Neoehrlichia mikurensis Causing Thrombosis and Relapsing Fever in a Lymphoma Patient Receiving Rituximab

Neoehrlichia (N.) mikurensis, an intracellular tick-borne bacterium not detected by routine blood culture, is prevalent in ticks in Scandinavia, Central Europe and Northern Asia, and may cause long-standing fever, nightly sweats, migrating pain, skin rashes and thromboembolism, especially in patients treated with rituximab. The multiple symptoms may raise suspicion of both infection, inflammation and malignancy, and lead in most cases to extensive medical investigations across many medical specialist areas and a delay of diagnosis. We describe a complex, albeit typical, case of neoehrlichiosis in a middle-aged splenectomised male patient with a malignant lymphoma, receiving treatment with rituximab. The multifaceted clinical picture associated with this tick-borne disease is addressed, and longitudinal clinical and laboratory data, as well as imaging, are provided. Longstanding relapsing fever in combination with thrombosis in superficial and deep veins in an immunocompromised patient living in a tick-endemic region should raise the suspicion of the emerging tick-borne disease neoehrlichiosis. Given the varied clinical presentation and the risk of delay in diagnosis and treatment, we believe it is important to raise clinicians’ awareness of this emerging infection, which is successfully treated with doxycycline.

Case report: first symptomatic Candidatus Neoehrlichia mikurensis infection in Slovenia

Background Candidatus Neoehrlichia mikurensis (CNM) is an emerging tick-born pathogen and usually causes symptomatic infection only in immunocompromised patients. Apart from one described case found in the literature where cultivation was successful, all cases so far were diagnosed by using broad-range 16S rDNA PCR. Case presentation Our patient presented with a prolonged febrile state of unknown origin. Clinical presentation, extensive medical workup and classic microbiologic testing were non-conclusive. Several infectious agents and other causes for the febrile state were excluded. In the end, a broad-range 16S rDNA PCR was to be performed to confirm the diagnosis of CNM infection. Treatment was successful with doxycycline. Conclusions Due to the obscurity of the pathogen, diagnostic workup in CNM is prolonged and challenging. More awareness is need about this emerging infectious disease in countries with high prevalence of tick-borne diseases as standard microbiological methods are not successful in confirming the diagnosis.

A brief review: the prevalence of tick-borne pathogens in urban and suburban areas

Ticks are widely distributed blood-sucking ectoparasites and vectors for numerous zoonotic pathogens that cause infectious diseases in humans and animals. The increase in the incidence of tick-borne diseases (TBD) is partially associated with climatic changes, such as shorter and warmer winters, prolonged growing seasons, and also with increasing urbanisation. In recent decades, a rising number of established populations of medically important ticks have been reported in urban and suburban areas such as city parks or suburban forests over many regions in Europe. The transformation of natural ecosystems into urban areas becomes actual significant problem because it could affect the circulation of tick-borne pathogens and increase the risk of infection for humans and domestic animals. Tick-borne pathogens, including Borrelia burgdorferi s. l., Rickettsia spp., Anaplasma phagocytophilum, Candidatus Neoehrlichia mikurensis, and Babesia spp., have been detected in urban tick populations in Europe. Such places as parks, leisure-time areas, green spaces, and gardens become endemic zones of tick-borne pathogens. This review describes the investigations on the prevalence of tick-borne pathogens in urbanised areas conducted in Europe during the last fifteen years (2005–2020).

Spatial patterns of pathogen prevalence in questing Ixodes ricinus nymphs in southern Scandinavia, 2016

Tick-borne pathogens cause diseases in animals and humans, and tick-borne disease incidence is increasing in many parts of the world. There is a need to assess the distribution of tick-borne pathogens and identify potential risk areas. We collected 29,440 tick nymphs from 50 sites in Scandinavia from August to September, 2016. We tested ticks in a real-time PCR chip, screening for 19 vector-associated pathogens. We analysed spatial patterns, mapped the prevalence of each pathogen and used machine learning algorithms and environmental variables to develop predictive prevalence models. All 50 sites had a pool prevalence of at least 33% for one or more pathogens, the most prevalent being Borrelia afzelii, B. garinii, Rickettsia helvetica, Anaplasma phagocytophilum, and Neoehrlichia mikurensis. There were large differences in pathogen prevalence between sites, but we identified only limited geographical clustering. The prevalence models performed poorly, with only models for R. helvetica and N. mikurensis having moderate predictive power (normalized RMSE from 0.74–0.75, R2 from 0.43–0.48). The poor performance of the majority of our prevalence models suggest that the used environmental and climatic variables alone do not explain pathogen prevalence patterns in Scandinavia, although previously the same variables successfully predicted spatial patterns of ticks in the same area.

