Version July 2025
INTRODUCTION —
Borrelia miyamotoi is a zoonotic pathogen that is transmitted by the same genus of ticks (ie, Ixodes) that transmit Borreliella burgdorferi (the agent that causes Lyme disease), Anaplasma phagocytophilum, Babesia species, and tickborne flaviviruses [1]. B. miyamotoi is in the same taxonomic group as agents of soft tick relapsing fever and louse-borne relapsing fever [2]. In the large majority of patients, it causes an acute undifferentiated febrile illness during the summer. Symptomatic infection with B. miyamotoi is the most common cause of hard tick relapsing fever in North America and Europe [3-5]. A second, less frequent cause of hard tick relapsing fever in the United States is Borrelia lonestari, which is transmitted by the Amblyomma americanum tick of the southern and eastern United States.
This topic will review the microbiology, epidemiology, clinical manifestations, diagnosis, and treatment of B. miyamotoi. Detailed discussions of other tickborne pathogens are found elsewhere:
•(See "Clinical manifestations of Lyme disease in adults".)
•(See "Diagnosis of Lyme disease".)
•(See "Treatment of Lyme disease".)
•(See "Human ehrlichiosis and anaplasmosis".)
•(See "Babesiosis: Clinical manifestations and diagnosis".)
•(See "Clinical features, diagnosis, and management of relapsing fever".)
•(See "Arthropod-borne encephalitides".)
MICROBIOLOGY —
B. miyamotoi and B. lonestari belong to the spirochete genus Borrelia, which also includes the agents of soft tick relapsing fever and louse-borne relapsing fever [6]. (See "Microbiology, pathogenesis, and epidemiology of relapsing fever".)
There are genetic differences between strains of B. miyamotoi obtained from different tick species or human cases in the three geographic areas where it occurs: North America, Europe, and Asia [2,7]. However, B. miyamotoi isolates from within the same geographic area or that share the same tick species association are near identical in their sequences [3,7-9].
B. miyamotoi undergoes antigenic variation during infection, as occurs during relapsing fever, and can sequentially express different surface proteins during the course of infection. Antigenic variation may account for the recurrences of fever and infection persistence that have been reported in some cases [10,11]. (See 'Clinical manifestations' below.)
B. miyamotoi was difficult to isolate in the broth medium that is routinely used for other Borrelia species [12]. Modifications of that medium have been more successful for achieving serial propagation [13-15]. A discussion on how to diagnose B. miyamotoi infection is found below. (See 'Tests that detect the organism' below.)
Comparatively little is known about the microbiology of B. lonestari or the best conditions for cultivation in the laboratory [16,17].
TRANSMISSION —
In North America and Eurasia, the vector ticks and vertebrate reservoirs in a given area are generally the same arthropods and vertebrates that transmit or harbor the agents of Lyme disease. The natural reservoirs for B. miyamotoi are deer mice of the genus Peromyscus, as well as voles, woodrats, squirrels, and shrews in North America [18,19], and other small rodents in Asia and Europe [3,20]. Birds may also serve as natural hosts for B. miyamotoi [21]. In North America deer serve as hosts for adult stages of ticks that transmit B. miyamotoi, and ingested deer blood provides for further growth of numbers of spirochetes in the tick [22]. (See "Microbiology of Lyme disease" and "Epidemiology of Lyme disease", section on 'Tick vectors' and "Epidemiology of Lyme disease", section on 'Reservoir hosts'.)
B. miyamotoi is transmitted to humans through hard ticks of the genus Ixodes. The organism was first identified in Ixodes persulcatus in Japan in 1994 [12]. B. miyamotoi was subsequently associated with other Ixodes species ticks, including:
●Ixodes scapularis (commonly known as the "deer tick" or "blacklegged tick") in Northeastern and north-central United States and adjacent areas of Canada [23].
●Ixodes pacificus ("western blacklegged tick") in far-western North America [24].
●Ixodes ricinus (the "sheep tick") in Europe and western Russia [25,26].
●I. persulcatus in eastern Russia, Siberia, and northern Asia [9,10].
●Ixodes ovatus in Japan and China [27].
There are several differences in the transmission of the spirochete species that cause Lyme disease and B. miyamotoi. As an example, transmission of B. miyamotoi may occur within the first 24 hours after the tick embeds in skin and begins to feed [28]; like other relapsing fever species, B. miyamotoi is already in the salivary glands of ticks at the time their feeding commences. This is in contrast to B. burgdorferi infection, in which the tick must usually be attached for 36 to 48 hours before transmission occurs. Consequently, removing a tick within the first 24 to 48 hours of attachment may not prevent infection with B. miyamotoi, as it usually will with B. burgdorferi. (See "Prevention of Lyme disease", section on 'Checking for and removing ticks'.)
