Neoehrlichiosis A28.-

Neoehrlichiosis is a systemic inflammatory zoonosis caused by the bacterium Neoehrlichia mikurensis. Carriers are ticks of the genus Ixodes. The disease usually affects people with underlying hematologic or autoimmunologic diseases.

Candidatus Neoehrlichia mikurensis is a gram-negative intracellular bacterium from the Anaplasmataceae family that was first discovered in 2010 and is transmitted by ticks. Candidatus Neoehrlichia is closely associated with rodents in which transplacental transmission occurs. Transovarial transmission by ticks has not yet been proven. Infection rates in ticks and rodents vary greatly, but the causes of the spatio-temporal variations are largely unknown.

The world's first case was reported in Sweden in 2010 (Glans H et al. 2023). Since then, further cases have been reported, mainly in the south and southwest of Sweden. To date, 123 cases have been diagnosed in Sweden. In neighboring Finland, an increased prevalence of N micurensis in ticks was observed between 2013-2014 and 2015-2018.

In northern Norway, N. micurensis was detected in 11.2 % of all I. ricinus ticks collected (Larsson C et al. 2018). The prevalence differed between ticks collected from vegetation (18.2 %; 90/495) and ticks collected from dogs and cats (5.6 %; 34/609) (Larsson C et al. 2018). Co-infections with N. mikurensis and Borrelia afzelii were detected in 2.1 % of the tick populations examined in Sweden. There is a risk of simultaneous transmission of both pathogens (Andersson M et al. 2013)

Among other things, the bacterium infects endothelial cells in the vascular wall, which can cause a vascular effect and an increased risk of thrombosis in superficial and deep venous vessels in immunocompromised individuals, but can also cause arteritis in immunocompromised individuals. There are isolated case reports of hemophagocytic lymphohistiocytosis caused by neoehrlichiosis and development of B-cell lymphoma caused by neoehrlichiosis (Glans H et al. 2023).

Neoehrlichiosis can cause prolonged intermittent fever with night sweats and migratory muscle pain and multiforme exanthema (Glans H et al. 2023). N micurensis has been diagnosed mainly in immunocompromised individuals. Risk factors for neoehrlichiosis are splenectomy, malignant B-cell lymphomas and immunomodulatory therapies that affect B cells, especially rituximab, a monoclonal antibody against CD20 used to treat various diseases in rheumatology, hematology, neurology and dermatology.

Diagnosis is based on TaqMan real-time PCR, which enables the detection of the gene coding for 16S rRNA and a blood smear. The diagnosis can be made from blood or bone marrow. The intracellular bacterium cannot be detected with a conventional blood culture. An antibody test for N micurensis is not yet available.

Neoehrlichiosis should be discussed as a possible diagnosis in cases of intermittent persistent fever, especially in cases of immunosuppression or after splenectomy.

The recommended treatment is doxycycline 100 mg 2x/day for 21 days, but shorter treatment periods have also proved successful. For patients who cannot tolerate doxycycline, rifampicin 300-450 mg 2x/day is an alternative.

The most urgent research tasks are to cultivate the pathogen in vitro, develop specific serological tests, determine the complete genome sequence, routinely perform molecular diagnosis in diseased patients with a specific group of underlying diseases and promote knowledge about neoehrlichiosis among general practitioners, hospital physicians and at-risk groups such as forest workers or people with weakened immune systems in order to raise awareness of this disease, which can be easily treated if correctly diagnosed (Silaghi C et al. 2016).

Acute onset with muscular thrombosis

A 48-year-old man with azathioprine-treated Crohn's disease and chronic thrombocytosis, who had a splenectomy in his youth for spherocytosis, presented acutely in the fall of 2021 with two weeks of persistent fever and pain in his calves. He had previously visited a health center where the fever was interpreted as an upper respiratory tract infection and the pain as muscle inflammation/strain. Treatment with amoxicillin was started. When the pain in the calves increased, deep vein thrombosis was suspected and the patient was referred to the emergency room. The medical history revealed a new cough. He had a temperature of 39.1 °C, CRP 55 mg/l and an ECG with left bundle branch block. In view of the abnormal ECG and the clinical suspicion of deep vein thrombosis, pulmonary embolism was suspected. The CT scan of the chest did not reveal a pulmonary embolism, but the duplex ultrasound showed a muscle vein thrombosis. The patient received blood-thinning treatment. The patient was admitted for examination due to unexplained fever and elevated CRP. A detailed medical history revealed mild headaches and neck pain as well as several tick bites in recent months. Despite treatment with anticoagulant medication, the patient developed thrombophlebitis during the treatment period. Blood cultures and tests for Epstein-Barr virus and cytomegalovirus were negative. The tick history and the occurrence of new thromboses despite ongoing blood-thinning medication led to the suspicion of neoehrlichiosis. A test for N micurensis was performed and treatment with doxycycline 100 mg × 2 was started. The patient became afebrile within 2 days.