Putative morphology of Neoehrlichia mikurensis in salivary glands of Ixodes ricinus

Neoehrlichia mikurensis is an emerging tick-borne intracellular pathogen causing neoehrlichiosis. Its putative morphology was described in mammalian, but not in tick cells. In this study, we aim to show the presumptive morphology of N. mikurensis in salivary glands of engorged females of Ixodes ricinus. To accomplish this, we collected I. ricinus ticks in a locality with a high N. mikurensis prevalence, allowed them to feed in the artificial in vitro feeding system, dissected salivary glands and screened them by PCR for N. mikurensis and related bacteria. Ultrathin sections of salivary glands positive for N. mikurensis but negative for other pathogens were prepared and examined by transmission electron microscopy. We observed two individual organisms strongly resembling N. mikurensis in mammalian cells as described previously. Both bacteria were of ovoid shape between 0.5–0.8 μm surrounded by the inner cytoplasmic and the rippled outer membrane separated by an irregular electron-lucent periplasmic space. Detection of N. mikurensis in salivary glands of I. ricinus suggests that this bacterium uses the “salivary pathway of transmission” to infect mammals.

Tick-borne Pathogens Detected in the Blood of Immunosuppressed Norwegian Patients Living in a Tick-endemic Area

Background The knowledge regarding the occurrence and the clinical implications of tick-borne infections in immunosuppressed patients living in tick-endemic areas is limited. Methods Adult patients with autoimmune conditions requiring immunosuppressive treatment such as infliximab and rituximab were invited to participate in the study when they attended the hospital for treatment and/or control of the disease. Whole-blood samples were analyzed by real-time polymerase chain reaction for Borrelia burgdorferi sensu lato, Borrelia miyamotoi, Anaplasma phagocytophilum, Rickettsia spp., Candidatus Neoehrlichia mikurensis, and Babesia spp. Results The occurrence of tick-borne pathogens in the blood of patients (n = 163) with autoimmune conditions requiring immunosuppressive treatment was evaluated. Pathogen DNA was detected in 8.6% (14/163) of the patients. The predominant pathogen was Ca. Neoehrlichia mikurensis (12/14), which was carried in the blood of infected patients for 10–59 days until treatment with doxycycline. B. burgdorferi s.l. and Rickettsia spp. were detected in 1 patient each. The B. burgdorferi–infected patient presented with fever, whereas the remaining patients were judged to have subclinical infections. B. miyamotoi, A. phagocytophilum, and Babesia spp. were not detected in any patient. Conclusions Patients treated with biologicals and living in a tick-endemic area seem to have a high risk of contracting Ca. Neoehrlichia mikurensis infection, which, if left untreated, could result in thromboembolic complications.

Correction to: Detection of Candidatus Neoehrlichia mikurensis in Norway up to the northern limit of Ixodes ricinus distribution using a novel real time PCR test targeting the groEL gene

After publication of our article [1] it came to our notice that the source of the sequence for the control plasmid, pNeo (Materials and methods: Controls) was incorrectly stated as AB094461. The correct accession number is AB074461. The authors apologize for any confusion this may have caused.

Monitoring of vector-borne diseases in the west part of Ukraine

During recent years, infectious and invasive animal diseases caused by viruses, bacteria, and protozoa and transmitted by ticks have been a new problem in medical and veterinary practice. Many of these diseases are zoonoses and lead to the disability and mortality of humans and animals. Ixodes ricinus and Dermacentor reticulatus are species of ticks that are commonly attack animals and humans in Europe. These ticks are spread throughout the EU and are involved in the transmission of a large number of vector-borne diseases. To date, relatively limited data on the circulation of tick-borne diseases and their transmission in western Ukraine are presented. The purpose of this study was to monitor the types of ixodid ticks, as well as to identify pathogens in ticks collected from the environment in urban parks and from dogs and cats. A total of 215 ticks (22 Ixodes ricinus and 193 Dermacentor reticulatus) collected in two regions of Lviv and Ivano-Frankivsk were investigated. Pathogens, namely, Rikettsia spp., Candidatus Neoehrlichia mikurensis, Anaplasma phagocytophilum and Bartonella spp., were detected in 64.0% of the I. ricinus ticks. Overall, 18.2% of I. ricinus ticks were positive for Rikettsia spp., 54.5% for Candidatus Neoehrlichia mikurensis, 9.1% for A. phagocytophilum and Bartonella spp. confirmed in 4.5% of the studied ticks. Mixed infestations were found in 5 samples of I. ricinus DNA, representing 22.7%. In addition, 74.6% of D. reticulatus ticks were infested with these pathogens. Overall, 30.0% of D. reticulatus ticks were positive for Rikettsia spp., Candidatus Neoehrlichia mikurensis was confirmed in 54.9%, A. phagocytophilum in 1.6%, and Bartonella spp. in 6.2% of the studied ticks. Mixed infestations were found in 35 D. reticulatus DNA samples, representing 18.1%. The prevalence of Rikettsia spp. in two regions of Lviv and Ivano-Frankivsk, among the studied ticks was 28.8%, Bartonella spp. – 6.0%, A. phagocytophilum – 2.3%, Candidatus Neoehrlichia mikurensis – 54.9%. Our data indicate the presence of pathogens in urban populations of ticks of I. ricinus and D. reticulatus in west part of Ukraine. Monitoring of tick-borne diseases is an important tool in the prevention and control of infections transmitted to humans and animals.