Factsheet on Human granulocytic anaplasmosis
Human granulocytic anaplasmosis (HGA) is a tick-borne infection caused by the bacterium Anaplasma phagocytophilum, a small bacterium infecting typically neutrophils transmitted by Ixodes ticks. Granulocytic anaplasmosis is the most widespread tick-borne infection in animals in Europe (Stuen et al. 2007) and both its geographic distribution and that of its tick vector, Ixodes ricinus complex (mainly Ixodes ricinus and Ixodes persulcatus in Europe) are increasing in latitude and altitude (Stuen et al. 2015; Medlock et al. 2013). Individuals are at greatest risk when ticks are active during the spring through to autumn period.
Despite the increasing prevalence of Anaplasma phagocytophilum in animal hosts, human cases are not frequent, though probably they are underestimated due to the nonspecific clinical signs (flu-like symptoms). The USA strains have shown higher morbidity and mortality (< 1%) and until now no fatal case has been reported in humans in Europe.
Clinical features and sequelae
Incubation times are varied, with a range of 5-21 days, with most cases occurring between April and October. Clinical presentation is usually that of an acute nonspecific febrile infection (duration 2-11 days). Of those infected, 70-95% present with pyrexia (>38.5oC), malaise, myalgia and headaches, some also present with arthralgia, liver involvement (elevated hepatic transaminases), central nervous (confusion, neurological problems), gastrointestinal (nausea and vomiting) or respiratory signs (difficulty breathing). Rash (erythematous, non-pruritic) can occur in a minority of patients. Fatal infections rarely occur, but infection can cumulate in multi-system failure. Suspicion should be raised in patients with tick exposure presenting with thrombocytopenia and/or leukopenia. Cases have been associated with blood transfusion with A. phagocytophilum surviving for a week in chilled blood samples.
Transient infection may occur in the absence of associated clinical signs, and consequently cases may not always be detected. Co-infection with other tick-borne pathogens should be investigated, particularly in cases where a rash has been present.
Though cases acquired in Europe share the clinical picture observed in USA, European cases are generally considered milder. There is evidence of strain heterogeneity that could correlate with host predilections and resulting pathogenesis. Most European HGA cases present as a mild or even asymptomatic infection, with a complete recovery in 2 weeks, even in the absence of specific treatment (Bakken and Dumler, 2006).
The main reservoir of A. phagocytophilum in Europe is I. ricinus tick, with a prevalence within countries ranging between 0.5% and 34% (Christova et al., 2001; Egyed et al., 2012), with a high variability within countries and between them. In Central and Eastern Europe, high prevalence variability was found in different countries, from low values in Hungary and Republic of Moldova (0.5%-2.4%), medium values in Slovakia and Russia (8%-9%) to high values of 34% in Bulgaria. However, this variability could be influenced by the studies themselves (method used, target genes), by the tick population structure since a higher prevalence of the bacteria was found in adults compared to nymphs (Matei et al. 2015) or by geographical patterns and habitat structure. Other Ixodes ticks have also been implicated as carriers. In Eastern Europe, I. persulcatus species was also reported as a significant vector (Stuen et al. 2015). Other species belonging to Ixodes genus seem to be involved in distinct epidemiologic sub-cycles (Silaghi et al. 2012).
Mode of transmission
The disease is most commonly spread through a tick bite. A tick can become infected after feeding on infected hosts. The strains pathogenic for humans can be transmitted to a tick by feeding on a horse, dog, domestic or wild ruminants (some strains), hedgehogs and wild boars. Other modes of transmission of A. phagocytophilum have been observed. Human granulocytic anaplasmosis cases after blood or red blood cell transfusion have been described in both USA and Europe. Also, perinatal transmission from mother to child has been described in USA.
