, and play a role in the geographic distribution and transmission of tick-borne diseases [2]. Therefore, it is important to emphasize that the diagnosis of “STARI” remains suspect until more effective molecular testing is done in a systematic fashion. While current diagnosis is based on clinical evaluation, which includes evaluating for the presence of EM and considering tick exposure, presentation, and geographic region, it is crucial to acknowledge that this may not be sufficient for accurate diagnosis. It is important to note that current diagnostic methods may not be adequate to accurately identify STARI, and further research is necessary to better understand the nature and prevalence of this disease to differentiate it from other tick-borne illnesses that are prevalent in the southern USA.

Additionally, the discovery of new species of Borrelia underscores the need for more comprehensive molecular testing to identify the pathogens responsible for tick-borne diseases accurately [51, 52]. These new species may have distinct clinical manifestations and may respond differently to treatment, highlighting the importance of accurate diagnosis. Furthermore, these new species may be responsible for some cases of tick-borne illness that have previously been attributed to known species, such as B. burgdorferi in the case of STARI.

Tick-borne coinfections are also an important consideration in the diagnosis and treatment of tick-borne diseases. Coinfections occur when a tick carries more than one pathogen and transmits them to the host during a single bite. This can complicate diagnosis and treatment, as different pathogens may respond differently to antibiotics or require different treatment regimens. Coinfections have been documented in several tick-borne diseases, including Lyme disease, and may also be contributing to the development of STARI [53]. Therefore, it is important to understand the role of coinfections in patients with suspected STARI and to conduct systematic molecular testing to identify all potential pathogens. By identifying and treating all underlying infections, clinicians can improve patient outcomes and reduce the risk of long-term complications associated with tick-borne diseases.

In Lyme disease, several weeks or months may pass before the host immune system gains control of the infection following EM, even in the presence of antibiotics [54]. If untreated, the spirochete or spirochetal products may survive in tissues causing arthritis or neurological sequelae [55]. Even after completion of antibiotic treatment, a fraction of patients may have lingering symptoms [56, 57].

STARI, compared with Lyme disease, is consistently described as a mild disease, but the extent of long-term sequelae remains uncertain. So far, there are no known reports of extracutaneous sequelae [53]. However, it is important to note that since STARI is not reportable and has no definitive diagnostic serology, its long-term sequelae may not be fully appreciated [58].

A prospective study comparing clinical features of 21 cases of EM-like skin lesions from Missouri with 101 cases from New York reported that the skin lesions in both groups resolved with oral antibiotic therapy, although there were geographical differences in symptoms at the third month of follow-up [42].

There is still a knowledge gap and insufficient data to provide clear antibiotic treatment recommendations for all cases of STARI [53]. While some experts, such as Dr. Masters, advocate for the use of antibiotic treatment for Master’s disease, it is important to consider the risks and benefits of such treatment [59]. The argument that “because we have not found an infection does not mean that one does not exist” is a reasonable one, but prescribing antibiotic courses in the absence of a proven or demonstrable infection can lead to risks such as antimicrobial resistance and other adverse effects. Therefore, it is important to exercise caution and consider the individual patient’s needs when recommending antibiotics for STARI. Typically, doxycycline is usually employed as it may be therapeutically helpful and aligns with standard EM treatment recommendations [60]. Doxycycline, a tetracycline antibiotic, is administered for a 14-day course. There is evidence that cephalexin is not effective in treating Lyme disease, and some do not recommend its use in treating STARI [10].

EM will eventually heal spontaneously without antibiotic treatment; however, the main reason for antibiotic treatment is to decrease the duration of rash and associated symptoms and to prevent potential long-term sequelae, which are not well understood in the case of STARI [41]. For patients with more severe symptoms, such as fever, flu-like illness, severe headache, lymphadenopathy, multiple lesions, or other evidence of dissemination beyond the rash, a longer course of antibiotic treatment may be recommended [60]. Until the exact cause of STARI is determined, proper treatment and follow-up will remain uncertain. The potential impact on chronic symptomatology due to a delayed antibiotic treatment is unknown.

Given that in certain geographic regions, both STARI and Lyme disease are endemic, distinguishing the origin of EM may not be possible clinically unless the responsible tick has been identified [54]. In this case, antibiotic therapy directed towards Lyme disease is indicated to treat possible coinfection [53]. On the other hand, in areas of low endemicity of Lyme disease where lone star ticks are abundant, observation for EM may be chosen over antibiotic treatment [53].

