European tick-borne diseases information resource

ESCMID Study Group for Tick-Borne Diseases – ESGBOR

Borrelia miyamotoi disease

History
Borrelia miyamotoi is related to the relapsing fever borreliae and was first described from Ixodes persulcatus ticks collected in Japan (Fukunaga et al., 1995). A relapsing fever-like borrelia was subsequently found in the North American tick, Ixodes scapularis (Scoles et al., 2001) and since then similar spirochaetes have been reported from over a wide geographical area in Eurasia and North America. At the time of writing these spirochaetes are all considered to be variants of B. miyamotoi.
Initially, the main significance of B. miyamotoi appeared to be that it is transmitted by the same tick species that are vectors of the Lyme borreliosis (LB) agent, B. burgdorferi sensu lato (s.l.), though with a markedly lower tick infection prevalence, but that unlike the LB borreliae, significant transovarial transmission occurs and also, similar to relapsing fever borrelias, B. miyamotoi can be observed in blood. Mistaken identity therefore almost certainly explains early reports of B. burgdorferi s.l. transovarial transmission in ticks and occurrence in blood smears from tick-exposed laboratory mice (Stanek et al., 1986), and also B. burgdorferi s.l.-infection prevalences in field-collected I. ricinus larvae as high as 21.0% (Rijpkema et al., 1994).
The first indication that B. miyamotoi may be pathogenic was a report in 2011 of an influenza-like illness in hospitalized Russian patients, who responded satisfactorily to treatment with ceftriaxone or doxycycline (Platonov et al., 2011). North American cases were first reported in 2013 and in one of these, an elderly and immunocompromised patient, the disease manifested as meningoencephalitis with spirochaetes demonstrable in the spinal fluid (Gugliotta et al., 2013). The first case in western Europe occurred in the Netherlands, also manifesting as meningencephalitis in an immunocompromised patient and having demonstrable spirochaetes in the spinal fluid (Hovius et al., 2013). Since then, similar cases of meningoencephalitis in immunocompromised patients have been reported from Germany and Sweden (Boden et al., 2016 and Henningsson et al., 2019), but also one case of subacute meningitis in an apparently immunocompetent individual (Henningsson et al., 2019). B. miyamotoi infection has also been reported in an immunocompetent Dutch patient presenting with fever, myalgia and an erythematous skin lesion but no signs of meningitis (Hoornstra et al., 2018). All of these cases resolved after treatment with antibiotics, i.e. doxycycline or ceftriaxone.
At present, clinical disease resulting from infection with B. miyamotoi is considered to be very rare, though case rates may rise with increased awareness and improved diagnostic tests.

Clinical features
Most clinical cases have presented with fever a few weeks after the tick bite, and showed general symptoms such as mild fever, headache, fatigue and myalgia, though several American patients had concurrent LB or babesiosis infections, which may have complicated the presentation. In  four cases in immunocompromised patients, one American (Gugliotta et al., 2013),  one Dutch (Hovius et al., 2013), one German (Boden et al., 2016) and one Swedish (Henningsson et al., 2019) the infection manifested as meningoencephalitis with or without fever episodes, with slow cognitive processing, memory deficits and a disturbed gait that developed slowly over a period of months. All patients had been treated with rituximab – a B cell depletor that can interfere with antibody responses.  Serology for B. burgdorferi s.l. was typically negative or showed only weak reactivity while B. miyamotoi DNA could be detected in cerebrospinal fluid (CSF) and blood by panbacterial 16S rRNA PCR or PCR targeting the flaB, GlpQ or p66 genes with subsequent sequencing of the amplicons. The B cell-attracting chemokine CXCL13 was analysed in CSF from two of the cases and was found to be clearly elevated.    Motile spirochaetes were observed in pre-treatment CSF  from three of the patients, however culture attempts in MKP-F or BSK medium were futile.  Considering that the organism is widespread in ticks in Europe, transmission to humans is probably not uncommon. However, most infections are probably only mildly symptomatic or asymptomatic, though some may occasionally lead to an acute febrile illness, and immunocompromised individuals can develop more severe symptoms. Thus, although there are some similarities with LB, B. miyamotoi-induced disease appears to be a distinct clinical entity.

Biology of the infectious agent
The original organism identified in Japan was designated B. miyamotoi sensu stricto and related organisms in America and Eurasia as B. miyamotoi sensu lato. So far this classification stands, though it is evident that distinct genotypes exist in these three geographical regions (Barbour et al., 2014). This spirochete is present in Ixodes ticks across the Northern Hemisphere where it co-circulates with B. burgdorferi s.l., although at a lower frequency (Cutler et al., 2019).
The limited studies carried out on B. miyamotoi so far suggest that it can be transmitted both transstadially and transovarially, so that all tick stages are potential vectors.  Little is known about where in the unfed infected tick the spirochaetes reside or about the transmission process, but emerging evidence supports the presence of  B. miyamotoi  in the tick salivary glands and a more rapid transmission to the vertebrate host than is described for B. burgdorferi s.l. (Cutler et al., 2019). The reservoir hosts of B. miyamotoi have yet to be definitively identified, but in Europe small rodents have been incriminated as reservoirs by xenodiagnosis (Burri et al., 2014).

