Human granulocytic anaplasmosis (HGA) is an acute tick-borne bacterial infection caused by Anaplasma phagocytophilum, transmitted by Ixodes spp. ticks (black-legged/deer tick), with an incubation period of 5–14 days. [1-2] It is an increasingly recognized cause of nonspecific febrile illness, particularly in the Upper Midwest and Northeastern United States, with geographic overlap with Lyme disease. [2-3] Mortality is <1% with appropriate treatment but rises with delayed diagnosis in elderly and immunocompromised patients. [1][4]
1. History
- Tick exposure: Ask about known tick bite (reported in ~62–76% of cases), outdoor activities (hiking, gardening, hunting), occupational exposure (forestry, farming, veterinary work) [5-6]
- Timing: Symptom onset 5–14 days after tick bite; patients typically present 4–8 days into illness [1][4]
- Symptom characterization: High fever (92–100%), severe headache (82%), malaise (97%), myalgias (77%), rigors/chills [4][7]
- GI symptoms: Nausea, vomiting, diarrhea, anorexia — less frequent than in ehrlichiosis [4][7]
- Important negatives: Rash is present in <10% of cases (unlike RMSF or Lyme); CNS involvement is rare. Absence of erythema migrans does not exclude coinfection with Lyme disease. [4][7]
- Seasonality: Spring and summer months (peak May–September) [8]
2. Alarm Features
- Altered mental status [4][9]
- Respiratory distress / dyspnea (ARDS reported in ~6.3% of complicated cases) [10]
- Signs of shock or hemodynamic instability
- Hemorrhagic manifestations or DIC-like coagulopathy [4]
- Severe thrombocytopenia with bleeding
- Multi-organ dysfunction (renal failure ~9.8%, multi-organ failure ~7.5%) [10]
- Features of hemophagocytic lymphohistiocytosis (HLH) or TTP-like syndrome [4-5]
- Failure to improve within 48 hours of doxycycline — consider alternative diagnosis or coinfection [3-4]
3. Medications
- First-line treatment: Doxycycline 100 mg PO BID for all ages, including children and elderly [1][7]
- Children: doxycycline 2.2 mg/kg BID [2]
- Duration: 10–14 days (10 days covers possible Lyme coinfection) [2][4]
- Pregnancy: Doxycycline is not considered safe; however, in life-threatening HGA, it may be warranted. Rifampin has been used anecdotally in pregnant women and young children with limited data [3]
- Contraindicated: Chloramphenicol, sulfonamides, and beta-lactams are not effective against A. phagocytophilum [7]
- Pearl: Use of antibiotics other than doxycycline increases the risk of death per CDC guidance [7]
- Medication contributors: Immunosuppressive medications (chemotherapy, biologics, chronic corticosteroids) increase risk of severe disease [4][9]
4. Diet
- No specific dietary triggers or restrictions
- Maintain adequate hydration, especially in febrile patients with GI symptoms (nausea, vomiting, diarrhea)
- Doxycycline should be taken with food and water to reduce GI side effects; avoid dairy products within 2 hours of dosing
5. Review of Systems
- Constitutional: Fever, chills, rigors, fatigue, malaise, night sweats
- Musculoskeletal: Myalgias, arthralgias
- Neurologic: Headache (severe), altered mental status (red flag), peripheral neuropathy (rare)
- GI: Nausea, vomiting, diarrhea, anorexia
- Respiratory: Cough, dyspnea (concerning for ARDS)
- Dermatologic: Rash (uncommon, <10%; if present, consider Lyme coinfection) [4][7]
- Hematologic: Easy bruising, petechiae (thrombocytopenia)
6. Collateral History and Family History
- Confirm tick exposure from family members or travel companions
- Ask about shared outdoor exposures — household members may also be at risk
- Inquire about pets (dogs can carry Ixodes ticks into the home)
- No hereditary predisposition; family history is not a major factor
- Social context: Rural residence, recreational outdoor activities, occupational exposure (forestry, farming, hunting, veterinary work) [5-6]
7. Risk Factors
- Geographic: Upper Midwest and Northeastern US (VT, ME, RI, MN, MA, WI, NH, NY account for 90% of cases); also endemic in parts of Europe and Asia [2]
- Seasonal: Spring and summer (tick activity peak)
