Human Granulocytic Anaplasmosis

Human granulocytic anaplasmosis (HGA; ICD-10 A79.2) is an emerging tick-borne infection caused by the bacterium Anaplasma phagocytophilum. Infection in humans occurs following a bite from the Ixodes scapularis tick (also known as the blacklegged or deer tick), which is the same type that can carry the pathogens causing Lyme disease, babesiosis, ehrlichiosis, Powassan disease. Though not as well-studied as Lyme disease, Anaplasma phagocytophilum may be transmitted after being attached for 24 hours, possibly as short as 12 hours (transmission of the etiologic agent of Lyme disease, Borrelia burgdorferi, requires the tick to be attached for at least 24-36 hours).

After an incubation of 5 to 21 days (usually 7 to 14 days), the infection typically presents with acute, undifferentiated fever, potentially with severe headache, malaise, myalgia, gastrointestinal symptoms, rash (<10%). Approximately 31% of infections are significant enough to warrant hospitalization and 3-7% of patients have life threatening complications including respiratory insufficiency, septic shock, disseminated intravascular coagulation, or renal failure.¹

• Reservoir: The mammalian hosts of A. phagocytophilum primarily include wild rodents (such as mice, rats, voles, etc.), but dogs and cats can become infected by consuming them. The Ixodes scapularis tick becomes a vector of A. phagocytophilum after feeding on these mammals.
• Modes of Transmission: Human infection can occur following a bite from an Ixodes scapularis tick. Excluding rare situations where A. phagocytophilum has been transmitted by blood transfusion² and a report of possible perinatal transmission,³ there is no person-to-person transmission. HGA has a seasonal occurrence with an incidence peak in June but continuing as long as November.¹
• Host Susceptibility and Resistance: Susceptibility is general. Infection with A. phagocytophilum is associated with outdoor activity, but there is evidence for transmission in suburban settings in the United States.^1,4,5 Importantly, up to 25% of patients with HGA will not recall a tick bite.

Blacklegged ticks in various stages of feeding:

Three nymphs of the blacklegged tick are shown in different stages of feeding.

The following image shows 5 female blacklegged ticks in different stages of feeding.

For additional photos showing blacklegged ticks in various phases of engorgement from feeding visit the Tick Encounter Resource Center website.

https://www.ajtmh.org/view/journals/tpmd/101/6/article-p1249.xml (Nelder MP, Russell CB, Lindsay LR, Dibernardo A, Brandon NC, Pritchard J, Johnson S, Cronin K, Patel SN. Recent Emergence of Anaplasma phagocytophilum in Ontario, Canada: Early Serological and Entomological Indicators. Am J Trop Med Hyg. 2019 Dec;101(6):1249-1258. doi: 10.4269/ajtmh.19-0166. PMID: 31628739; PMCID: PMC6896876).

The incubation period of Human Granulocytic Anaplasmosis (HGA) is between 5-21 days long, and some infections may be asymptomatic. Common symptoms include fever (93%), headache (73%), myalgia (73%), and rigors (60%), with less common symptoms including nausea, vomiting, abdominal pain, anorexia, and cough (<30%). Rash is very infrequent and is more likely related to co-infection with Lyme disease. Lymphocytic meningoencephalitis is also very rare with HGA.

Serious complications include acute respiratory distress syndrome (ARDS), toxic shock syndrome-like illness, myocarditis, rhabdomyolysis, hemophagocytic lymphohistiocytosis (HLH), renal failure, demyelinating disorders, and opportunistic infections.

Laboratory findings include leukopenia (57-80%), thrombocytopenia (38-93%), mild anemia (14-48%), neutrophilic inclusion bodies on blood smear (20-80%), and mild to severe elevation in hepatic transaminases (40-50%). Hyponatremia and elevated C-reactive protein are present in most cases. Disseminated intravascular coagulation has also been reported.

The diagnosis of Human Granulocytic Anaplasmosis (HGA) can be challenging due to patients’ non-specific symptoms and laboratory findings but should be suspected in cases of fever of unknown origin especially if there is a history of outdoor activities in a region where Ixodes scapularis is found. When Anaplasma is suspected, consultation with an infectious diseases specialist is strongly recommended and treatment with doxycycline based on clinical signs and symptoms should be initiated before the diagnosis is confirmed (but not before blood specimens have been obtained to avoid compromising the sensitivity of the PCR assay).

