Anaplasmosis

1. Overview
2. Pathogen and Biology
3. Epidemiology and Tick Vector
4. Pathophysiology
5. Clinical Manifestations
6. Diagnostic Laboratory Clues
7. Diagnosis
8. Treatment
9. Prognosis and Complications
10. Prevention
11. References
12. Connections
13. Featured Videos

Overview

Human Granulocytic Anaplasmosis (HGA) is a tick-borne bacterial infection caused by Anaplasma phagocytophilum, an obligate intracellular gram-negative bacterium in the order Ehrlichiales. It is transmitted by the same Ixodes scapularis tick (black-legged tick/deer tick) responsible for Lyme disease and babesiosis, and its endemic geography overlaps almost entirely — the northeastern United States, upper Midwest, and Pacific Northwest. Co-infection with Lyme disease and/or babesiosis from a single tick bite is well recognized and clinically important.

First described in 1994, HGA is the second most common tick-borne illness in the United States after Lyme disease. The CDC reports approximately 5,000–8,000 confirmed cases annually, though this is widely considered a significant undercount due to underreporting and misdiagnosis as viral illness. The disease is usually self-limited in healthy adults but can become life-threatening in elderly patients, those with underlying immunocompromise, or patients in whom the diagnosis is missed and doxycycline treatment is delayed.

Back to Table of Contents

Pathogen and Biology

Anaplasma phagocytophilum is a small, obligate intracellular gram-negative coccobacillus. It belongs to the family Anaplasmataceae, which also includes the Ehrlichia species responsible for human monocytic ehrlichiosis. Key features:

• Obligate intracellular: cannot replicate outside host cells; standard blood cultures are always negative.
• Tropism for granulocytes (primarily neutrophils): infects and replicates within neutrophil phagosomes.
• Morulae: clusters of organisms within membrane-bound vacuoles in the cytoplasm of neutrophils; visible on Wright-Giemsa–stained peripheral blood smear as dark-purple mulberry-like inclusions; this is the pathognomonic finding when present.
• Gram stain is NOT reliable for diagnosis; the organism cannot be cultured on routine media.
• No plasmids; entire lifecycle within host cells.

The organism was historically classified as Ehrlichia phagocytophila (a cattle pathogen in Europe) and Ehrlichia equi (equine granulocytic ehrlichiosis) before being reclassified as a single species, A. phagocytophilum, in 2001.

Back to Table of Contents

Epidemiology and Tick Vector

Vector: Ixodes scapularis (northeastern/midwestern USA, black-legged tick) and Ixodes pacificus (Pacific Coast, western black-legged tick). The same ticks transmit Borrelia burgdorferi (Lyme), Babesia microti, Borrelia miyamotoi, and Powassan virus.

Reservoir hosts: The white-footed mouse (Peromyscus leucopus) is the primary amplifying host for both A. phagocytophilum and B. burgdorferi. White-tailed deer serve as the reproductive host for adult ticks. Small mammals (chipmunks, shrews, voles) are secondary reservoirs.

Transmission: Requires tick attachment for approximately 12–24 hours (shorter than the 36–48 hours typically cited for Lyme disease transmission). Nymphal ticks (May–August) are the primary transmission-season vectors due to their small size making them difficult to detect.

Geography: Endemic states include Connecticut, New York, New Jersey, Rhode Island, Massachusetts, Pennsylvania, Minnesota, Wisconsin, and the Pacific Northwest states. Risk maps expand slightly northward each decade consistent with climate shifts extending tick habitat.

Seasonality: Peak incidence May–July (nymphal season) and September–October (adult season). Most cases present May through August.

Incidence: CDC NNDSS reports show rising incidence — from approximately 2,000 cases per year in 2010 to over 8,000 cases per year by 2020, likely reflecting true increases plus improved ascertainment.

Back to Table of Contents

Pathophysiology

After tick-bite inoculation, A. phagocytophilum enters the bloodstream and selectively invades neutrophils (and occasionally eosinophils). Once inside the neutrophil phagosome, it actively prevents phagolysosomal fusion, surviving in what would normally be a bactericidal environment.

Mechanism of disease — a paradox: Neutrophils are being infected, yet the clinical picture is one of immunosuppression rather than pyogenic infection. A. phagocytophilum actively reprograms neutrophil gene expression: it downregulates respiratory burst (oxidative killing), impairs chemotaxis, alters cytokine signaling (suppresses IL-12, upregulates IL-10), and reduces antimicrobial peptide production.

