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Borrelia miyamotoi infection

Borrelia miyamotoi infection
Author:
Alan G Barbour, MD
Section Editor:
Daniel J Sexton, MD
Deputy Editor:
Keri K Hall, MD, MS
Literature review current through: Jan 2024.
This topic last updated: Apr 07, 2022.

INTRODUCTION — Borrelia miyamotoi is a zoonotic pathogen that is transmitted by the same genus of ticks (ie, Ixodes) that transmits Borreliella burgdorferi (the agent that causes Lyme disease), Anaplasma phagocytophilum, Babesia species, and tickborne flaviviruses [1-3]. B. miyamotoi is in the same taxonomic group as agents of relapsing fever, such as Borrelia hermsii and Borrelia recurrentis. In a large majority of patients, it causes an acute febrile illness during the summer. The symptomatic infection is most commonly called "Borrelia miyamotoi disease"; it is also known as "hard tickborne relapsing fever" [4,5].

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 belongs to the spirochete genus Borrelia, which also includes the agents of tickborne and louse-borne relapsing fever. (See "Microbiology, pathogenesis, and epidemiology of relapsing fever".)

There are substantial genetic differences between strains of B. miyamotoi obtained from different tick species or human cases in different geographic areas. This finding is based upon genetic analysis of organisms from a variety of areas, including Asia, Europe, and eastern and western North America [6,7]. However, B. miyamotoi isolates from within the same geographic area or that share the same tick species association are nearly identical in their sequences [7-10].

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 [4,11] and could potentially limit immunity against reinfection. (See 'Clinical manifestations' below.)

The original isolate of B. miyamotoi was cultured in media used for other species of Borrelia [12,13], but success of in vitro cultivation varied by laboratory. There are now improved medium formulations to help isolate the organism [14-16]. A discussion on how to diagnose B. miyamotoi infection is found below. (See 'Tests that detect the organism' below.)

TRANSMISSION — B. miyamotoi has been found in some of the same small mammal reservoirs and tick vectors as the Borreliella species that cause Lyme disease in North America, Europe, and Asia. The natural reservoirs for B. miyamotoi include the white-footed mouse (Peromyscus leucopus) in eastern North America [17] and other small rodents in Asia and Europe [18,19]. Birds may also serve as natural hosts for B. miyamotoi [20]. (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 and not the soft ticks that transmit the Borrelia agents of relapsing fever. The organism was first identified in Ixodes persulcatus (the "taiga tick") in Japan in 1994 [12]. This tick is also the vector for Borreliella species and tickborne encephalitis virus as well as B. miyamotoi in other parts of east and north Asia and Russian Siberia [6,11,12]. B. miyamotoi was subsequently associated with other Ixodes species ticks that transmit Lyme disease; these include:

Ixodes scapularis (commonly known as the "deer tick" or "blacklegged tick") in northeastern and north-central United States and adjacent areas of Canada [21]

Ixodes pacificus ("western blacklegged tick") in far-western North America [22]

Ixodes ricinus (the "sheep tick") in Europe and western Russia [23,24]

I. persulcatus (the "taiga tick") in eastern Russia and northern Asia [10,11]

Ixodes ovatus in Japan and China [25]

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 [26]; 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 [27,28]. 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. 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 [29]. (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 [30]. 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.

EPIDEMIOLOGY

Prevalence — The prevalence of B. miyamotoi in five different species of Ixodes ticks ranges from 1 to 5 percent in areas such as North America and Eurasia [9,11,12,17,22,31-33]. In comparison, the prevalences 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 [34,35].

Studies of humans have described the frequency of B. miyamotoi infection among patients with suspected tickborne disease or the prevalence of antibodies to B. miyamotoi in serosurveys of individuals from different geographic areas [4,36-42]. Representative studies include:

United States

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 [4]. The survey screened specimens for the presence of B. miyamotoi, A. phagocytophilum, and B. microti. 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 years, 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.