In addition, unlike the spirochete species that cause Lyme disease, B. miyamotoi can be vertically transmitted from an adult female through its eggs to larval offspring [29,30]. Thus, infection can be acquired from the bite of a previously unfed larval Ixodes tick, as well as from a nymphal or adult tick. In the Northeastern United States, larval ticks have their peak in activity in August, one to two months after the peak of activity for nymphal ticks (the stage that most commonly transmits Lyme disease). Larval Ixodes ticks are particularly hard to detect on the skin because of their small size (equivalent to a poppy seed), even when engorged.
Ticks that bear B. miyamotoi may also transmit coinfecting pathogens [31]. In a study in New York State, about half of the 3 percent of I. scapularis infected with B. miyamotoi had at least one other agent, most commonly B. burgdorferi but also A. phagocytophilum and/or Babesia microti. (See "Clinical manifestations of Lyme disease in adults" and "Human ehrlichiosis and anaplasmosis" and "Babesiosis: Clinical manifestations and diagnosis".)
B. miyamotoi has been transmitted through blood transfusion in a mouse model [32]. Although no transfusion-related cases of B. miyamotoi have been reported, there have been cases of transfusion-related transmission of Borrelia species that cause relapsing fever.
B. lonestari was first identified in Amblyomma americanum (the "Lone Star tick") [16]. A. americanum is also the vector of Ehrlichia chaffeensis, the cause of human monocytic ehrlichiosis, Ehrlichia ewingii, and the Heartland and Bourbon viruses. Bites from or exposure to A. americanum is also risk factor with Southern Tick-Associated Rash Illness (STARI), an erythema migrans-like rash with mild constitutional symptoms and occurring in the geographic distribution of the tick [33].
EPIDEMIOLOGY
B. miyamotoi
Prevalence in ticks — The prevalence of B. miyamotoi in five different species of Ixodes ticks ranges from 1 to 3 percent in areas such as North America, Europe, and Asia [3,8,10,12,18,24,34-36]. In comparison, the prevalence of B. burgdorferi in the same type of ticks is generally 15 to 30 percent in the Northeastern and north-central United States. However, in California, the frequencies of B. miyamotoi and B. burgdorferi in I. pacificus nymphs and adults are about the same [37,38].
Prevalence of antibodies
Studies of humans have described the frequency of B. miyamotoi infection among patients with suspected tick-borne disease or the prevalence of antibodies to B. miyamotoi in serosurveys of individuals from different geographic areas [11,39-43]. Representative studies include:
•A study evaluating tick-transmitted diseases in the Northeastern United States was carried out using polymerase chain reaction (PCR) testing on whole blood samples from 11,515 patients with an acute febrile episode from April through November in 2013 and 2014 [11]. B. miyamotoi and A. phagocytophilum were seen in approximately 1 percent of the samples, compared with 3 percent for B. microti. Clinical records were available for 51 of the cases that had B. miyamotoi infection. Of those cases, the mean age was 55, and 57 percent were male. The highest incidence of positive PCR assays for B. miyamotoi was in August, approximately one month after the peak incidence of early Lyme disease in this region.
•Serologic testing to detect antibodies against B. miyamotoi GlpQ protein was performed on archived samples collected between 1990 and 2010 in Lyme disease-endemic regions in the United States [39]. The seroprevalence of antibodies against B. miyamotoi was 6 (1 percent) among 584 healthy blood donors, 9 (3 percent) among 277 patients with suspected Lyme disease, and 3 (21 percent) among 14 patients who presented with an undifferentiated febrile illness in the late spring or summer.
•A seroprevalence survey was carried out on 1153 blood samples obtained in 2018 in five New England states [44]. The samples had been submitted for medical testing for reasons other than suspected tickborne disease. The study identified an overall prevalence of antibodies to B. miyamotoi of 2.8 percent. This compared to a prevalence of antibodies to B. burgdorferi of 11 percent in the same samples.
•A seroprevalence study of 1700 blood donor sera from California identified two (0.12 percent) individuals with antibodies specific for a Borrelia species, either B. miyamotoi or a soft tick relapsing fever agent. Among the same serum collection, there were eight (0.47 percent) individuals with antibodies to B. burgdorferi [42].
•In a meta-analysis of 19 seroprevalence studies, mainly in North America but also Europe and Asia, between 2011 and 2021 revealed that the overall prevalence of antibodies to B. miyamotoi was 5 percent in individuals with risk factors for tick exposure, 5 percent in patients with suspected Lyme disease, and 1 percent in healthy controls [3].
