Bourbon virus (BRBV) is an emerging tick-borne RNA virus in the Orthomyxoviridae family (genus Thogotovirus), first isolated in 2014 from a fatal case in Bourbon County, Kansas. [1-2] It is transmitted by the **Lone Star tick (Amblyomma americanum) and causes a severe acute febrile illness with leukopenia and thrombocytopenia. There are [1][3]no approved antiviral therapies or vaccines, and several reported cases have been fatal. [4-5] Seroprevalence data (~0.6% in Missouri and North Carolina) suggest infections are likely more common than recognized. [4][6]
1. History
- Key HPI questions: Recent tick exposure or outdoor activity in endemic areas (Midwest and southern US); timeline from tick bite to symptom onset
- Symptom characterization: Acute onset of fever, fatigue, headache, myalgias, arthralgias, nausea, vomiting, and rash [1-2]
- Timing: Onset typically days after tick bite; incubation period not precisely defined due to limited case data
- Progression: Rapid deterioration possible — the index case progressed to multiorgan failure and death within ~11 days of symptom onset [5][7]
- Important negatives: Ask about erythema migrans (suggests Lyme), eschar (suggests Rickettsia parkeri), conjunctival suffusion, hemolysis
2. Alarm Features
- Rapidly worsening cytopenias (severe thrombocytopenia, leukopenia)
- Hemodynamic instability, altered mental status
- Evidence of DIC or multiorgan dysfunction (liver, spleen pathology prominent in animal models) [5]
- Failure to improve on empiric doxycycline (should raise suspicion for viral rather than bacterial tick-borne illness) [8]
- Immunocompromised patients may be at particular risk for severe disease — mouse models demonstrate that intact type I/II interferon signaling is essential for viral containment [9]
3. Medications
- No FDA-approved antiviral therapy exists [4][10]
- Investigational agents with preclinical activity:
- Favipiravir — prevented mortality in Ifnar1⁻/⁻ mice when given prophylactically or up to 3 days post-infection [5]
- Ribavirin — inhibited BRBV in cell culture [9]
- Molnupiravir — showed in vitro and in vivo efficacy in mice, including therapeutic benefit when started 24–48 hours post-infection; improved thrombocytopenia and reduced liver/spleen pathology [4]
- Doxycycline should be started empirically in undifferentiated tick-borne febrile illness to cover ehrlichiosis/anaplasmosis while awaiting diagnostics, but it has no activity against BRBV [8][11]
- Avoid antiplatelet agents and anticoagulants in the setting of severe thrombocytopenia
4. Diet
- No specific dietary triggers or recommendations
- Maintain adequate hydration, especially with fever, nausea, and vomiting
- NPO considerations if clinical deterioration warrants ICU admission
5. Review of Systems
- Constitutional: Fever, chills, fatigue, malaise, night sweats
- Dermatologic: Rash (character not well-defined in limited case reports) [1][8]
- GI: Nausea, vomiting, anorexia, diarrhea
- MSK: Myalgias, arthralgias, body aches
- Neurologic: Headache, altered mentation (assess for meningoencephalitis)
- Hematologic: Easy bruising, petechiae, mucosal bleeding (thrombocytopenia)
6. Collateral History and Family History
- Collateral: Outdoor occupation or recreation (farming, hunting, hiking), geographic location, known tick bites in household contacts or pets
- Family history: No known hereditary predisposition, though innate immune deficiencies (e.g., interferon pathway defects) may predispose to severe disease [9]
- Social context: Occupational exposure (forestry, agriculture), travel to endemic areas (Kansas, Missouri, Oklahoma, North Carolina, and broader central/eastern/southern US) [3-4][6]
7. Risk Factors
- Geographic exposure: Residence in or travel to the central, eastern, and southern United States where A. americanum is prevalent [4][12]
- Seasonal: Spring through fall (peak Lone Star tick activity)
- Outdoor activities: Hiking, camping, yard work, farming in wooded or brushy areas
- Immunocompromised state: Defects in type I/II interferon signaling may predispose to severe/fatal disease [5][9]
- Lack of tick-bite prevention measures (no repellent, no protective clothing)
8. Differential Diagnosis