- Age: Older adults at higher risk for severe disease (median age of hospitalized patients: 71 years) [9]
- Immunosuppression: Chemotherapy, organ transplant, HIV, chronic corticosteroids [4][9]
- Comorbidities: Diabetes, chronic medical conditions [4]
- Occupational/recreational: Outdoor workers, hikers, hunters, gardeners [6]
- Male sex: Male-to-female ratio approximately 2–3:1 [5][11]
8. Differential Diagnosis
- Ehrlichiosis (E. chaffeensis): Similar presentation but more common in southeastern/south-central US; rash more common (~30%); morulae in monocytes rather than granulocytes [2][4]
- Rocky Mountain Spotted Fever: Petechial rash starting on wrists/ankles; more rapidly fatal; different tick vector (Dermacentor) [4][12]
- Lyme disease: Erythema migrans rash in 70–80%; same tick vector — coinfection is possible and should be considered [12-13]
- Babesiosis: Hemolytic anemia, intraerythrocytic parasites on smear; same tick vector; coinfection common [8][13]
- Viral syndromes: Influenza, EBV, CMV — can mimic early HGA
- Meningococcemia: Petechial rash, rapid deterioration
- TTP/HUS: Thrombocytopenia, microangiopathic hemolytic anemia, renal failure [4]
- Hemophagocytic lymphohistiocytosis (HLH): Cytopenias, ferritin elevation, hepatosplenomegaly [4-5]
- Sepsis from other causes: Bacterial sepsis with cytopenias and transaminitis
9. Past Medical History
- Prior tick-borne illness (reinfection can occur; prior HGA does not confer lasting immunity)
- Immunosuppressive conditions or medications
- Splenectomy (increased risk of severe tick-borne infections)
- Chronic liver disease (may confound transaminase interpretation)
- Diabetes mellitus [4]
- History of organ transplantation
10. Physical Exam
- Vital signs: Fever (often high, 92–100%), tachycardia; hypotension is a red flag for shock [4]
- General: Ill-appearing, diaphoretic
- Skin: Thorough skin survey for embedded ticks, tick bite sites, rash (<10%); if erythema migrans is present, suspect Lyme coinfection [4][7]
- HEENT: No specific findings; conjunctival suffusion is more suggestive of leptospirosis
- Lymph nodes: Lymphadenopathy uncommon
- Abdomen: Hepatosplenomegaly may be present in severe cases
- Neurologic: Mental status assessment — altered sensorium is a red flag [9]
- Respiratory: Auscultate for crackles (ARDS) [4]
11. Lab Studies
- CBC with differential: Thrombocytopenia (71–95%), leukopenia (49–59%), lymphopenia with left shift, mild anemia [4-5][10]
- CMP/hepatic panel: Elevated AST/ALT (2–4× normal in ~67% of cases), elevated CRP (100% in one series) [4-5]
- Peripheral blood smear: Look for morulae (intracytoplasmic inclusion bodies) within neutrophils — seen in 20–80% of acute cases [3][11]
- PCR (NAAT): Confirmatory test of choice during acute illness (<10 days); sensitivity >95% [1][13]
- Serology (IFA): Acute serology alone is insensitive; paired acute + convalescent titers (2–4 weeks apart) with ≥4-fold rise is diagnostic; titers typically reach ≥1:640 during acute infection [3][14]
- Labs to rule out dangerous mimics: Blood cultures (sepsis), thick/thin smear (babesiosis/malaria), Lyme serology, coagulation studies (DIC), LDH, haptoglobin (hemolysis)
- Monitoring: Repeat CBC and LFTs to track recovery
The classic triad of leukopenia + thrombocytopenia + transaminitis is present in only ~24% of cases but is associated with increased hospitalization risk (OR 1.78). [9]
12. Imaging
- Imaging is generally not required for uncomplicated anaplasmosis
- Chest X-ray: Indicated if respiratory symptoms are present to evaluate for ARDS or pulmonary infiltrates [4]
- CT head: If altered mental status to rule out other etiologies
- No gold-standard imaging study for HGA
13. Special Tests
- Anaplasma PCR (NAAT) on whole blood (EDTA tube, transport on ice): Primary diagnostic test during acute illness [13]
- Buffy coat smear (Wright or Giemsa stain): Look for morulae in granulocytes — rapid but sensitivity 20–80% depending on operator experience [3][13]
- IFA serology: For retrospective confirmation; not useful acutely [13-14]