Seasonal distribution for B. miyamotoi — The seasonal distribution of B. miyamotoi infection parallels the activity of the transmitting ticks. In the case of larval I. scapularis, which might be carrying B. miyamotoi but not B. burgdorferi, the peak of activity generally is later in summer than for nymphs. In a study of 300 cases reported from nine states from 2013 to 2019, 70 percent of the cases occurred between June and September, with a peak in August [4]. In California and other areas with mild climates, the risk of tick exposure may extend into the fall and winter months and may be comparatively low in the dry, hot months of summer.
Coinfection of B. miyamotoi with other pathogens — Although I. scapularis with B. miyamotoi in the Northeastern United States frequently also bear B. burgdorferi [45], B. miyamotoi coinfections of patients with early Lyme disease may be less common than the prevalence of coinfections of ticks would predict. Of 52 adult patients in New York State with erythema migrans, approximately 10 percent were coinfected with B. microti by serologic assay, but none were infected by B. miyamotoi [46]. In another report of 51 patients in the eastern United States with B. miyamotoi present in the blood by PCR, 3 also had B. burgdorferi by PCR in blood, and another 2 seroconverted to B. burgdorferi in follow-up [11].
B. lonestari — Amblyomma americanum is a frequent biter of humans in the Southeastern, south-central, and, increasingly, the Northeastern United States, and as such poses the largest risk as a vector of B. lonestari for humans. The prevalence of B. lonestari in surveys of collected A. americanum has been 1 to 3 percent. As is the case for I. scapularis, the preferred host for adult A. americanum are deer. The sizes and distributions of populations of both types of ticks have risen and expanded in parallel with increases in deer populations in the United States [47]. There have been no reported serosurveys for evidence of B. lonestari infection, but it may not be possible to distinguish B. lonestari infection from infection with B. miyamotoi with currently available serological tests.
CLINICAL MANIFESTATIONS —
The clinical manifestations of B. miyamotoi infection have been described in several reports [10,11,39,40,48-51]. Most reported cases are in adults; among 300 cases in the United States, the median age was 52, with approximately equal numbers for all sexes [4]. But B. miyamotoi infection has been documented in children as well.
B. miyamotoi
Incubation period — In a meta-analysis of studies from North America, Europe, and Asia, the median incubation period between tick exposure or bite and symptoms was 14 days with an interquartile range of 10 to 18 days [3].
Immunocompetent patients — Many instances of B. miyamotoi infection are minimally symptomatic or asymptomatic and, as such, never come to clinical attention [46].
In a retrospective study that evaluated 51 patients with fever and evidence of B. miyamotoi diagnosed using polymerase chain reaction (PCR) testing of the blood [11], the majority had headache, myalgia, arthralgia, malaise, and/or fatigue. Approximately 50 percent were suspected of having sepsis, and 24 percent were hospitalized. One patient, who was not treated with antibiotics initially, had a recurrence of fever a month later; specimens from both episodes were positive for B. miyamotoi. Symptoms resolved after treatment with doxycycline, and except for fatigue in two patients no chronic sequelae were observed.
In a PCR study of blood samples carried out in 984 persons from Northeastern China who sought medical care after a recent tick bite [52], 14 (1.4 percent) were infected with B. miyamotoi. All patients presented with a nonspecific febrile illness that included headache, fatigue, and arthralgias. Four of the 14 were hospitalized for persistent or relapsing fever.
Among 300 cases identified in nine states through surveillance for 2013 to2019, the most common symptoms were fever and headache with recurrence of fever in 28 percent. Thirteen percent hospitalized, and there were no reported deaths [4].
In a meta-analysis of 504 patients in North America, Europe, or Asia with symptomatic B. miyamotoi infection, the frequencies of individual symptoms were 95 percent for fever, 86 percent for headache, 68 percent for chills or rigors, 65 percent for myalgia, 45 percent for arthralgia, and 39 percent for fatigue. Forty-three percent reported abdominal symptoms, mainly nausea or vomiting. A relapse of the fever occurred in 9 percent of the cases [3].
Meningitis with B. miyamotoi infection has been reported in one immunocompetent patient [53].
Immunocompromised patients — Individuals who are immunocompromised, especially those with an immunoglobulin or other B-cell deficiency, may be at greater risk for developing neurologic signs and symptoms (eg, meningoencephalitis) and/or persistent fever and bacteremia compared with immunocompetent hosts.