The presentation of acute febrile illness with leukopenia and thrombocytopenia after tick exposure has a broad differential: [13-14]
- Ehrlichiosis (E. chaffeensis) — same vector (Lone Star tick), same geography; responds to doxycycline; morulae on smear
- Anaplasmosis (A. phagocytophilum) — similar labs; different tick vector (Ixodes); responds to doxycycline
- Heartland virus — nearly identical presentation and vector; also a tick-borne virus with leukopenia/thrombocytopenia; no specific treatment [14]
- Rocky Mountain spotted fever — rash more prominent; can be fatal; responds to doxycycline
- Babesiosis — hemolytic anemia distinguishes; ring forms on smear
- Colorado tick fever — western US; biphasic fever; leukopenia
- Powassan virus — meningoencephalitis predominates
- Viral syndromes (influenza, EBV, CMV, dengue) — consider based on exposure and travel history
Key distinguishing feature: Failure to respond to empiric doxycycline in a patient with tick-borne febrile illness and cytopenias should raise suspicion for a viral etiology (BRBV, Heartland virus). [8]
9. Past Medical History
- Prior tick-borne illnesses or tick bites
- Immunosuppressive conditions or medications (transplant, biologics, HIV, primary immunodeficiency) — may increase risk of severe disease [9]
- Splenectomy (worsens thrombocytopenia management)
- Chronic liver disease (may confound lab interpretation)
10. Physical Exam
- Vitals: Fever (often high-grade), tachycardia; monitor for hypotension
- Skin: Rash (maculopapular reported); search for embedded ticks, eschar (would suggest alternative diagnosis); petechiae/purpura if thrombocytopenic [1][8]
- HEENT: Conjunctival injection, pharyngeal erythema
- Lymph nodes: Lymphadenopathy (regional or generalized)
- Abdomen: Hepatosplenomegaly (liver and spleen are major target organs) [5]
- Neuro: Mental status assessment, meningeal signs
11. Lab Studies
- CBC with differential: Expect leukopenia (lymphopenia) and thrombocytopenia — hallmark findings [1][7]
- CMP: Elevated hepatic transaminases (AST/ALT); monitor renal function
- Coagulation studies: PT/INR, fibrinogen, D-dimer (assess for DIC)
- LDH, haptoglobin, reticulocyte count: To evaluate for hemolysis (helps distinguish from babesiosis)
- Peripheral blood smear: Rule out morulae (ehrlichiosis/anaplasmosis), ring forms (babesiosis)
- Blood cultures: Rule out bacteremia
- Procalcitonin: May help differentiate bacterial vs. viral etiology
12. Imaging
- Chest X-ray: If respiratory symptoms present; assess for ARDS
- CT abdomen: Consider if hepatosplenomegaly or abdominal pain; may show splenomegaly
- Imaging is generally not the primary diagnostic modality — diagnosis rests on laboratory and molecular testing
- CT/MRI brain: If meningoencephalitis suspected
13. Special Tests
- RT-PCR for BRBV RNA — most useful in acute phase; testing available through CDC and select state health departments [6-7]
- Serology: Virus-specific IgM/IgG antibodies; four-fold rise in paired sera confirms diagnosis (acute + convalescent 2–4 weeks later) [14]
- Plaque reduction neutralization test (PRNT): Used for confirmatory serologic diagnosis [7]
- Tick-borne illness panel: Send concurrent testing for ehrlichiosis, anaplasmosis, RMSF, babesiosis, and Heartland virus given overlapping presentations
- Note: Commercial diagnostic testing for BRBV is extremely limited; coordinate with state health department and CDC [6]
14. ECG
- No BRBV-specific ECG findings described
- Obtain ECG if tachycardia, hypotension, or concern for myocarditis
- Monitor for arrhythmias in critically ill patients with electrolyte derangements from severe illness
15. Assessment
- BRBV infection should be suspected in patients presenting with acute febrile illness, leukopenia, and thrombocytopenia after tick exposure in endemic areas who fail to improve on empiric doxycycline [1][8]
- The clinical presentation is nearly indistinguishable from ehrlichiosis, anaplasmosis, and Heartland virus disease — definitive diagnosis requires molecular/serologic testing [12][14]
- Severity ranges from self-limited illness to fatal multiorgan failure; the true case-fatality rate is unknown due to likely underdiagnosis of mild cases [6]