In a multiplexed PCR study that included 7292 specimens submitted by providers to reference laboratories for suspected tickborne disease, B. miyamotoi was identified in the blood in 8 specimens (0.1 percent), while 34 specimens had a Lyme disease agent (either B. burgdorferi or B. mayonii), and 2 had a relapsing fever agent [40].

In a PCR study of 796 blood samples from patients with suspected tickborne disease in New York State, only 8 (1 percent) had detectable B. miyamotoi compared with 216 (27 percent) that had A. phagocytophilum [43].

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 [37]. 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.

In another serosurvey, archived sera were examined using B. miyamotoi GlpQ enzyme-linked immunosorbent assay (ELISA) and Western blot assays [38]. The seroprevalence was 4 percent for 639 healthy individuals in Rhode Island or Massachusetts and 10 percent of 194 patients with early-stage Lyme disease in Connecticut, Massachusetts, New York, or Rhode Island. None of 300 sera from healthy blood donors in Arizona or Florida were seropositive by both assays.

A third serosurvey was carried out on 1153 blood samples obtained in 2018 from five New England states [44]. The samples had been submitted for medical testing for reasons other than suspected tickborne disease. In this study, the overall prevalence of antibodies to B. miyamotoi was 2.8 percent, compared to a prevalence of 11 percent for antibodies to B. burgdorferi in the same samples.

In contrast, a seroprevalence study of 1700 blood donor sera from areas of high and low Lyme disease risk in California identified two (0.12 percent) individuals with antibodies specific for a Borrelia species, either B. miyamotoi or a relapsing fever agent. Among the same serum collection, there were eight (0.47 percent) individuals with antibodies to B. burgdorferi [41]. However, by the end of 2021, there were no documented cases of B. miyamotoi infection acquired in California.

Europe

In the Netherlands, a B. miyamotoi GlpQ bead-based immunoassay was used to examine sera from 120 forestry workers who had a high exposure to tick bites and a random sampling of 150 blood donors [39]. The seroprevalence was 10 percent among the forestry workers and 2 percent among the blood donors (odds ratio 5.4; 95% CI 1.5-20).

In Austria, a PCR study of 489 people bitten by 1295 I. ricinus ticks over a four-year period found the prevalence of B. burgdorferi species and B. miyamotoi in ticks to be 15 and 2 percent, respectively [36].

Seasonal distribution — The seasonal distribution of B. miyamotoi infection parallels the activity of the transmitting ticks. In the northeastern and north-central United States, Europe, and Japan, tick exposure is most commonly seen in the late spring and summer months. 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 with other pathogens — Although I. scapularis with B. miyamotoi in the northeastern United States frequently also bear B. burgdorferi [29], 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 [3]. 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 [4].

CLINICAL MANIFESTATIONS — The clinical manifestations of B. miyamotoi infection have been described in several reports [4,11,37,38,45-48]. Most reported cases are in adults, but B. miyamotoi infection has been documented in children as well.

Incubation time — The time between tick bite and symptom onset can range from 3 to 40 days [49]. In a series of 46 cases from Russia, symptoms developed 12 to 16 days after the tick bite [11].

Immunocompetent patients — Many instances of B. miyamotoi infection are minimally symptomatic or asymptomatic and, as such, never come to clinical attention [3]. In the study from Austria described above, one person who had been bitten by an Ixodes tick had B. miyamotoi detected in the blood by polymerase chain reaction (PCR) but remained asymptomatic [36].

For those with symptoms, B. miyamotoi can cause a nonspecific febrile illness that includes chills, sweats, moderate-to-severe headache, neck stiffness, fatigue, myalgias, and arthralgias [4]. Patients may defervesce in the absence of antibiotics; however, relapses in this setting have been reported [4]. The clinical manifestations may vary if coinfection with another pathogen is present. Some patients may also have vomiting.

Less-common findings include abdominal pain, lymphadenopathy, recurrence of fever, and/or neurocognitive and gait abnormalities [1,4,11,45]. Meningoencephalitis has been reported in immunocompetent patients [50], although it is more likely to occur in those who are immunocompromised. (See 'Immunocompromised patients' below.)