- Tick-borne coinfection panel: Consider concurrent testing for Lyme disease (serology), babesiosis (smear + PCR), and ehrlichiosis (PCR) given shared Ixodes vector [13][15]
- Clinical decision support: Patients with platelet count >177 × 10³/μL and age <48 years are very unlikely to have a positive Anaplasma PCR [16]
14. ECG
- ECG is not routinely indicated for uncomplicated anaplasmosis
- Consider ECG if:
- Concern for myocarditis (rare complication)
- Concurrent Lyme disease with possible cardiac involvement (Lyme carditis with AV block)
- Hemodynamic instability or shock
- No pathognomonic ECG pattern for HGA
15. Assessment
- HGA is an acute, nonspecific febrile illness that should be suspected in any patient with fever, cytopenias, and transaminitis after tick exposure in an endemic area during spring/summer [3][15]
- Most cases are self-limiting and respond rapidly to doxycycline (fever resolves within 24–48 hours) [4][10]
- Atypical presentations occur — HGA can present without fever, with isolated neurologic symptoms, or with minimal lab abnormalities [9][17]
- Complications (40.5% of reported cases, though reporting bias exists): acute renal failure (9.8%), multi-organ failure (7.5%), ARDS (6.3%), DIC, rhabdomyolysis, pancreatitis, HLH [4][10]
- Coinfection with Lyme disease and/or babesiosis should always be considered given shared tick vector [13]
16. Treatment Plan
Initial stabilization
- ABCs; IV fluid resuscitation if dehydrated or hemodynamically unstable
- Empiric doxycycline should be started immediately on clinical suspicion — do not wait for confirmatory testing [1][7]
Medications and dosing
- Adults: Doxycycline 100 mg PO BID × 10–14 days [2][4]
- Children (all ages): Doxycycline 2.2 mg/kg PO BID × 10–14 days (no tooth staining at recommended dose/duration) [2][7]
- Pregnancy: Rifampin 300 mg PO BID has been used with limited data; doxycycline may be warranted in life-threatening cases [3]
- IV doxycycline: For patients unable to tolerate PO, obtunded, or severely ill [4]
Response monitoring
- Expect clinical improvement (defervescence) within 24–48 hours of starting doxycycline [4][10]
- Failure to improve within 48 hours → reconsider diagnosis or evaluate for coinfection (especially babesiosis, which does not respond to doxycycline) [3-4]
17. Disposition
Outpatient management (majority — 67% in a large cohort): [9]
- Young, immunocompetent patients with mild symptoms
- Able to tolerate oral medications
- Reliable follow-up
Admission criteria: [4][9]
- Altered mental status
- Evidence of organ dysfunction (renal failure, ARDS, DIC)
- Severe thrombocytopenia with bleeding
- Hemodynamic instability
- Immunocompromised patients with significant illness
- Inability to tolerate oral medications
- Advanced age with comorbidities
ICU admission: ~7% of hospitalized patients require ICU care [4]
Specialist consultation triggers
- Infectious disease: Severe or complicated cases, pregnancy, doxycycline allergy, suspected coinfection
- Hematology: If HLH or TTP is suspected
- Critical care: Shock, ARDS, multi-organ failure
18. Follow Up / Return Precautions
Follow-up timing
- Primary care or infectious disease follow-up within 1–2 weeks of discharge
- Repeat CBC and LFTs to confirm normalization
Return precautions — instruct patients to return immediately for:
- Persistent or recurrent fever after 48 hours of doxycycline
- Worsening headache, confusion, or altered mental status
- Shortness of breath or chest pain
- New bleeding, bruising, or petechiae
- Inability to keep medications or fluids down
Patient counseling
- Complete the full course of doxycycline even if feeling better
- Avoid sun exposure (doxycycline photosensitivity)
- Tick prevention education: DEET-based repellents, permethrin-treated clothing, daily tick checks, prompt tick removal [12]
- Prophylactic antibiotics after tick bite are not recommended for anaplasmosis (unlike Lyme disease) [12]
Expected recovery
- Most patients recover fully without sequelae (sequelae in only ~2.1% of cases) [10]
- Fever typically resolves within 1 day of starting doxycycline; full recovery expected within 1–2 weeks [10]