Diagnosis of HGA can be achieved with the following tests:

• Complete Blood Count and Differential and Smear – notify your local hematopathologist or hematopathology technician of your suspicion for HGA, and they will review a blood smear for the presence of neutrophilic inclusions, which may be seen in HGA

• Serologic Testing – Serology tends to become positive 1-2 weeks after the onset of illness, making it less useful for diagnosis in the acute setting. Turnaround time reported by Public Health Ontario Laboratory (PHOL) is up to 42 days from receipt of specimen by PHOL, as the samples are sent to the National Microbiology Laboratory (NML) in Winnipeg. Acute and convalescent serology should be done 2-4 weeks apart.⁷
  • A downloadable requisition form is available from the Public Health Ontario Laboratory’s website. Note, the request will be rejected unless a clinical and travel history is provided. 
• Blood PCR testing – Specimens are sent to the NML. This test is generally positive in the first 1-2 weeks of illness and is the most useful test in the acute setting.⁸ However, the turn-around time for this test tends to be about 21 days and so when there is sufficient clinical suspicion of HGA, treatment should be initiated prior to the confirmation of the diagnosis (but after specimen collection). 

For further information about human diagnostic testing, the following resources are available:

• Refer to the Public Health Ontario Laboratory Services webpage
• Contact the Public Health Ontario Laboratories

Suspected or confirmed cases of human granulocytic anaplasmosis are reportable to local public health under the Health Protection and Promotion Act.

Monday to Friday from 8:30 am to 4:30 pm: Call 613-580-2424, extension 24224 and leave a detailed, confidential message including your contact information; or fax 613-580-9640. 

After hours, on weekends, or holidays: Call 3-1-1 and ask to speak to Public Health on call. 

For more details on how to report, please visit Reporting a communicable disease. 

Antibiotic treatment of Human Granulocytic Anaplasmosis (HGA):

For drugs, dosages, and durations, please consult a reference such as the American Academy of Pediatrics Red Book. The treatment of choice is doxycycline for patients of any age, and a prompt response to treatment should be expected. Previously, use of doxycycline was avoided in children less than eight years of age due to concerns with tooth staining and enamel hypoplasia, but recent data on the safety and efficacy of short courses (≤21 days) of doxycycline in this age group has prompted its more permissive use.⁹ However, doxycycline has not been adequately studied in pregnancy, and the risks and benefits of its use should be discussed with pregnant patients as other classes of antibiotics (i.e., penicillins, cephalosporins, aminoglycosides, and macrolides) are ineffective against A. phagocytophilum. The clinical efficacy of rifampin has not yet been evaluated, but it has been used during pregnancy.^10,11

Short-term use of doxycycline is considered acceptable in breastfeeding mothers, though it does penetrate readily into breast milk. The possibility of adverse events in infants of lactating mothers on doxycycline is considered to be unlikely.¹²

When a patient has been exposed to ticks in other health units:

Public Health Ontario has a risk area map that indicates places where Ixodes scapularis ticks are found. For the most current map visit the Public Health Ontario Lyme disease webpage, under “Type of Resource” click on “Surveillance Report” and look for most current year.

Please visit specific health units' websites for the current recommendations for exposure to ticks in their respective health units. A listing of Ontario public health units can be found at the Ministry of Health and Long-Term Care website.

The Institut national de santé publique Québec (INSPQ) publishes a risk area map for Québec at: https://www.inspq.qc.ca/zoonoses/maladie-de-lyme

Visit the Health Canada website for a risk area map for Canada.

If a patient presents with the tick attached:

1. Use tweezers to grasp the tick where it attaches to the skin.
2. Pull the tick straight out, slowly and firmly, and do not jerk or twist the tick as this can cause the tick's mouthparts to break off. Avoid squeezing the tick's abdomen.
3. Disinfect the feeding site after the tick is removed.

4. Tick identification:

a) Revised Tick Surveillance Program: (As of September 20, 2021)

1. Public Health Ontario will continue to accept ticks for identification from members of the public through health care providers. Ottawa Public Health does not accept ticks for identification. The tick identification results will be reported to submitters. It may take up to three weeks to receive identification results back from PHO’s laboratory during peak season. The online platform (etick.ca) may be an alternative option if you require a faster result.
2. PHO will no longer send blacklegged ticks to the National Microbiology Laboratory (NML) for pathogen testing (except in rare instances by special request after consultation with NML staff). As a result of this change, submitters will no longer receive pathogen results from their submitted ticks.

Refer to LAB-SD-146 Changes to Passive Tick Surveillance Program in Ontario for further information

b) Use Bishop’s University electronic tick identification platform (eTick.ca): anyone can submit a picture of a tick and receive species identification results within 48 hours, along with public health education and awareness messaging.

c) Try to identify the tick yourself using the ID guide at the University of Rhode Island’s TickEncounter Resource Center (https://tickencounter.org/).