- Severe disease may reflect underlying innate immune deficiency (interferon pathway) [9]
16. Treatment Plan
- Initial stabilization: IV fluids, antipyretics, antiemetics
- Empiric doxycycline (100 mg PO/IV BID) should be started immediately for any undifferentiated tick-borne febrile illness pending diagnostics [11][14]
- Supportive care is the mainstay once viral etiology is confirmed — there are no approved antivirals [1][4]
- Platelet transfusion for severe thrombocytopenia with active bleeding or platelet count <10,000/μL
- Packed RBCs if significant anemia
- ICU-level care for hemodynamic instability, DIC, ARDS, or multiorgan failure
- Investigational antivirals: In severe/life-threatening cases, consider compassionate use discussion with CDC/infectious disease:
- Favipiravir [5]
- Molnupiravir [4]
- Ribavirin [9]
17. Disposition
- Admission criteria: Hemodynamic instability, severe cytopenias, evidence of organ dysfunction, inability to tolerate PO, altered mental status
- ICU admission: DIC, ARDS, multiorgan failure, refractory hypotension
- Observation: Stable patients with moderate cytopenias and preserved organ function
- Discharge criteria: Afebrile, improving counts, tolerating PO, no evidence of organ dysfunction
- Specialist consultation: Infectious disease (mandatory for suspected/confirmed cases); hematology if severe cytopenias; critical care if ICU-level illness; contact state health department and CDC for diagnostic coordination and case reporting [6]
18. Follow Up / Return Precautions
- Follow-up: Repeat CBC within 48–72 hours after discharge; infectious disease follow-up within 1 week
- Convalescent serology: Draw second sample 2–4 weeks after acute specimen for paired serologic confirmation
- Return immediately for: Recurrent fever, worsening fatigue, new rash, bleeding (gums, petechiae, melena), confusion, shortness of breath
- Patient counseling:
- Tick-bite prevention: DEET or permethrin-treated clothing, daily tick checks, prompt tick removal [14]
- No person-to-person transmission documented
- Recovery course is poorly characterized; prolonged fatigue is possible
- No vaccine is available
References
1. 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.
2. Bourbon Virus, a Newly Discovered Zoonotic Thogotovirus. — Bendl E, Fuchs J, Kochs G. The Journal of General Virology. 2023.
3. Bourbon Virus in Field-Collected Ticks, Missouri, USA. — Savage HM, Burkhalter KL, Godsey MS, et al. Emerging Infectious Diseases. 2017.
4. Molnupiravir Inhibits Bourbon Virus Infection and Disease-Associated Pathology in Mice. — Bamunuarachchi G, Zhao FR, Bricker TL, et al. Journal of Virology. 2025.
5. Therapeutic Efficacy of Favipiravir Against Bourbon Virus in Mice. — Bricker TL, Shafiuddin M, Gounder AP, et al. PLoS Pathogens. 2019.
6. Evidence of Human Bourbon Virus Infections, North Carolina, USA. — Zychowski DL, Bamunuarachchi G, Commins SP, Boyce RM, Boon ACM. Emerging Infectious Diseases. 2024.
7. Molecular, Serological and in Vitro Culture-Based Characterization of Bourbon Virus, a Newly Described Human Pathogen of the Genus Thogotovirus. — Lambert AJ, Velez JO, Brault AC, et al. Journal of Clinical Virology : The Official Publication of the Pan American Society for Clinical Virology. 2015.
8. Dermatological Manifestations of Tick-Borne Viral Infections Found in the United States. — Rupani A, Elshabrawy HA, Bechelli J. Virology Journal. 2022.
9. Essential Role of Interferon Response in Containing Human Pathogenic Bourbon Virus. — Fuchs J, Straub T, Seidl M, Kochs G. Emerging Infectious Diseases. 2019.
10. Establishment of a Replicon Reporter of the Emerging Tick-Borne Bourbon Virus and Use It for Evaluation of Antivirals. — Hao S, Ning K, Wang X, et al. Frontiers in Microbiology. 2020.
11. 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.
12. Emerging Tickborne Viruses Vectored by Amblyomma Americanum (Ixodida: Ixodidae): Heartland and Bourbon Viruses. — Dupuis AP, Lange RE, Ciota AT. Journal of Medical Entomology. 2023.
13. Fever of Unknown Origin. — Haidar G, Singh N. The New England Journal of Medicine. 2022.
14. 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.