There is no evidence that B. miyamotoi can cause persistent infection or have chronic sequelae in immunocompetent hosts. This is based upon clinical observations of patients with B. miyamotoi, as well as the natural history of individuals who are infected with the closely related organisms that cause relapsing fever. (See 'When to suspect the diagnosis' below.)

There have been several reports describing the clinical manifestations of B. miyamotoi infection [4,11,37,38,45-48]. In a retrospective study that evaluated 51 patients with fever and evidence of B. miyamotoi diagnosed using PCR testing of the blood [4], 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 [49], 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.

Immunocompromised patients — Immunocompromised patients may have more severe disease since the clinical manifestations depend, in part, upon the immune status of the host [3]. As an example, like Borrelia species that cause relapsing fever, B. miyamotoi has the capacity to invade the central nervous system (CNS). Individuals who are immunosuppressed may be at greater risk for developing neurologic signs and symptoms (eg, meningoencephalitis) compared with immunocompetent hosts.

Many of the immunocompromised patients with B. miyamotoi infection have had acquired immunodeficiency as a consequence of B-cell depletion by the therapeutic antibody rituximab. As an example, 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 [46], and a 70-year-old man who was in remission from non-Hodgkin lymphoma in the Netherlands [47]. Each patient had received the B-cell-depleting therapeutic antibody 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 penicillin G for 30 days or ceftriaxone for 14 days.

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, garbled speech, and vision changes (the latter attributable to uveitis) [51]. 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 intravenous ceftriaxone followed by doxycycline.

Of two cases of B. miyamotoi meningoencephalitis or meningitis in Sweden, one was 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 [50]. The second patient had otherwise been healthy, without evidence of immunodeficiency, and presented with fever, headache, and stiff neck for one week. Both patients had increased white cells with mononuclear predominance, elevated protein, and elevated levels of the chemokine CXCL13 in the CSF. The diagnoses were confirmed by PCR of the CSF. Both patients improved with antibiotics. (See 'Treatment' below.)

Laboratory findings

Routine laboratories – Patients with B. miyamotoi infection commonly have laboratory studies that reveal leukopenia, thrombocytopenia, and/or mildly elevated transaminase levels [4].

B. miyamotoi was identified through PCR testing of blood samples in two previously healthy patients who presented with acute onset of fever and constitutional symptoms [45]; each was initially thought to have anaplasmosis because of thrombocytopenia, relative leukopenia, and abnormal liver tests.

On Long Island, New York, where 3 to 5 percent of I. scapularis ticks were infected with B. miyamotoi, a retrospective study of 5 years of results from 8575 PCR assays for suspected tickborne infection revealed 17 (0.2 percent) PCR-positive cases of B. miyamotoi [52]. This was approximately the same frequency as positive PCR assays for each of three other infections transmitted by ticks in the area (A. phagocytophilum, Babesia species, and Ehrlichia species). Common symptoms of B. miyamotoi infection were fever, fatigue, arthralgias, and myalgias. The majority had mildly elevated liver transaminases, and about half had leukopenia and/or thrombocytopenia.

CSF findings – In patients with meningoencephalitis, the CSF can reveal an elevated white blood cell count (with a lymphocyte predominance) and an elevated protein concentration [46,47].

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 are from an area where B. miyamotoi has been previously identified and the illness occurs while ticks are active (eg, late spring and summer in the northeastern and north-central United States or in Europe). The patient does not need to have a history of a tick bite to consider the diagnosis, since tick bites often go undetected. (See 'Transmission' above.)

In some patients (eg, those who present with severe disease), empiric antibiotics are reasonable pending the results of the initial evaluation. (See 'Evaluation' below and 'Treatment' below.)

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 cases of infection with B. miyamotoi alone [53] 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. (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 [4,11,46]. The CSF but not the blood can be frozen. 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 [17,54].