Prevention of tick bites is a cornerstone of Human Granulocytic Anaplasmosis (HGA) prevention. Patients are advised to adopt the following practices:

• Application of a Health Canada approved insect repellent containing DEET or icaridin to exposed skin and to clothing
• Wearing long pants, a long-sleeved shirt, shoes and socks to cover exposed skin
• Tucking pants into socks
• Wearing light coloured clothing so it is easier to spot ticks
• If possible, staying on the trails when hiking in the woods or walking in long grass

Suspected and confirmed cases of human granulocytic anaplasmosis are reportable to local public health under the Health Protection and Promotion Act.

For Provincial surveillance case definitions and disease-specific direction for the public health management of human granulocytic anaplasmosis, please see the Ontario Ministry of Health’s Appendix 1 - Case Definitions and Disease Specific Information. 

For details on how to report, please see the Reporting Requirements section. 

Prevention of tick bites is a cornerstone of Human Granulocytic Anaplasmosis (HGA) prevention. Patients are advised to adopt the following practices:

• Application of a Health Canada approved insect repellent containing DEET or icaridin [CE1] to exposed skin and to clothing
• Wearing long pants, a long-sleeved shirt, shoes and socks to cover exposed skin
• Tucking pants into socks
• Wearing light coloured clothing so it is easier to spot ticks
• If possible, staying on the trails when hiking in the woods or walking in long grass

Performing a "full body" check (also on children, and pets if applicable) for ticks. Ticks often attach in areas such as between toes, behind knees, in the groin, armpits and scalp.

• Anaplasmosis, U.S. Centers for Disease Control and Prevention (CDC)
• Ehrlichiosis and anaplasmosis, Mayo Clinic

Lab Testing

• Lab Requisition form, Public Health Ontario
• Anaplasma (Anaplasma phagocytophilum) – Serology, Public Health Ontario Laboratory
• Tick Identification – Surveillance, Public Health Ontario (PHO will continue to accept ticks for identification from members of the public through health care providers.  Ottawa Public Health does not accept ticks for identification.)

General information on Anaplasma phagocytophilum

• Anaplasmosis Fact Sheet, Canada Food Inspection Agency
• Summary: Tick Species in Ontario (in English only), Public Health Ontario: This report brings together the scientific literature and surveillance information on ticks of Ontario into a single source. Explore the tick species reported from Ontario in the last 120 years, with information on their distribution, establishment status and medical and veterinary importance.
• Surveillance for Ixodes scapularis and Ixodes pacificus ticks and their associated pathogens in Canada, 2020, Canada Communicable Disease Report (CCDR). 

International Resources on Anaplasma phagocytophilum 

• Anaplasmosis: Informationfor Health Care Providers, U.S. Centers for Disease Control and Prevention (CDC)
• Factsheet on Human granulocytic anaplasmosis, European Centre for Disease Prevention and Control

1. Dahlgren FS, Heitman KN, Drexler NA, Massung RF, Behravesh CB. Human granulocytic anaplasmosis in the United States from 2008 to 2012: a summary of national surveillance data. Am J Trop Med Hyg. 2015;93(1):66-72.
2. Atif FA. Anaplasma marginale and Anaplasma phagocytophilum: Rickettsiales pathogens of veterinary and public health significance. Parasitology Research. 2015;114(11):3941-3957.
3. Horowitz HW, Kilchevsky E, Haber S, et al. Perinatal Transmission of the Agent of Human Granulocytic Ehrlichiosis. New England Journal of Medicine. 1998;339(6):375-378.
4. Aguero-Rosenfeld ME, Horowitz HW, Wormser GP, et al. Human Granulocytic Ehrlichiosis: A Case Series from a Medical Center in New York State. Annals of Internal Medicine. 1996;125(11):904-908.
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7. American Academy of Pediatrics. Committee on Infectious D. Red book : report of the Committee on Infectious Diseases. 1994.
8. John E. Bennett RDMJB. Mandell, Douglas, and Bennett&#39;s principles and practice of infectious diseases. Eighth edition. Philadelphia, PA : Elsevier/Saunders, [2015]; 2015.
9. Sood SK. Lyme Disease in Children. Infect Dis Clin North Am. 2015;29(2):281-294.
10. Buitrago MI, Ijdo JW, Rinaudo P, et al. Human Granulocytic Ehrlichiosis During Pregnancy Treated Successfully with Rifampin. Clinical Infectious Diseases. 1998;27(1):213-215.
11. Krause PJ, Corrow CL, Bakken JS. Successful Treatment of Human Granulocytic Ehrlichiosis in Children Using Rifampin. Pediatrics. 2003;112(3):e252.
12. Wilson CB, Nizet V, Maldonado YA, Remington JS, Klein JO. Remington and Klein's infectious diseases of the fetus and newborn infant. Elsevier Health Sciences; 2015.