Consequences of neutrophil dysfunction:

• Impaired neutrophil killing creates a window for opportunistic infections.
• Documented opportunistic complications: invasive aspergillosis, CMV reactivation, HSV-2 esophagitis, disseminated candidiasis, and Pneumocystis pneumonia — all in previously immunocompetent adults after anaplasmosis.
• Cytokine storm from massive neutrophil turnover contributes to systemic inflammation and organotoxicity.

Thrombocytopenia occurs through megakaryocyte suppression, splenic sequestration, and platelet consumption. Leukopenia results from margination of neutrophils plus direct destruction; this is the characteristic WBC finding.

Back to Table of Contents

Clinical Manifestations

Incubation: 5–14 days after tick bite (range 1–21 days).

Presentation: Abrupt onset of high fever (>39°C/102°F), severe headache, profound myalgias, and malaise — essentially indistinguishable from severe influenza. There is no reliable clinical sign that distinguishes HGA from Rocky Mountain Spotted Fever, ehrlichiosis, or viral syndromes on history alone.

Key negative finding — rash is rare in anaplasmosis (occurs in fewer than 10% of patients). This is critically different from Rocky Mountain Spotted Fever, where the petechial rash is the defining feature (though it can also be absent early). The rule of thumb: tick bite + fever + prominent rash = think RMSF first; tick bite + fever + no rash = think Anaplasmosis/Ehrlichiosis first.

Gastrointestinal symptoms: nausea, vomiting, and anorexia in approximately 30–40% of patients — can lead to misdiagnosis as gastroenteritis.

Physical examination: usually unremarkable; no rash, no adenopathy, no specific findings; fever with relative bradycardia occasionally; pulmonary crackles if respiratory involvement is present.

Severe manifestations (uncommon in healthy adults; higher risk in elderly and immunocompromised patients):

• ARDS and respiratory failure
• Acute kidney injury
• Meningoencephalitis (rare; CSF pleocytosis with lymphocytosis, mononuclear predominance)
• Peripheral neuropathy
• Rhabdomyolysis
• Opportunistic infections (see Pathophysiology above)
• Demyelinating polyneuropathy (case reports)

Mortality: less than 1% in treated patients; 5–7% in untreated or delayed-treatment elderly or immunocompromised patients.

Back to Table of Contents

Diagnostic Laboratory Clues

The characteristic laboratory triad that distinguishes HGA from common viral illness:

1. Thrombocytopenia: platelet count typically 50,000–150,000/μL at presentation; the most consistent laboratory abnormality (occurs in 70–90% of cases).
2. Leukopenia: low WBC (typically 2,000–4,000/μL), specifically neutropenia; unusual in viral illness of comparable severity; most sensitive when combined with thrombocytopenia.
3. Elevated transaminases: AST and ALT mildly to moderately elevated (typically 2–5× upper limit of normal); hepatocellular pattern; occurs in more than 80% of patients.

Supporting findings:

• Normal or mildly elevated CRP and ESR (often lower than expected for degree of clinical illness — this is characteristic)
• Elevated LDH
• Hyponatremia (common)
• Normal CSF in most cases, unless meningoencephalitis is present
• Negative standard blood cultures

The combination of tick-season exposure + fever + thrombocytopenia + leukopenia + elevated transaminases in an endemic region is so characteristic that empiric doxycycline should be started before any confirmatory test result returns.

Back to Table of Contents

Diagnosis

Blood smear (Wright-Giemsa stained peripheral blood smear): Look for morulae in neutrophils — dark purple mulberry-like clusters in the cytoplasm. Sensitivity varies widely (20–80%); depends on timing (first week of illness) and examiner experience. A positive smear is diagnostic, but a negative smear does not rule out anaplasmosis.

PCR (Anaplasma phagocytophilum PCR, blood): The most sensitive diagnostic test in the first week of illness (sensitivity 67–90%, specificity >99%). Blood drawn before antibiotic therapy is essential — PCR sensitivity falls rapidly after doxycycline initiation. This is the preferred confirmatory test.

Serology (IFA, indirect immunofluorescence antibody): IgM and IgG. A fourfold rise between acute (first week) and convalescent (3–4 weeks later) serum samples is confirmatory; a single titer ≥1:64 with compatible illness is supportive. Single acute-phase serology is often negative because antibodies take 2–4 weeks to develop — do not use a negative acute serology to rule out anaplasmosis.