Many of the immunocompromised patients with B. miyamotoi infection were immunodeficient as a consequence of B-cell depletion by the therapeutic antibody rituximab [54]. As examples, B. miyamotoi was detected by microscopy and PCR in cerebrospinal fluid (CSF) samples of an 80-year-old woman in New Jersey who was in remission from non-Hodgkin lymphoma [49], and a 70-year-old man who was in remission from non-Hodgkin lymphoma in the Netherlands [50] after treatment with rituximab. Both patients presented with progressive mental decline and gait abnormalities over several weeks to months, and neither had a fever. For both patients, cognitive abilities improved, and other symptoms resolved after they were treated with intravenous (IV) penicillin G for 30 days or ceftriaxone for 14 days. (See 'Treatment' below.)
Another case of meningoencephalitis was diagnosed in a 63-year-old man who was receiving rituximab for maintenance management of primary membranous glomerulonephritis. He had a three-month illness culminating in admission for fever, confusion, stiff neck, garbled speech, and vision changes (the latter attributable to uveitis) [55]. A lumbar puncture revealed a lymphocytic pleocytosis and elevated protein. The diagnosis was made by PCR detection of B. miyamotoi in the CSF and by the detection in the serum of immunoglobulin (Ig)G antibodies to the GlpQ protein. The patient’s symptoms resolved with treatment with IV ceftriaxone followed by doxycycline.
A case of B. miyamotoi meningoencephalitis in Sweden occurred in an individual who had been treated with rituximab and methotrexate for rheumatoid arthritis before onset. The patient was ill for six weeks with fever, impaired cognitive function, and symptoms of uveitis [53].
Laboratory findings
●Routine laboratories – Thirty to 50 percent of patients with B. miyamotoi infection and accompanying laboratory studies have mild to moderate leukopenia, thrombocytopenia, and/or elevations of alanine aminotransferase and aspartate aminotransferase levels [11]. Elevated levels of C-reactive protein may occur [3].
●CSF findings – As in all patients with meningoencephalitis, CSF analysis may reveal an elevated white blood cell count (with a lymphocyte predominance) and an elevated protein concentration [49,50]. When measured, the chemokine Cxcl13 level has commonly been elevated [3].
B. lonestari
A report of a case of STARI documented the presence of B. lonestari by PCR in both a skin biopsy of a rash and the embedded A. americanum tick that was removed [56], but this finding was not replicated in a subsequent microbiologic study of other erythema migrans-like rashes in Missouri [57]. The infectiousness and potential pathogenicity of B. lonestari was confirmed in a case report of a 75-year old male in Alabama who had recurrent fevers and extreme fatigue for three months [58]. He was receiving maintenance rituximab for non-Hodgkin lymphoma before the onset. Evaluation showed hepatosplenomegaly and pancytopenia and mildly elevated alkaline phosphatase by laboratory study. Spirochetes were observed in peripheral blood smear. These were confirmed to be B. lonestari by PCR and sequence of the 16S rRNA gene. The patient was treated with oral doxycycline and manifested typical symptoms of a Jarisch-Herxheimer (JH) reaction after the first dose. The patient completed treatment without additional complication, and pancytopenia resolved.
DIAGNOSIS
When to suspect the diagnosis — B. miyamotoi should be considered in the evaluation of patients who present with an acute nonspecific febrile illness if they reside in or have traveled to an area where B. miyamotoi has been previously identified when ticks are active (eg, late spring and summer in the Northeastern and north-central United States or in Europe). Patients do not need to have a history of a tick bite in order for physicians to consider the diagnosis since tick bites, especially those of larval or nymphal states of Ixodes ticks, often go undetected. (See 'Transmission' above.)
Patients who have long-standing symptoms and/or disabilities should not be evaluated for B. miyamotoi infection unless the patient is immunocompromised or there is evidence of an intercurrent acute febrile illness. There is no evidence that B. miyamotoi causes persistent infection or chronic sequelae in immunocompetent hosts. (See 'Clinical manifestations' above and 'Microbiology' above and "Clinical features, diagnosis, and management of relapsing fever".)
Evaluation — In patients suspected of having B. miyamotoi based upon their clinical presentation, the approach to diagnosis depends upon the availability of laboratory testing:
●If testing is available – In patients who present with an acute illness compatible with B. miyamotoi infection, a polymerase chain reaction (PCR) assay of whole blood is the preferred test. Since one or more other tickborne illnesses besides B. miyamotoi infection may be in differential diagnosis (eg, anaplasmosis, babesiosis), custom panels of PCR assays that test for several tickborne pathogens can often be requested. In patients with symptoms of meningoencephalitis, PCR testing can also be used to detect the presence of the organism in cerebrospinal fluid (CSF). In the United States, none of the commercially available direct detection diagnostic assays for B. miyamotoi infection are Food and Drug Administration (FDA) approved; however, testing is available through some commercial laboratories. (See 'Tests that detect the organism' below.)