References
1. Human Granulocytic Anaplasmosis. — MacQueen D, Centellas F. Infectious Disease Clinics of North America. 2022.
2. Wilderness Medical Society Clinical Practice Guidelines for the Prevention and Management of Tick-Borne Illness in the United States. — Ho BM, Davis HE, Forrester JD, et al. Wilderness & Environmental Medicine. 2021.
3. Diagnosis, Treatment, and Prevention of Lyme Disease, Human Granulocytic Anaplasmosis, and Babesiosis: A Review. — Sanchez E, Vannier E, Wormser GP, Hu LT. The Journal of the American Medical Association. 2016.
4. Diagnosis and Management of Tickborne Rickettsial Diseases: Rocky Mountain Spotted Fever and Other Spotted Fever Group Rickettsioses, Ehrlichioses, and Anaplasmosis - United States. — Biggs HM, Behravesh CB, Bradley KK, et al. MMWR. Recommendations and Reports : Morbidity and Mortality Weekly Report. Recommendations and Reports. 2016.
5. Retrospective Multicenter Study of Human Granulocytic Anaplasmosis, France, 2012-2024. — Gerber V, Lemmet T, Bonijoly T, et al. Emerging Infectious Diseases. 2025.
6. A Review on the Eco-Epidemiology and Clinical Management of Human Granulocytic Anaplasmosis and Its Agent in Europe. — Matei IA, Estrada-Peña A, Cutler SJ, et al. Parasites & Vectors. 2019.
7. Tickborne Diseases of the United States: A Reference Manual for Healthcare Providers Sixth Edition. — Nancy Shadick MD MPH, Nancy Maher MPH, Dennis Hoak MD United States Centers for Disease Control and Prevention (2022). 2022.
8. Fever of Unknown Origin. — Haidar G, Singh N. The New England Journal of Medicine. 2022.
9. Trends in Anaplasmosis Over the Past Decade: A Review of Clinical Features, Laboratory Data, and Outcomes. — Katragadda S, Yetmar ZA, Chesdachai S, et al. Clinical Infectious Diseases : An Official Publication of the Infectious Diseases Society of America. 2026.
10. Human Granulocytotropic Anaplasmosis-a Systematic Review and Analysis of the Literature. — Schudel S, Gygax L, Kositz C, Kuenzli E, Neumayr A. PLoS Neglected Tropical Diseases. 2024.
11. Clinical Diagnosis and Treatment of Human Granulocytotropic Anaplasmosis. — Bakken JS, Dumler JS. Annals of the New York Academy of Sciences. 2006.
12. Tickborne Diseases: Diagnosis and Management. — Pace EJ, O'Reilly M. American Family Physician. 2020.
13. Guide to Utilization of the Microbiology Laboratory for Diagnosis of Infectious Diseases: 2024 Update by the Infectious Diseases Society of America (IDSA) and the American Society for Microbiology (ASM). — Miller JM, Binnicker MJ, Campbell S, et al. Clinical Infectious Diseases : An Official Publication of the Infectious Diseases Society of America. 2024.
14. Rickettsial Diseases. — David W. McCormick and William L. Nicholson CDC Yellow Book. 2025.
15. Anaplasmosis: Emerging Threat in Canada. — Ngo C, Koubaesh C, MacFadden D, Joo P. Canadian Family Physician Medecin De Famille Canadien. 2025.
16. Clinical Decision Support Trees Can Help Optimize Utilization of Anaplasma Phagocytophilum Nucleic Acid Amplification Testing. — Hamilton R, Pandora TR, Parsonnet J, Martin IW. Journal of Clinical Microbiology. 2021.
17. Trigeminal Neuralgia Unmasked: A Case of Anaplasma Phagocytophilum Infection. — Merrill R, Pratt I, Simon EL. The Journal of Emergency Medicine. 2025.