Full CBC: essential to demonstrate the thrombocytopenia and leukopenia triad.

Liver function tests (AST, ALT): part of the characteristic diagnostic triad.

Co-infection evaluation: In any confirmed HGA case in Lyme-endemic areas, also test for Borrelia burgdorferi (Lyme serology) and Babesia (smear + PCR) — co-infection with one or more pathogens from the same tick is well documented.

Back to Table of Contents

Treatment

Doxycycline is the definitive and only first-line treatment for HGA.

Standard adult dosing: Doxycycline 100 mg twice daily (BID) for 5–7 days. Severely ill patients: 100 mg IV every 12 hours initially, transitioning to oral when clinical improvement occurs.

Key principle — empiric treatment: Do not wait for laboratory confirmation if clinical suspicion is moderate-to-high (tick exposure + fever + appropriate labs + endemic area + right season). Doxycycline should be started immediately. A dramatic clinical response within 24–48 hours of doxycycline initiation is so characteristic that clinical improvement itself supports the diagnosis.

Doxycycline in children: Unlike most tick-borne illnesses where doxycycline use in children under 8 years is typically discouraged due to dental staining, the severity of anaplasmosis (and RMSF) overrides this concern. The AAP, CDC, and IDSA all endorse doxycycline for children of any age with suspected anaplasmosis or RMSF because delayed treatment causes greater harm than dental staining.

Lyme co-infection: Doxycycline at 100 mg BID for 10–14 days covers both anaplasmosis and early Lyme disease simultaneously. If Lyme carditis or neurological Lyme is present, extend to 21 days.

Alternatives (when doxycycline is contraindicated):

• Rifampin 300 mg BID for 7–10 days — preferred alternative in pregnancy (doxycycline is contraindicated in pregnancy; however, rifampin is also FDA category C and should be weighed carefully).
• Rifampin is also used in pediatric cases where the parent refuses doxycycline.

Do NOT use: fluoroquinolones, chloramphenicol, beta-lactams, or macrolides — none have adequate efficacy against A. phagocytophilum.

Failure to improve after 48–72 hours of doxycycline should prompt reconsideration of the diagnosis, evaluation for co-infection (especially babesiosis), and specialist consultation.

Back to Table of Contents

Prognosis and Complications

Overall prognosis is excellent with prompt doxycycline therapy. Most patients defervesce within 24–48 hours. Myalgias and fatigue may persist for 1–2 weeks. Full recovery is the rule in treated patients.

Groups with higher complication risk:

• Age over 60 years
• Asplenia
• HIV infection or other immunosuppression
• Diabetes mellitus
• Delayed diagnosis (more than 5 days of illness before treatment)

Opportunistic infections as a complication: The most dramatic severe presentations are not from the bacteria itself, but from secondary opportunistic infections triggered by A. phagocytophilum-induced neutrophil immunosuppression in otherwise healthy adults — including cases of invasive aspergillosis, cryptococcal pneumonia, CMV pneumonitis, and HSV-2 esophagitis. These should be investigated when a patient with HGA fails to improve on doxycycline.

Long-term neurological sequelae are rare but documented in meningoencephalitis cases.

Back to Table of Contents

Prevention

Tick avoidance:

• Use EPA-registered repellents: DEET (≥20%) or picaridin on skin; permethrin on clothing and gear (do not apply permethrin directly to skin; treat clothing before wearing; remains effective through multiple washes).
• Wear long sleeves and pants tucked into socks; light-colored clothing makes ticks easier to spot.
• Stay on trails; avoid leaf litter and brush margins where nymphal ticks wait at grass-blade tips (questing behavior).
• Perform full-body tick checks within 2 hours of returning from outdoor activity; shower promptly.
• Check pets for ticks before allowing indoor access.

Tick removal: Grasp the tick as close to the skin as possible with fine-tipped tweezers; pull upward with steady, even pressure; do not twist or jerk; do not use petroleum jelly, heat, or alcohol to remove attached ticks. Clean the bite site with alcohol or soap and water.

Prophylactic doxycycline: A single dose of doxycycline 200 mg within 72 hours of a recognized high-risk Ixodes tick bite (engorged nymphal tick attached more than 36 hours in an endemic area) is FDA-approved for Lyme disease prevention and also provides protection against anaplasmosis. This prophylaxis is a one-time dose, not a 5-day course.

Landscaping modifications: Clear leaf litter, keep grass short, create wood chip barriers between wooded areas and the yard, and remove deer attractants.

