European tick-borne diseases information resource

ESCMID Study Group for Tick-Borne Diseases – ESGBOR

Overview of Human Anaplasmosis

History
The pathogen causing human anaplasmosis was first observed as a tick-borne pathogen of sheep and cattle, in which it was found to cause transient fever (tick-borne fever), sometimes resulting in increased susceptibility to other pathogens, and also causing abortion in cattle (Woldehiwet, 2010). The observation that it occurs within circulating neutrophils initially resulted in the name Rickettsia phagocytophila subsequently changed to Cytoecetes phagocytophila and then to Ehrlichia phagocytophila (Stuen et al., 2013). Over the next few decades disease caused by this pathogen was also observed in dogs and horses, and in 1992 it emerged as a zoonotic organism in the USA (Chen et al., 1994), where it was referred to as Human Granulocytic Ehrlichiosis (HGE). The first European case was observed in 1996 (Petrovec et al., 1997). Following a review of taxonomy, especially concerning molecular markers, the pathogen was assigned to the genus Anaplasma (Dumler et al., 2001), and is now referred to as Anaplasma phagocytophilum, with the disease in humans known as human anaplasmosis or Human Granulocytic Anaplasmosis (HGA).

Clinical features
The incubation period is 5-14 days and patients present with high fever, myalgia, headache and malaise. These symptoms may be accompanied by arthralgias, nausea, anorexia and a non-productive cough. Occasionally (10% of patients) a non-specific rash may be present. In many cases the illness lasts for only a few days but few patients have remained ill for more than 60 days in the absence of antimicrobial therapy (Bakken & Dumler, 2000). In the USA clinical cases are both more severe and more frequent than in Europe. Whereas up to 6729 cases (in 2021) were reported each year in the USA, fewer than 100 cases have been reported in Europe since the first case was described by Petrovec et al., (1997) in 1996 (Dugat et al., 2015). The case fatality rate has been estimated as about 1% in the USA (Bakken & Dumler, 2015), but in Europe no fatalities have been reported so far. Most of the reported European HGA cases presented as a mild infection, common clinical signs being pyrexia, headache, myalgia and arthralgia. However, the average seroprevalence in Europe is approximately 8.3%, and the discrepancy between the seropositivity rate and the low number of reported cases may suggest that asymptomatic or mild symptoms with spontaneous recovery is common. Other possible explanations are underdiagnosis of the condition or serological crossreactivity leading to overestimation of the seroprevalence (Matei et al., 2019). Coinfection with other tick-borne infections is possible and may cause some diagnostic confusion, but in contrast to the situation in domestic ruminants, there is no evidence to suggest that infection with A. phagocytophilum in humans can result in chronic disease or exacerbation of other infections.

Biology of the infectious agent and its vector
A. phagocytophilum is a tick-borne obligate intracellular bacterium that parasitises neutrophils in which it forms clusters of bacteria known as morulae. Characterisation of genotypes is in its infancy but it is now evident that considerable diversity exists, with two independent epidemiological cycles apparently occurring in Europe, one involving rodents as reservoir hosts, with Ixodes trianguliceps as the vector, and another with ruminants as reservoir hosts and I. ricinus as the vector (Dugat et al., 2015). Those found in deer differ from those in sheep, which differ again from those in horses and dogs (Stuen et al., 2013). Ruminants are probably the source of genotypes infective for humans in Europe, but in the USA rodents appear to be the main reservoir hosts of American zoonotic genotypes, which can also infect dogs and horses (Dugat et al., 2015). The main vectors of A. phagocytophilum in Europe are the ticks Ixodes ricinus in western, central and eastern Europe and I. persulcatus in parts of Eastern Europe. The distribution of the two species overlaps in the Baltic states and European Russia.
Almost all human disease results from transmission by ticks, in which the pathogen persists mainly transstadially but basically not transovarially. Transmission via blood transfusion occurs and so far one case has been reported in Europe (Jereb et al., 2016), while several cases have been reported in the USA  as well as  transplacental transmission (Bakken & Dumler, 2015).

Diagnosis
Patients with HGA usually present with a non-specific febrile illness (see Clinical features above) and most have a history of tick-bite or access to tick-infested habitats. Leucopenia, thrombopenia, elevation of hepatic transaminases and C-reactive protein concentration are frequent findings, but although many patients report headache and/or stiff neck, spinal fluid analysis is unremarkable. Rashes rarely occur in HGA patients. In the USA, laboratory confirmation is possible at an early stage of infection by examination of Giemsa-stained blood smears for morulae within neutrophils; however, the method is not very sensitive and requires experienced diagnosticians. Indirect immunofluorescence using A. phagocytophilum whole antigen is often considered the gold standard serological test for diagnosis of HGA. Analysis of paired serum samples taken 2-4 weeks apart enables demonstration of a significant rise (4-fold) in antibody titres (Matei et al., 2019). IgM antibodies are less specific than IgG antibodies and should not be used alone for laboratory diagnosis due to the low specificity. Detection of pathogen DNA by PCR is more effective in the acute phase but accessibility to this test may be limited. The sensitivity for PCR testing is approximately 60% and highest during the first week of illness. Thus, a positive blood smear or PCR result may be helpful but negative results do not exclude the diagnosis. Confirmation is most commonly achieved by analysis of acute and convalescent sera for IgG with an indirect immunofluorescence test (Bakken & Dumler, 2015 and Matei et al., 2019).