PCR testing is most likely to be positive during the first week of the illness [55]. 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 [4]. PCR assays also detect B. miyamotoi in serum samples [54], but 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 Borrelia 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 [56]. It may only reveal spirochetes in cases with pre-existing immunodeficiency and remitting disease course. Peak numbers of B. miyamotoi spirochetes in the blood of most cases are lower than what occurs during febrile episodes of relapsing fever [4,57]. (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 [46].

Culture – Culturing the organism from a clinical specimen in a broth medium is feasible, but the complex medium is only available in few places [46].

Serology — Serologic testing using a GlpQ-based ELISA, bead assay, or immunoblot can be performed to diagnose B. miyamotoi infection [1,58]. 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, are most useful for retrospectively confirming a diagnosis.

The overall sensitivity of the GlpQ is 60 to 80 percent with sera from convalescent cases [3,4]. A GlpQ protein is not made by the spirochete species that cause Lyme disease [59], but it is produced by some other types of bacteria such as Haemophilus influenzae. In addition, there is cross-reactivity among the highly similar GlpQ proteins of different relapsing fever species [60]. This can lead to positive reactions among those exposed to Borrelia species that cause tickborne relapsing fever, such as individuals in western North America. (See "Clinical features, diagnosis, and management of relapsing fever", section on 'Diagnosis'.)

In populations at low risk of tick bites, there is a background of positive GlpQ assay reactions of 1 to 5 percent that is unaccounted for [41,61].

There is no established Western blot assay for B. miyamotoi infection using whole cells. Immunoassays that are in development add one or more antigens to GlpQ; these include a selection of variable major proteins, which B. miyamotoi has in common with relapsing fever agents [58]. (See 'Differential diagnosis' below.)

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, and whole cell-based ELISA assays used to diagnose Lyme disease [4,38,53,62,63]. 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".)

DIFFERENTIAL DIAGNOSIS — Many of the clinical signs and symptoms of B. miyamotoi are of an acute undifferentiated febrile illness and are indistinguishable from other tickborne illnesses, such as anaplasmosis, babesiosis, ehrlichiosis, or early Lyme disease without rash. (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 not invariably present, one clinical feature that points to B. miyamotoi as the etiology is a relapse of the fever and other constitutional symptoms a few days after recovery from an earlier febrile episode. The initial fever may have been attributed to a virus and went untreated. In addition, there are other laboratory and diagnostic findings that may suggest one diagnosis over the other:

Anaplasmosis – A relative leukopenia and/or thrombocytopenia commonly occur in both anaplasmosis and B. miyamotoi infection; however, patients with anaplasmosis are more likely to have marked elevations in their aminotransaminase levels. In addition, evaluation of a blood smear reveals intracellular organisms in the white blood cells of a patient with anaplasmosis, whereas extracellular spirochetes are seen in those with B. miyamotoi. 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 – Unlike individuals with B. miyamotoi infection, symptomatic patients with babesiosis are likely to present with evidence of hemolysis such as anemia and indirect hyperbilirubinemia. In addition, patients with Babesia 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 Lyme test that reveals a positive enzyme-linked immunosorbent assay (ELISA) and a negative Western blot does not distinguish B. miyamotoi from early Lyme disease without a rash. A convalescent IgG Western blot for B. burgdorferi obtained four to six weeks after the patient’s initial presentation may suggest the cause of infection. In addition, antibodies to the GlpQ protein of B. miyamotoi would not be expected in cases of Lyme disease alone. However, serology is less reliable if appropriate antimicrobial therapy was administered early in the illness. (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 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 the bite of A. americanum.

Other tickborne infections to consider include infection with a spotted fever group rickettsial species (eg, Rickettsia rickettsii or Rickettsia parkerii) and relapsing fever; however, these diseases are transmitted by different types of ticks. Rocky Mountain spotted fever is most frequent in the south-central United States, an area where Lyme disease is uncommon, and is transmitted by Dermacentor species that are easily distinguishable from Ixodes ticks. (See "Clinical manifestations and diagnosis of Rocky Mountain spotted fever" and "Other spotted fever group rickettsial infections".)