No vaccine exists for anaplasmosis.

Back to Table of Contents

References

1. Dumler JS, et al. Reorganization of genera in the families Rickettsiaceae and Anaplasmataceae. Int J Syst Evol Microbiol. 2001;51(6):2145-2165. PMID 11760965
2. Bakken JS, Dumler JS. Human granulocytic anaplasmosis. Infect Dis Clin North Am. 2015;29(2):341-355. PMID 25999228
3. Wormser GP, et al. The clinical assessment, treatment, and prevention of Lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by IDSA. Clin Infect Dis. 2006;43(9):1089-1134. PMID 17029130
4. Horowitz HW, et al. Concurrent infections with Anaplasma phagocytophilum and Borrelia burgdorferi in Ixodes scapularis-infested patients. Emerg Infect Dis. 1998;4(4):642-646. PMID 9866741
5. Bakken JS, et al. Human granulocytic ehrlichiosis in the upper Midwest United States. A new species emerging? JAMA. 1994;272(3):212-218. PMID 8022040 [Original description of HGA]
6. Thomas RJ, et al. Microscopically detected morulae in granulocytes in human ehrlichial diseases. J Infect Dis. 1989;160(4):643-650. PMID 2778462
7. Chen SM, et al. Identification of a granulocytotropic Ehrlichia species as the etiologic agent of human disease. J Clin Microbiol. 1994;32(3):589-595. PMID 8195367
8. Grab DJ, et al. Borrelia burgdorferi, host-derived proteases, and the blood-brain barrier. Infect Immun. 2005;73(2):1014-1022. PMID 15664943
9. Blanco JR, Oteo JA. Human granulocytic ehrlichiosis in Europe. Clin Microbiol Infect. 2002;8(12):763-772. PMID 12519363
10. Stuen S, Granquist EG, Silaghi C. Anaplasma phagocytophilum — a widespread multi-host pathogen with highly adaptive strategies. Front Cell Infect Microbiol. 2013;3:31. PMID 23885337
11. Cheng C, Nair AD, Indukuri VV, Gong S, Felsheim RF, Jaworski D, et al. Targeted and random mutagenesis of Anaplasma phagocytophilum for the identification of genes required for in vivo infection. PLoS Pathog. 2013;9(9):e1003641. PMID 24068937
12. Anaplasma phagocytophilum. CDC National Notifiable Diseases Surveillance System data. Morb Mortal Wkly Rep. 2021;70(6):212-217. PMID 33571167

Back to Table of Contents

Connections

• Lyme Disease
• Babesiosis
• Ehrlichiosis
• Rocky Mountain Spotted Fever
• Q Fever
• Tick-Borne Co-Infections
• Prevention and Tick Removal

Back to Table of Contents

Featured Videos

Medical Education — Anaplasmosis: symptoms, diagnosis, and treatment overview.

Infectious Disease Education — Clinical presentation of human granulocytic anaplasmosis.

Microbiology Review — Anaplasma phagocytophilum: intracellular pathogen biology and morulae.

Public Health — Tick identification, safe removal technique, and disease prevention.

Clinical Pharmacology — Doxycycline as first-line treatment for anaplasmosis and co-infections.

Infectious Disease — Lyme disease co-infections: anaplasmosis, babesiosis, and ehrlichiosis.

Vector Biology — Ixodes scapularis life cycle and tick-borne pathogen transmission dynamics.

Laboratory Medicine — PCR, serology, and blood smear diagnosis of tick-borne infections.

Hematology — Understanding thrombocytopenia and leukopenia as diagnostic clues in anaplasmosis.

Clinical Diagnosis — Differentiating anaplasmosis from Rocky Mountain Spotted Fever.

Preventive Medicine — DEET, picaridin, and permethrin for effective tick repellent protection.

Immunology — How intracellular pathogens evade neutrophil killing and cause immunosuppression.

Epidemiology — Rising incidence of tick-borne diseases across the northeastern and midwestern United States.

Infectious Disease — Babesiosis: the intraerythrocytic co-infection often presenting alongside anaplasmosis.

Infectious Disease — Ehrlichiosis: monocytic counterpart to anaplasmosis, shared tick vector.

Patient Education — Comprehensive guide to tick-borne illness recognition, treatment, and long-term prevention.

Play All Anaplasmosis Videos

▶ Play All 16 Videos on YouTube

Back to Table of Contents