Serologic assays using a GlpQ-based enzyme-linked immunosorbent assay (ELISA), bead assay, or immunoblot can also be performed to diagnose infection with B. miyamotoi, although these tests are less useful than PCR for diagnosing acute infection since serologic tests are not always positive early in the course of disease. However, if acute and convalescent sera are obtained four to six weeks apart, a diagnosis of B. miyamotoi is supported by conversion of an ELISA result from negative to positive. (See 'Tests that detect the organism' below and 'Serology' below.)
●If testing is not available – If testing for B. miyamotoi is not available, an empiric diagnosis of B. miyamotoi infection can be made in patients with consistent clinical findings and epidemiologic risk factors, if an evaluation for other possible causes of infection is unrevealing. (See 'Differential diagnosis' below.)
In addition, the C6 peptide antibody assay, commonly used for serologic testing for Lyme disease, has been found to be positive in some cases of infection with B. miyamotoi alone [59] and may be a reasonable alternative for initial testing when the GlpQ assay is not available. A positive result with the C6 peptide antibody assay in combination with a negative Western blot for B. burgdorferi antibodies is consistent with the diagnosis of B. miyamotoi infection, but a negative result does not exclude the diagnosis. (See 'Serology' below and 'Differential diagnosis' below.)
Types of tests
Tests that detect the organism
●PCR-based assays – The best way to confirm a diagnosis of B. miyamotoi infection at the time of presentation is through a PCR-based assay of anticoagulated whole blood or, if indicated, CSF [10,11,49]. CSF can be frozen; blood samples cannot. Citrate ("ACD") or ethylenediaminetetraacetic acid (EDTA) is preferred over heparin for anticoagulation. The lower limit of detection of quantitative PCR assays with a probe is approximately 100 organisms per milliliter of whole blood [18,60].
PCR testing is most likely to be positive during the first week of the illness [61]. In a retrospective study of PCR-positive cases, hospitalized patients had a higher number of spirochetes in the blood as assessed by quantitative PCR than patients who were not hospitalized [11]. PCR assays of serum samples may also detect B. Miyamotoi [60], even though the numbers of organisms are lower than in whole blood.
Although PCR testing is the best way to confirm the diagnosis, a negative PCR assay does not exclude infection with B. miyamotoi given the waxing and waning nature of Borrelia bacteremia. Thus, in some patients (eg, those with severe disease who are improving on therapy), it may be reasonable to continue antibiotics despite a negative result.
PCR testing can be performed at commercial reference laboratories (eg, Quest Diagnostics, Mayo Clinic Laboratories, ARUP Laboratories). Most of these laboratories will distinguish B. miyamotoi from Lyme disease agents but do not usually discriminate B. miyamotoi from relapsing fever Borrelia species. Thus, a "positive" result of the PCR assay for B. miyamotoi may represent instead a relapsing fever agent: B. hermsii or B. turicatae depending on the region in North America. A multiplex PCR assay that distinguishes B. miyamotoi from Borrelia species that cause tickborne and louse-borne relapsing fever is performed by the Centers for Disease Control and Prevention (CDC) in Fort Collins, Colorado on a referral basis.
●Microscopy – A Wright- or Giemsa-stained thin blood smear can be examined under the microscope for the appearance of the coiled filaments of spirochetes amidst the blood cells. However, the sensitivity of the blood smear for diagnosis of B. miyamotoi infection is low [62]. It may only reveal spirochetes in cases with pre-existing immunodeficiency and remitting disease course. Peak numbers of B. miyamotoi or B. lonestari spirochetes in the blood are generally lower than what occurs during febrile episodes of louse-borne or soft tick relapsing fever [11,63]. (See "Clinical features, diagnosis, and management of relapsing fever", section on 'Diagnosis'.)
In patients with meningoencephalitis, spirochetes in the CSF may be observed in a wet mount under darkfield or phase-contrast microscopy [49].
●Culture – Culturing the organism from a clinical specimen in a broth medium is feasible, but the complex medium is only available in few places [49]. An alternative to broth culture for isolation and propagation of B. miyamotoi (but probably not B. lonestari) is injection of blood or CSF into mice, preferably severe-combined immunodeficient (SCID) [64].
Serology — Serologic testing using a GlpQ-based ELISA, bead assay, or immunoblot can be performed to diagnose B. miyamotoi infection [1,65]. Immunoassays of sera for IgM or IgG antibodies to GlpQ are available from certain commercial laboratories. Antibody-based tests are usually negative at the time a patient presents with an acute infection, and therefore, is most useful for retrospectively confirming a diagnosis.