Relapsing fever agents in North America are transmitted by soft ticks. These are encountered in mountain cabins and at lower elevations in caves, not from woodland exposures outside of homes or during outdoor work or recreation. The only United States region where B. miyamotoi and a relapsing fever agent are known to coexist among the wildlife is the Sierra Nevada mountain range and its foothills. Microscopic examination of stained smears of blood is typically used to diagnose relapsing fever. Additional information on these infections is presented separately. (See "Clinical features, diagnosis, and management of relapsing fever" and "Human ehrlichiosis and anaplasmosis" and "Clinical manifestations and diagnosis of Rocky Mountain spotted fever".)

Non-tickborne 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. It is likely that the organism has similar antibiotic susceptibilities as other Borrelia species [3], and the treatment of B. miyamotoi infection generally parallels recommendations for the treatment of Lyme disease. (See "Treatment of Lyme disease".)

Approach for most patients

Preferred regimen – For most patients with B. miyamotoi infection, we suggest doxycycline 100 mg twice a day for 14 days as initial therapy. This agent also treats anaplasmosis and Lyme disease, which often cannot be excluded during the initial evaluation [45]. Although data are limited, observational studies suggest treatment shortens the duration of symptoms in patients with B. miyamotoi and may reduce the risk of developing severe disease [1,2,4,45].

Alternative regimens – In some patients (eg, pregnant persons or children younger than eight years of age), doxycycline is avoided if there is a reasonable alternative. (See "Treatment of Lyme disease", section on 'Pregnancy' and "Treatment of Lyme disease", section on 'Children <8 years old'.)

The preferred oral alternative agent is a beta-lactam antibiotic such as amoxicillin and cefuroxime [1,2]; we use the same regimens as those used to treat Lyme disease (table 1). Although one study suggested that certain strains of B. miyamotoi may be resistant to amoxicillin in vitro [64], there are insufficient data to change our treatment approach. However, oral penicillin V (phenoxymethylpenicillin) in an equivalent dose may be an alternative to amoxicillin [65].

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 much 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 B. miyamotoi.

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 [46,47,51]. 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 [46]. By contrast, patients without CNS disease can be transitioned to oral therapy, such as doxycycline, when clinically stable.

Response to therapy — For most individuals with B. miyamotoi, resolution of fever is expected within two to three days of initiating antibiotics [4]. However, on occasion, a Jarisch-Herxheimer reaction (a sudden worsening of symptoms, often with hypotension) may occur after the first dose or two of antibiotics [11,46]. 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, and they may reduce the severity of symptoms and the duration of the reaction. The occurrence of a Jarisch-Herxheimer reaction should not lead to a change in antibiotics. A more detailed description of the Jarisch-Herxheimer reaction is found elsewhere. (See "Clinical features, diagnosis, and management of relapsing fever", section on 'Jarisch-Herxheimer reactions'.)

Since the diagnosis of B. miyamotoi infection can be empiric, a convalescent serum can reveal antibodies to GlpQ, or the C6 peptide of a common Lyme disease assay, which were not present in an acute serum. However, this antibody response may not be seen in patients who were treated early in the course of disease. (See 'Serology' above.)

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 (Lyme disease, ehrlichiosis, anaplasmosis, babesiosis, and Rocky Mountain spotted fever)".)

SUMMARY AND RECOMMENDATIONS

MicrobiologyBorrelia miyamotoi is a zoonotic pathogen that belongs to a group of Borrelia species that includes the agents of relapsing fever. Each isolate has the genetic capacity for antigenic variation during infection, as occurs during relapsing fever. (See 'Microbiology' above.)

TransmissionB. 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.)

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 manifestationsB. 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 diagnosisB. 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 reaction (a sudden worsening of symptoms) may occur after the first dose or two of antibiotics. (See 'Response to therapy' above.)

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Topic 101368 Version 17.0

References

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