It is important to note that the use of antibiotics for STARI remains controversial due to the lack of definitive evidence supporting their efficacy in treating this condition. As such, the decision to prescribe antibiotics should be made on a case-by-case basis, considering the patient’s individual circumstances, including the potential risks and consequences of developing STARI, the unknown risk of late complications, as well as the economic costs and potential adverse effects of prophylactic antimicrobials [55].

To reduce the risk of acquiring STARI, avoiding tick-infested areas is the best prevention measure [61, 62]. Personal protection measures such as wearing long trousers tucked into boots and using repellents containing DEET can minimize the risk of tick bites; treating clothing with permethrin is also indicated for the prevention of tick bites, as well as frequent clothing checks while in tick-infested areas [61, 62]. Optimal concentration of DEET in tick repellent is between 15% and 33%; however, young children should use lower concentrated products not more than 7% [61]. Permethrin on clothing remains effective for up to several weeks and can be utilized with any age group [61].

Additionally, a crucial protective measure is to remove clothing (dry clothing on hot heat to kill undetected ticks on clothing) to shower/bathe in order to thoroughly examine the naked body for ticks for removal after returning from potentially tick-infested areas; bathing primarily aids in removing clothes for examining the body, though running water could also potentially remove ticks that have not yet attached to the body surface [62]. As it is still unknown how long A. americanum must remain attached before it can transmit the infection, inspection and prompt removal of attached ticks may constitute important strategies to minimize the risk of STARI [53].

Despite the emergence of STARI, the understanding of this disease is limited due to the lack of definitive diagnostic tests and of national notification requirements. To fully grasp the public health impact of STARI and understand the etiology of this disease, enhanced surveillance programs are needed to raise the level of diagnostic suspicion for STARI and improve reporting [20, 53]. At this moment STARI may be grossly under-reported. Since mathematical model calculations rely on recorded cases that are diagnosed based on the presence of EM clinically, the estimated incidence figures even for Lyme borreliosis are conservative and underestimate actual infection rates [63, 64]. This could underestimate the true incidence of the infection in certain areas of the world like Europe where the percentage of adult patients with EM is low [15].

Tick-borne diseases are a growing problem in many parts of the world. This could bring important financial implications of a well-hidden or ignored condition that could expand and develop into a pandemic. Borreliosis has been increasingly spreading in Europe [65]. Although STARI does not occur in Europe, presumably because A. americanum ticks are not found in that geographic area, other species of Amblyomma harbor Borrelia burgdorferi sensu lato in China [23]. The Baggio-Yoshinari syndrome, a disease similar to Lyme disease observed in Brazil and caused by B. burgdorferi s.s. transmitted by Amblyomma, may be the perfect example of how the spirochete adapts to use new vectors in other latitudes [28]. This Brazilian Lyme-like borreliosis may utilize capybaras as reservoirs and Amblyomma and Rhipicephalus ticks as vectors [28]. B. burgorferi s.s. is also present in small mammals such as rodents and bats in South America [66]. Novel Borrelia species appear already to be using these same reservoirs [36, 67, 68].

Surveillance and control measures involve a multidisciplinary approach [69]. Standardized surveillance and reporting procedures are needed [64]. Surveillance systems and monitoring efforts should encompass distribution of risk, evidence-risk mapping [70] and tracking. Since reservoirs for new species of Borrelia include small mammals and birds, migratory species of the latter could be moving to North America [24]. A worldwide phenomenon, similar to the one observed for Lyme borreliosis, which has extended into regions and countries where the disease was not previously reported, is possible [3].

The annual NIH investment in Lyme disease research has been less compared to other infectious diseases [57]. More support for research in STARI and its transmission is justified. More molecular and epidemiological studies in different regions of the world are required [71]. Until we acquire additional essential information, we may just be seeing the tip of the iceberg.

Acknowledgments

None to declare.

Financial Disclosure

No funding available.

Conflict of Interest

None to declare.

Author Contributions

HR, VN, and JC wrote the manuscript.

Data Availability

Any inquiries regarding supporting data availability of this study should be directed to the corresponding author.

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