The overall sensitivity of the GlpQ is 60 to 80 percent with sera from convalescent cases [11,46]. A GlpQ protein is not made by the spirochete species that cause Lyme disease [66]. However, there is cross-reactivity between B. miyamotoi and highly similar GlpQ proteins present in soft tick relapsing fever species. This can lead to positive reactions among those exposed to Borrelia species that cause soft tick relapsing fever in western North America. It is also likely that there may be cross-reactions with the GlpQ protein of B. lonestari. (See "Clinical features, diagnosis, and management of relapsing fever", section on 'Diagnosis'.)
Background of positive GlpQ assay reactions occur in 1 to 2 percent of symptomatic people at low risk of tick bites [42,67]. These may represent cross-reactions by existing antibodies to GlpQ proteins of other bacteria such as Haemophilus influenzae [42].
Patients infected with B. miyamotoi commonly produce antibodies that cross-react with the C6 peptide antigen, the full-length VlsE protein, which includes the C6 peptide, or whole cell-based ELISA assays used to diagnose Lyme disease [11,40,59,68]. A positive result with one of these widely available assays together with a negative Western blot for B. burgdorferi antibodies may be the only serologic evidence of B. miyamotoi infection. A more detailed discussion of the C6 assay is presented elsewhere. (See "Diagnosis of Lyme disease".)
The close-relatedness of B. lonestari to B. miyamotoi suggests that the PCR tests for direct detection of B. miyamotoi in the blood and GlpQ serologic assay would also be suitable for laboratory evaluation of a suspected hard tick relapsing fever from B. lonestari.
DIFFERENTIAL DIAGNOSIS —
Many of the clinical signs and symptoms of B. miyamotoi mimic an array of acute undifferentiated febrile illnesses and also are indistinguishable from other tickborne illnesses, such as anaplasmosis, babesiosis, ehrlichiosis, early Lyme disease without rash, or soft tick relapsing fever. This likely also applies for symptomatic infections with B. lonestari, the primary difference between the two infections being in the areas of distribution of the tick vectors. (See "Clinical manifestations of Lyme disease in adults" and "Human ehrlichiosis and anaplasmosis", section on 'Clinical manifestations' and "Babesiosis: Clinical manifestations and diagnosis", section on 'Clinical manifestations'.)
While present in only a minority of patients reported in case series, one clinical feature that may suggest the possibility of B. miyamotoi infection is a relapse of the fever and constitutional symptoms a few days after recovery from an earlier febrile episode. In addition, other laboratory and clinical findings that help distinguish B. miyamotoi infection from other tick-borne infections include:
●Anaplasmosis – As in B. miyamotoi infection, a relative leukopenia and/or thrombocytopenia commonly occur in human granulocytic anaplasmosis. However, patients with anaplasmosis are more likely to have marked elevations in their aminotransaminase levels. In addition, evaluation of a blood smear may reveal intracellular organisms in the white blood cells in patients with anaplasmosis, whereas extracellular spirochetes may be seen in blood smears of patients with B. miyamotoi or B. lonestari infection. The best way to distinguish anaplasmosis from other tickborne illness is through polymerase chain reaction (PCR) or serologic testing. (See "Human ehrlichiosis and anaplasmosis".)
●Babesiosis – In the Northeastern and north-central United States and adjacent areas of Canada where Ixodes scapularis occurs, patients with an undifferentiated febrile illness from infection by Babesia microti may have organisms detectable in the red blood cells. Babesia can also be identified through PCR or serologic testing. (See "Babesiosis: Clinical manifestations and diagnosis".)
●Lyme disease – A minority of patients with early-stage Lyme disease have fever and constitutional symptoms without an observable localized skin rash. A positive enzyme-linked immunosorbent assay (ELISA) and a negative Western blot do not distinguish B. miyamotoi from early Lyme disease without a rash. In addition, antibodies to the GlpQ protein of B. miyamotoi would not be expected in cases of Lyme disease alone. (See "Diagnosis of Lyme disease" and 'Serology' above.)
●Ehrlichiosis – In the north-central United States, I. scapularis is a vector for an uncommon form of ehrlichiosis caused by Ehrlichia muris eauclairensis. In Mid-Atlantic and Northeastern states, the expanding range of the lone star tick, Amblyomma americanum, now overlaps that of I. scapularis. In this region in the absence of identification of the biting tick, an undifferentiated febrile illness in late spring and summer may be ehrlichiosis caused by E. chaffeensis, which was acquired from a bite of A. americanum.
