History
The first case reports of human infection with Neoehrlichia mikurensis were published in 2010 from Sweden, Switzerland and Germany (Welinder-Olsson et al; Fehr et al, von Loewenich et al). Prior to this, this bacterial species had been detected in ticks and wild rodents in the Netherlands and Norway but given other names. Its current name, Neoehrlichia mikurensis, is the result of work by Japanese scientists who characterized this species isolated from rats on the island of Mikura and chose to name it “Candidatus Neoehrlichia mikurensis” (Kawahara, 2004). The prefix Candidatus is given to bacterial species that have been identified by DNA sequencing but not by cultivation. “Candidatus” was abandoned after the bacteria were cultivated and propagated in tick cell lines and human endothelial cell lines in 2019 (Wass, 2019). The bacterial species is now referred to as Neoehrlichia mikurensis.
Clinical features
The first comprehensive description of the clinical features of human infection with N. mikurensis was published in 2014 (Grankvist, 2014). The infectious disease was named neoehrlichiosis and typical cases feature fever with chills and sweats, localized pain engaging muscles, and thromboembolic vascular events, notably deep vein thrombosis. Most patients diagnosed with neoehrlichiosis have been immunocompromised, which has led to the erroneous assumption that this is an opportunistic infection only affecting patients with reduced immune defenses. Although it is true that patients with compromised B-cell immunity risk developing more severe symptoms of infection, people with normal immune defenses can also become sick. However, it is individuals with risk factors for severe neoehrlichiosis, e.g., malignant B-cell lymphomas, autoimmune rheumatological and neurological diseases treated with B-cell suppressive mediation, that are likely to be tested for N. mikurensis. The reason being that the molecular methods for detection of N. mikurensis are only available at a few specialized reference laboratories in Europe. Another explanation for the underdiagnosis of neoehrlichiosis is that infected individuals with normal immunity may present with non-specific symptoms such as fatigue, headache, and reduced physical fitness, or specific findings such as swollen ankles, sudden deafness or arterial vasculitis (inflamed arteries), which in the absence of fever may not raise the suspicion of an underlying infection (Wennerås, 2024).
Biology of the infectious agent and its vector
N. mikurensis is a member of the genus Neoehrlichia, which belongs to the family Anaplasmataceae. The bacteria are parasitic in the sense that they depend on eukaryotic host cells for their intracellular lifestyle. They can survive, grow and replicate in tick cell lines and human endothelial cell lines. The endothelial cells of blood vessels are probably the target of human infection, which probably accounts for the vascular damage and thromboembolic events associated with this infection (Wass, 2019). The immune response to the bacteria is also likely to have a role in the development of the vascular events since the veins are afflicted in patients with reduced B-cell immunity, whereas it is the arteries that are targeted in the individuals with normal immunity (Höper, 2022). Intriguingly, no cases of N. mikurensis infection have been described in children, not even in immunocompromised children residing in N. mikurensis-endemic regions.
N. mikurensis infection is transmitted by tick bites of the Ixodes ricinus species complex. The infection is present in large parts of Europe and northern Asia but apparently absent from the American continent. Voles are the reservoir of the infection. The incubation period of the infection after a tick bite is unknown and may be irrelevant as multiple reports indicate long-term asymptomatic carriage of the infection by healthy human beings. This suggests that N. mikurensis may cause persistent latent infections that can reactivate (become symptomatic) under certain conditions, e.g., compromised immunity after start of immunosuppressive therapy to treat an autoimmune or malignant disease. Another possible means of transmission of N. mikurensis infection is blood transfusion, although there is no solid evidence of this yet. However, bacterial DNA has been detected in apparently asymptomatic blood donors although it has not been possible to determine if this has resulted in transmission of the infection (Labbe, 2022).
Diagnosis
It is challenging to diagnose infections with N. mikurensis because it escapes detection by routine microbiologic methods such as blood culture. Moreover, there are no serologic methods available for antibody-based diagnosis. Although the clinical picture of neoehrlichiosis in immunocompromised patients is more easily recognizable as an infection due to the almost universal presence of fever, clinicians can be led astray by negative results from extensive microbiologic diagnostic investigations and conclude that the condition is non-infectious (Grankvist, 2014). Today, the recommended diagnostic procedure is analysis of EDTA-blood for N. mikurensis either by specific PCR or 16S rRNA PCR followed by DNA sequencing.
Treatment
Oral doxycycline in the dose 100 mg twice daily for three weeks. Oral rifampin may be considered as an alternative for individuals who do not tolerate doxycycline.
Risk management
It is unknown if rapid removal of an attached tick can decrease the risk of transmission of N. mikurensis infection. The best way to avoid infection is to take general preventative measures against tick exposure such as wearing covering clothes, checking for ticks and removing attached ticks.
References
Welinder-Olsson C, Kjellin E, Vaht K, et al. First case of human “Candidatus Neoehrlichia mikurensis infection in a febrile patient with chronic lymphocytic leukemia. J Clin Microbiol. 2010; 48(5):1956-9.
Fehr J, Bloemberg G, Ritter C, et al. Septicemia caused by tick-borne bacterial pathogen Candidatus Neoehrlichia mikurensis. Emerg Infect Dis 2010; 16(7):1127-9.
Von Loewenich F, Geissdörfer W, Disqué C, et al. Detection of “Candidatus Neoehrlichia mikurensis” in two patients with severe febrile illnesses: evidence for a European sequence variant. J Clin Microbiol. 2010; 48(7):2630-5.
Kawahara M, Rikihisa Y, Isogai E, et al. Ultrastructure and phylogenetic analysis of “Candidatus Neoehrlichia mikurensis in the family Anaplasmataceae isolated from wild rats and found in Ixodes ovatus ticks. Int J Syst Evol Microbiol 2004; 54:1837-43.
Grankvist A, Andersson PO, Mattsson M, et al. Infections with the tick-borne bacterium “Candidatus Neoehrlichia mikurensis” mimic noninfectious conditions in patients with B-cell malignancies or autoimmune diseases. Clin Infect Dis. 2014; 58(12):1716-22.
Wennerås C, Wass L, Bergström B, et al. Ten years of detecting Neoehrlichia mikurensis infections in Sweden: demographic, clinical and inflammatory parameters. Eur J Clin Microbiol Infect Dis. 2024; 43(11):2083-92.
Wass L, Grankvist A, Bell-Sakyi L, et al. Cultivation of the causative agent of human neoehrlichiosis from clinical isolates identifies vascular endothelium as a target of infection. Emerg Microbes Infect. 2019; 8(1):413-25.
Höper L, Skoog E, Stenson M, et al. Vasculitis due to Candidatus Neoehrlichia mikurensis: a cohort study of 40 Swedish patients. Clin Infect Dis. 2021; 73(7):e2372-8.
Labbé Sandelin L, Olofsson J, Tolf C, et al. Detection of Neoehrlichia mikurensis DNA in blood donors in southeastern Sweden. Infect Dis (Lond). 2022;54(10):748-59.