The PCR for N micurensis was positive. The patient was treated with doxycycline for a total of 15 days and was fully recovered at the follow-up examination 2 weeks after the end of treatment. The examination in the coagulation clinic revealed no genetic marker for an increased tendency to thrombosis.

Unexplained fever and splenomegaly

A 65-year-old woman with rheumatoid arthritis and systemic sclerosis and pulmonary fibrosis, who had been treated with low-dose prednisolone and rituximab since 2013, developed fever, deep vein thrombosis in the right leg, and new-onset splenomegaly and anemia in February 2021. In spring 2021, an extensive fever workup was performed at the infectious disease clinic with sampling and PET-DT, without finding an explanation for the fever. There was a clinical improvement in the summer, but after another course of rituximab in August 2021, she suffered a relapse with fever and general and mental fatigue. The symptoms, as well as the return of anemia and the appearance of a transaminase increase, led to a re-investigation in the fall of 2021, which also included a broader sample of tick-borne infections.

The PCR for N micurensis was positive and the patient was treated with doxycycline 100 mg × 2 for 21 days. After 6-7 days, she was fever-free and gradually recovered both physically and mentally. She was fully recovered 6 weeks after the start of treatment. A control test 3 weeks after the end of treatment was N mikurensis PCR-negative.

Intermittent fever and weight loss

A 68-year-old man with rheumatoid arthritis treated with prednisolone and rituximab and highly malignant B-cell lymphoma treated with chemotherapy (R-CHOP) and radiotherapy in 2011 developed recurrent/intermittent fever and weight loss in the summer of 2021. Examination in the fall revealed elevated inflammatory tests and mild splenomegaly. An unexplained inflammation or infection was suspected and rituximab treatment was discontinued. Further investigations at an infectious disease clinic in January 2022 for unexplained fever did not provide an explanation. Tick bites appeared in the medical history, but TBE and Lyme disease were ruled out. Further investigations at the Department of Hematology and Rheumatology resulted in a diagnosis of Still's disease, and the patient was treated with prednisolone and tocilizumab, but the fever persisted. In the spring of 2022, the patient's breathing worsened and an examination in the rheumatology clinic revealed pneumocystis pneumonia. The patient was treated with sulfonamide/trimethoprim and his breathing improved. In the spring of 2022, two cases of neoehrlichiosis were diagnosed at the rheumatology clinic at Karolinska University Hospital, and the patient was therefore tested for N mikurensis as part of the investigation of the unexplained fever that had appeared long before the respiratory symptoms. The N mikurensis PCR was positive, and the patient received a three-week treatment with doxycycline 2x100 mg and became fever-free.

1. Andersson M et al. (2013) Co-infection with 'Candidatus Neoehrlichia Mikurensis' and Borrelia afzelii in Ixodes ricinus ticks in southern Sweden. Vector Borne Zoonotic Dis 13:438-442.
2. Andréasson K et al. (2014) Recurrent fever caused by Candidatus Neoehrlichia mikurensis in a rheumatoid arthritis patient treated with rituximab. Rheumatology (Oxford) 54:369-371.
3. Glans H et al. (2023) Ovanlig fästingsjukdom har gjort sitt intåg i Stockholmsregionen [Neoehrlichiosis has entered the Stockholm region]. Lakartidningen 120:23101.
4. Gynthersen RMM et al. (2023) Neoehrlichia mikurensis - an emerging opportunistic tick-borne infection in immunosuppressed patients. J Intern Med 293:782-90.
5. Larsson C et al. (2018) Candidatus Neoehrlichia mikurensis" in Ixodes ricinus ticks collected near the Arctic Circle in Norway. Parasite Vectors 11:620.
6. Silaghi C et al. (2016) Neoehrlichiosis: an emerging tick-borne zoonosis caused by Candidatus Neoehrlichia mikurensis. Exp Appl Acarol 68:279-297.
7. Wennerås C et al. (2023) Infection with Neoehrlichia mikurensis promotes the development of malignant B-cell lymphomas. Br J Haematol 201:480-488.