Diagnosis
There is no pathognomonic symptom for infection with B. miyamotoi. Fever is probably a common feature in immunocompetent individuals, but was not present in  all immunocompromised cases (Gugliotta et al., 2013; Hovius et al., 2013). Other reported nonspecific symptoms include headache, neck stiffness, fatigue, myalgias, arthralgias, abdominal pain, cough, and sore throat, and in cases of invasion of the central nervous system,  cognitive and co-ordination dysfunction. Recurrent fever has been reported from 10% of American and Russian cases, but this feature is quite different from classic tick-borne relapsing fever, caused by several Borrelia spp. and transmitted by soft ticks. This infection is much more severe and is characterized by episodes of high fever followed by hypotension and diaphoresis (Telford et al., 2015).
Most cases of B. miyamotoi disease identified so far have been diagnosed with the use of molecular methods after failure to detect other tick-borne pathogens such as B. burgdorferi s.l. and Anaplasma phagocytophilum. In the absence of cultures of American and Eurasian strains of B. miyamotoi, some retrospective serological studies have been conducted with the GlpQ protein (an antigen that occurs in B. miyamotoi and is also expressed by other bacteria but is nonreactive to anti-B. burgdorferi s.l. antibody) (Krause et al., 2013). Although strains of B. miyamotoi in addition to the original Japanese HT31can now be cultured (Margos et al., 2015; Wagemakers et al., 2014) no validated serological tests are  yet commercially available for clinical use. . However, variable major proteins have been identified as potential antigen targets (Wagemakers et al., 2016; Koetsveld et al., 2018).

Treatment
The few cases that have been identified so far have responded favourably to 2-week courses of cephalosporin or doxycycline antibiotics.

Risk management
The same preventative measures against most other pathogens transmitted by ticks of the I. ricinus species complex apply, i.e. wearing of appropriate protective clothing, application of repellents, examination of skin as soon as possible after potential tick exposure, prompt removal of attached ticks. The main significance of the infection may be in providing an alternative explanation for (acute) illness in cases initially presumed to be Lyme borreliosis or human granulocytic anaplasmosis, and diagnosing physicians should be aware of this possibility.

References

  1. Barbour AG. 2014. Phylogeny of a relapsing fever Borrelia species transmitted by the hard tick Ixodes scapularis. Infect Genet Evol. S1567-1348(14)00157-9.
  2. Boden K, Lobenstein S, Hermann B, Margos G, Fingerle V. 2016. Borrelia miyamotoi-associated neuroborreliosis in immunocompromised person. Emerg Infect Dis. 22:1617-20.
  3. Burri C, Schumann O, Schumann C, Gern L. 2014. Are Apodemus spp. mice and Myodes glareolus reservoirs for Borrelia miyamotoi, Candidatus Neoehrlichia mikurensis, Rickettsia helvetica, R. monacensis and Anaplasma phagocytophilum? Ticks Tick Borne Dis. 5(3):245-51.
  4. Cutler S, Vayssier-Taussat M, Estrada-Peña A, Potkonjak A, Mihalca AD, Zeller H. 2019. A new Borrelia on the block: Borrelia miyamotoi – a human health risk? Euro Surveill. 24(18):pii=1800170.
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  7. Henningsson AJ, Asgeirsson H, Hammas B, Karlsson E, Parke Å, Hoornstra D, Wilhelmsson P, Hovius JW. 2019. Two cases of Borrelia miyamotoi meningitis, Sweden, 2018. Emerg Infect Dis. 25(10):1965-8.
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  9. Hovius JW, de Wever B, Sohne M, Brouwer MC, Coumou J, Wagemakers A, Oei A, Knol H, Narasimhan S, Hodiamont CJ, Jahfari S, Pals ST, Horlings HM, Fikrig E, Sprong H, van Oers MH. 2013. A case of meningoencephalitis by the relapsing fever spirochaete Borrelia miyamotoi in Europe. Lancet. 382(9892):658. doi: 10.1016/S0140-6736(13)61644-X.
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  13. Platonov AE, Karan LS, Kolyasnikova NM, Makhneva NA, Toporkova MG, Maleev VV, Fish D, Krause PJ. 2011. Humans infected with relapsing fever spirochete Borrelia miyamotoi, Russia. Emerg Infect Dis.17(10):1816-23.
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