●Soft tick relapsing fever – Other microorganisms (all transmitted by soft ticks) also produce illnesses with relapsing fevers in patients in North America. Soft ticks may bite humans in mountain cabins and at lower elevations in caves, but they are not a risk to humans during woodland exposures outside of homes or during outdoor work or recreation. The only United States region where B. miyamotoi and a relapsing fever agent, namely Borrelia hermsii, are known to coexist among the wildlife is the Sierra Nevada mountain range and its foothills. In the south-central United States, the range of A. americanun overlaps the range of the soft tick that transmits another soft tick relapsing fever species, B. turicatae. In general, the illnesses from soft tick relapsing fever agents are typified by higher elevations of body temperature, more marked constitutional symptoms, and a higher frequency of disease relapses than would be expected for either B. miyamotoi or B. lonestari infections in immunocompetent individuals.
Additional information on these infections is presented separately. (See "Clinical features, diagnosis, and management of relapsing fever" and "Human ehrlichiosis and anaplasmosis" and "Epidemiology, clinical manifestations, and diagnosis of Rocky Mountain spotted fever" and "Other spotted fever group rickettsial infections".)
Nontickborne illnesses, such as viral infections, should also be included in the differential diagnosis of B. miyamotoi infection. The presence of symptoms of an upper respiratory infection (sore throat, rhinorrhea) would point in the direction of a viral illness (eg, influenza, COVID-19, enterovirus infection) rather than B. miyamotoi. If there are acute onset symptoms and signs of meningoencephalitis in a person exposed to I. scapularis ticks, Powassan virus encephalitis is another consideration. (See "Seasonal influenza in adults: Clinical manifestations and diagnosis" and "Seasonal influenza in children: Clinical features and diagnosis" and "COVID-19: Clinical features" and "Enterovirus and parechovirus infections: Clinical features, laboratory diagnosis, treatment, and prevention".)
TREATMENT —
There is limited experience with the treatment of B. miyamotoi infection and even less for B. lonestari infection. It is likely that these organisms have similar antibiotic susceptibilities as other Borrelia species and Borreliella species [46], and the treatment of B. miyamotoi infection generally parallels recommendations for the treatment of Lyme disease [69]. (See "Treatment of Lyme disease".)
Approach for most patients
●Preferred regimen – We suggest doxycycline 100 mg twice a day for 14 days as initial presumptive therapy for most patients with suspected or possible B. miyamotoi infection. Doxycyline is also effective for anaplasmosis and Lyme disease, which usually cannot be excluded at the time of initial medical contact [48]. Although data are limited, observational studies suggest treatment shortens the duration of symptoms in patients with B. miyamotoi [1,11,48,70].
●Alternative regimens – The preferred oral alternative agent is a beta-lactam such as amoxicillin or cefuroxime [1,70]; we use the same regimens for all three antibiotics when to treating Lyme disease (table 1). Although one study suggested that certain strains of B. miyamotoi may be resistant to amoxicillin in vitro [71], there are insufficient data to change our treatment approach. However, oral penicillin V (phenoxymethylpenicillin) in an equivalent dose may be an alternative to amoxicillin [72].
A macrolide (eg, azithromycin or clarithromycin) may also be effective. However, macrolides are a less desirable option as they are considered second-line therapy for Lyme disease, and there is less clinical experience with the use of macrolides compared with doxycycline or beta-lactam antibiotics for the treatment of other Borrelia infections. (See "Treatment of Lyme disease" and "Clinical features, diagnosis, and management of relapsing fever", section on 'Treatment'.)
As with Lyme disease, antibiotics such as fluoroquinolones, aminoglycosides, and certain first-generation cephalosporins (eg, cephalexin), which may be used as empirical therapy for undifferentiated febrile illnesses, would not be expected to be effective treatment for either B. miyamotoi or B. lonestari.
Patients with central nervous system or severe disease — For individuals with central nervous system (CNS) disease (eg, meningoencephalitis) and for those hospitalized with severe disease, we suggest intravenous (IV) therapy with ceftriaxone (2 g daily). Data supporting this approach are based upon case reports and small case series [49,50,55]. For those who cannot take ceftriaxone, doxycycline (100 mg twice daily) is a reasonable alternative since this agent has been used for treatment of CNS Lyme disease.
There are no data to determine the duration of therapy in patients with CNS disease. We administer IV therapy for 14 to 28 days in immunocompetent patients and continue therapy for 28 days in immunocompromised individuals [49]. By contrast, patients without CNS disease can be transitioned to oral therapy, such as doxycycline, when clinically stable.
Response to therapy — Resolution of fever is expected within two to three days of initiating antibiotics in most individuals with B. miyamotoi infection [11]. However, on occasion, A Jarisch-Herxheimer (JH) reaction (a sudden worsening of symptoms, often with hypotension) may rarely occur after the first dose antibiotics [10,49]. Although these symptoms often resolve without intervention within approximately 24 hours, nonsteroidal anti-inflammatory drugs (NSAIDs) or other antipyretics can be used if symptoms arise due to JH reaction occur, and they may reduce the severity of symptoms and the duration of the reaction. More severe manifestations, such as hypotension or delirium, may require more intensive monitoring and support. The occurrence of a JH reaction should not lead to a change in antibiotics. A more detailed description of the JH reaction is found elsewhere. (See "Clinical features, diagnosis, and management of relapsing fever", section on 'Jarisch-Herxheimer reactions'.)