Treatment
All symptomatic patients should receive antimicrobial treatment because even mild cases run the risk of complications. A. phagocytophilum is susceptible to tetracyclines and doxycycline is the antibiotic of choice. In addition to adults this applies to seriously ill children for whom doses should be divided and adjusted to the patient’s weight. Clinical improvement should occur in 24 – 48 hours, and in  cases without therapeutic response, alternative diagnoses should be sought. The required duration of treatment has not been established, but for those considered to be at risk of Lyme borreliosis, 14 days is recommended and 7-10 days in children. Based on in vitro studies and a few case reports, rifampicin for 7-10 days is also indicated as an alternative in cases of absolute contraindications to doxycycline (Wormser et al., 2006; Bakken & Dumler, 2015).

Risk management
The risk of contracting HGA after a bite by an Anaplasma-positive tick appears to be low in Europe (Henningsson et al., 2015). 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 in Europe may be in providing an explanation for (acute) illness in cases thought to have occurred as a result of a tick bite.

References

  1. Bakken JS, Dumler JS. Human granulocytic anaplasmosis. Infect Dis Clin North Am. 2015 Jun;29(2):341-55. doi: 10.1016/j.idc.2015.02.007. Review.
  2. Chen SM, Dumler JS, Bakken JS, Walker DH. Identification of granulocytotropic Ehrlichia species as the etiologic agent of human disease. J Clin Microbiol 1994; 32:589–95.
  3. Dugat T, Lagrée AC, Maillard R, Boulouis HJ, Haddad N. Opening the black box of Anaplasma phagocytophilum diversity: current situation and future perspectives. Front Cell Infect Microbiol. 2015 Aug 14;5:61. doi: 10.3389/fcimb.2015.00061. Review.
  4. Henningsson AJ, Wilhelmsson P, Gyllemark P, Kozak M, Matussek A, Nyman D, Ekerfelt C, Lindgren PE, Forsberg P. Low risk of seroconversion or clinical disease in humans after a bite by an Anaplasma phagocytophilum-infected tick. Ticks Tick Borne Dis 2015;6(6):787-92.
  5. Jereb M, Pecaver B, Tomazic J, Muzlovic I, Avsic-Zupanc T, Premru-Srsen T, Levicnik-Stezinar S, Karner P, Strle F. Severe human granulocytic anaplasmosis transmitted by blood transfusion. Emerg Infect Dis. 2012 Aug;18(8):1354-7.
  6. Katavolos P, Armstrong PM, Dawson JE, Telford SR 3rd. Duration of tick attachment required for transmission of granulocytic ehrlichiosis. J Infect Dis. 1998 May;177(5):1422-5.
  7. Matei IA, Estrada-Peña A, Cutler SJ, Vayssier-Taussat M, Varela-Castro L, Potkonjak A, Zeller H, Mihalca AD. A review on the eco-epidemiology and clinical management of human granulocytic anaplasmosis and its agent in Europe. Parasit Vectors. 2019;12:599.
  8. Petrovec M, Lotric Furlan S, Zupanc TA, Strle F, Brouqui P, Roux V, Dumler JS. Human disease in Europe caused by a granulocytic Ehrlichia species. J Clin Microbiol. 1997 Jun; 35(6):1556-9.
  9. Stuen S, Granquist EG, Silaghi C. Anaplasma phagocytophilum–a widespread multi-host pathogen with highly adaptive strategies. Front Cell Infect Microbiol. 2013 Jul 22;3:31. doi: 10.3389/fcimb.2013.00031. Review.
  10. Woldehiwet Z. The natural history of Anaplasma phagocytophilum. Vet Parasitol. 2010 Feb 10;167(2-4):108-22.
  11. Wormser GP, Dattwyler RJ, Shapiro ED, Halperin JJ, Steere AC, Klempner MS, Krause PJ, Bakken JS, Strle F, Stanek G, Bockenstedt L, Fish D, Dumler JS, Nadelman RB. The clinical assessment, treatment, and prevention of Lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis. 2006 Nov 1;43(9):1089-134.