All persons exposed to risk of tick bites, specifically:
- People living in endemic areas for ticks
- People living in rural areas
- Farm workers
- Forest workers
- Hunters (who are in close contact with reservoir hosts and their ticks)
- People who have dogs (spend more time in parks, with their dogs)
- People travelling to endemic HGA areas
No licensed vaccine is currently available, so to prevent infection, precautions should be taken to avoid exposure to ticks (avoid areas with high grass, ferns, etc.), by wearing of appropriate clothing (i.e. light coloured to spot ticks; cover exposed skin, particularly limbs, tuck pants into socks). Use of insect repellents (especially with DEET or permethrin) both for skin and clothes, frequent skin inspections for attached ticks, particularly at the end of the day (esp. armpits, groin, legs, navel, neck and head; head at hairline for children) should be encouraged as early removal minimizes the risk of infection transmission. Removal is done by grasping the tick as close to the mouthparts as possible with forceps or tweezers and then gently pulling it straight out, without squeezing, jerking or twisting. The area should be washed with soap and water, followed by the use of skin disinfectant (alcohol, iodine), if available. Removal methods that stress the tick should never be used (petrol, oil or with a match) because when stressed the tick can release a large quantity of material containing bacteria into bite location. Removed tick should be wrapped in toilet paper using tweezers and flushed down the toilet. For more detailed information, visit ECDC website: https://ecdc.europa.eu/en/disease-vectors/prevention-and-control/protective-measures-ticks
The diagnosis of anaplasmosis is usually suspected based on clinical signs, symptoms and patient’s history and can later be confirmed using specialized confirmatory laboratory tests. The symptoms of HGA may vary from patient to patient and can be difficult to distinguish from other diseases. Information on recent tick bites, exposure to areas where ticks are likely to be found, or history of recent travel to areas where HGA is endemic can be helpful in making the diagnosis.
The healthcare provider should also consider the results of routine blood tests, such as a complete blood cell count or a chemistry panel. Thrombocytopenia, leukopenia or elevated liver enzyme levels are helpful predictors of anaplasmosis but are not present in all patients. After a suspected diagnosis is made on clinical suspicion and treatment has begun, specialized laboratory testing should be used to confirm the diagnosis of anaplasmosis.
The gold standard serologic test for diagnosis of anaplasmosis is the indirect immunofluorescence assay (IFA) using A. phagocytophilum antigen, performed on paired serum samples to demonstrate a significant (four-fold) rise in antibody titres. The first sample should be taken the first week of illness (and is generally negative) and the second 2 to 4 weeks later. IgM antibodies are less specific than IgG antibodies and are more likely to generate false positive results. IgM results alone should not be used for laboratory diagnosis.
During the acute phase of illness, whole blood can be tested by polymerase chain reaction (PCR). This method is highly sensitive early on but quickly loses sensitivity following appropriate administration of antibiotics. Also, a negative result does not rule out the diagnosis, as intermittent levels of bacteraemia can produce false negative results. During the first week of illness, a microscopic examination of blood smears may reveal morulae of Anaplasma in the cytoplasm of the white blood cells but only in up to 20% of patients. Enzyme immunoassay (EIA) tests are available from some commercial laboratories. However, EIA tests are qualitative rather than quantitative, meaning they only provide a positive/negative result, and are less useful to measure changes in antibody titres between paired specimens. Identification through culture isolation is not routinely available and routine hospital blood cultures cannot detect A. phagocytophilum.
Management and treatment
Prophylaxis is not recommended after a tick bite, even in endemic regions. The drug of choice for HGA in adults as well as in children (including those younger than 8 years of age) is doxycycline and should be instituted on clinical suspicion alone. Therapy is most effective when started early in the disease course. Doxycycline is highly efficacious, and post therapeutic relapses have not been reported. There is generally a rapid response to treatment with a marked clinical improvement within 24 to 72 hours. A possible alternative for patients with a doxycycline allergy or with mild disease during pregnancy is rifampicin. Other antibiotics, such as quinolones, cephalosporins, penicillins, and macrolides, are ineffective (St Clair and Decker, 2012; Bakken and Dumler, 2015; Dumler and Walker, 2015), and the use of sulfa drugs during acute illness may worsen the severity of infection.
Key areas of uncertainty
Areas for further research include more detailed epidemiological and ecological understanding of the bacteria and its tick vectors in Europe, in particular regarding their spread.
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