Obtaining convalescent serology for A. phagocytophilum, B. burgdorferi, and B. microti may also be helpful to clarify the diagnosis in retrospect, especially when the cause is unclear and/or the patient continues to have symptoms after receiving appropriate therapy. This approach is particularly useful in cases of suspected coinfection with babesiosis, as patients with babesiosis would not be expected to respond to antibiotics used to treat B. miyamotoi. (See "Babesiosis: Treatment and prevention".)
Additional information on the use of serologic testing to differentiate tickborne pathogens is found above. (See 'Differential diagnosis' above and 'Serology' above.)
SOCIETY GUIDELINE LINKS —
Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Tick-borne infections (including Lyme disease, ehrlichiosis, babesiosis, rickettsial infections, and others)".)
SUMMARY AND RECOMMENDATIONS
●Microbiology – Borrelia miyamotoi and Borrelia lonestari are zoonotic pathogens that belong to the genus Borrelia that also include the agents of louse-borne relapsing fever and soft tick relapsing fever. Each isolate has the genetic capacity for antigenic variation during infection, as occurs during relapsing fever. (See 'Microbiology' above.)
●Transmission – B. miyamotoi is transmitted by the same species of ticks (eg, Ixodes scapularis, Ixodes pacificus) that transmit Borrelia burgdorferi (the agent that causes Lyme disease) and other tickborne infections. (see 'Transmission' above). B. lonestari is transmitted by Amblyomma americanum.
●Epidemiology – The seasonal distribution of B. miyamotoi infection parallels the activity of the transmitting ticks. In the Northeastern and north-central United States, exposure is most commonly seen in the summer months but may extend into fall and winter months in California. The prevalence of B. miyamotoi in ticks generally ranges from 1 to 5 percent in areas such as North America and Eurasia. (See 'Epidemiology' above.)
●Clinical manifestations – B. miyamotoi can cause a nonspecific febrile illness that includes chills, sweats, headache, neck stiffness, fatigue, myalgias, and arthralgias. Some patients have had recurrences of fever similar to relapsing fever. (See 'Clinical manifestations' above and 'Differential diagnosis' above.)
Serious manifestations include meningitis or meningoencephalitis, sometimes accompanied by uveitis. Most of such cases have had acquired immunodeficiency as a consequence of immunosuppression, most commonly B-cell depletion by the therapeutic antibody rituximab. (See 'Immunocompromised patients' above.)
●Evaluation and diagnosis – B. miyamotoi should be considered in patients who present with a nonspecific febrile illness in areas where B. miyamotoi has been identified and if illness occurs during the appropriate season. (See 'When to suspect the diagnosis' above.)
Polymerase chain reaction (PCR) assay of the blood is the preferred test. This assay is commercially available at reference laboratories, and PCR assays that test for other tickborne pathogens may be able to be done simultaneously. (See 'Evaluation' above and 'Tests that detect the organism' above.)
Assays of convalescent serum for antibodies to the GlpQ may confirm a diagnosis in retrospect. (See 'Serology' above.)
●Differential diagnosis – Many features of B. miyamotoi infection are indistinguishable from other tickborne illnesses such as anaplasmosis, babesiosis, or early Lyme disease without rash. (See 'Differential diagnosis' above.)
●Treatment – For most patients with symptomatic, presumed or confirmed B. miyamotoi infection, we suggest treatment with doxycycline (Grade 2C). Treatment should be administered for 14 days. This agent also treats anaplasmosis and Lyme disease, which often cannot be excluded based on the initial evaluation. For individuals with contraindications to doxycycline, alternative oral agents include amoxicillin, cefuroxime, or phenoxymethylpenicillin. (See 'Approach for most patients' above.)
For those with central nervous system (CNS) involvement (eg, meningoencephalitis) and those with severe disease requiring hospitalization, we suggest initial therapy with treatment with intravenous (IV) ceftriaxone (Grade 2C). For those who have a contraindication to ceftriaxone, doxycycline is a reasonable alternative. (See 'Patients with central nervous system or severe disease' above.)
●Response to therapy – Resolution of fever typically occurs within two to three days after initiating antibiotics. On occasion, a mild to moderate Jarisch-Herxheimer (JH) reaction (a sudden worsening of symptoms) may occur after the first dose of antibiotics. (See 'Response to therapy' above.)
