01Approach to the Critical Patient/attcp55

Immediate priorities

›Time-critical recognition

›Acute febrile illness with leukopenia and thrombocytopenia in tick season

›Midwest or southern US geographic context

›Tick exposure within prior 2 weeks

›Failure to improve on empiric doxycycline within 48 hours

›Key clinical clue distinguishing viral from bacterial tick-borne illness

›Prompt HRTV testing via state health department

›ICD-10: A93.8 (Other specified arthropod-borne viral fevers)

›Hemodynamic and airway priorities

›Hypotension or shock physiology

›SBP < 90 mmHg

›MAP < 65 mmHg

›Altered mental status with airway risk

›GCS < 13 warrants airway assessment

›Aspiration risk with vomiting and encephalopathy

›If hemodynamic compromise, initiate IV fluid resuscitation and ICU transfer

›0.9% NaCl or Lactated Ringer 1–2 L IV bolus

›Vasopressors if refractory to fluids

›Hemorrhagic complication recognition

›Thrombocytopenia-driven bleeding risk

›Platelet count < 50 x10^9/L with active bleeding warrants transfusion

›Avoid NSAIDs and anticoagulants

›DIC screen if hemorrhagic signs present

›PT/INR, PTT, fibrinogen, D-dimer

›Peripheral blood smear for schistocytes

Monitoring and targets

›Monitoring bundle

02History/hx53

Exposure history

›Tick exposure

›Attached tick found within prior 2 weeks

›88% of confirmed cases reported tick on themselves before illness onset

›Lone Star tick (Amblyomma americanum) is the primary vector

›Outdoor activities in high-risk settings

›Farming, forestry, hunting, hiking, yard work

›Wooded or brushy areas in Midwest and southern US

›Geographic location

›Midwest and southern US within Amblyomma americanum distribution range

›Over 60 confirmed cases spanning 14 states reported to CDC

Symptom timeline

›Illness onset and progression

›Acute febrile illness onset

›Fever, fatigue, decreased appetite, headache

›Myalgia, arthralgia, nausea, diarrhea

›Seasonal pattern

›April through September coinciding with Lone Star tick activity

›Incubation period estimated 1–2 weeks post-tick exposure

›Symptom worsening over first week

›Nadir of cytopenias around days 5–7 of illness

›Transaminase spike around days 7–8

Alarm features

›High-risk presentations

›Confusion or altered mental status

›Reported in majority of confirmed cases

›Correlates with severe disease and fatal outcomes

›Hemorrhagic manifestations

03Physical Exam/exam46

Vital signs

›Hemodynamic assessment

›Temperature

›Fever often high grade

›Antipyretic masking may blunt fever at presentation

›Heart rate and blood pressure

›Tachycardia common with fever and dehydration

›Hypotension indicates severe disease or dehydration

›Oxygen saturation

›Generally normal; respiratory involvement not typical

›Desaturation suggests alternative or co-existing diagnosis

Skin and lymph nodes

›Dermatologic examination

›Tick bite sites and embedded ticks

›Thorough skin survey including scalp, axillae, groin, popliteal fossa

›Remove any retained ticks with fine-tipped forceps

›Rash assessment

›Rash typically absent in HRTV

›Presence of rash should prompt consideration of RMSF or ehrlichiosis

›Hemorrhagic skin changes

›Petechiae, purpura, ecchymosis suggest severe thrombocytopenia

›Indicate high-risk disease state

›Lymph node examination

›Lymphadenopathy

›Mild lymphadenopathy may be present

›HRTV antigen detected in lymph nodes on autopsy

›Regional lymphadenopathy near tick bite site

04Differential Diagnosis/ddx70

Bacterial tick-borne infections

›Ehrlichiosis (most important mimic)

›Caused by Ehrlichia chaffeensis, same Lone Star tick vector

›ICD-10: A77.40 (Ehrlichiosis, unspecified)

›Responds to doxycycline within 48 hours

›Differentiation from HRTV

›HRTV fails to improve on doxycycline

›Ehrlichiosis responds promptly to doxycycline

›Anaplasmosis

›Anaplasma phagocytophilum; similar lab findings

›ICD-10: A79.82 (Anaplasmosis)

›Also responds to doxycycline

›Differentiation

›PCR and serology distinguish from HRTV

›Doxycycline response expected within 24–48 hours

›Rocky Mountain Spotted Fever

›Rickettsia rickettsii; petechial rash typical

›ICD-10: A77.0

›Rash present in majority; respond to doxycycline

›Differentiation

›Rash absent in HRTV

›PCR and serology distinguish

Other viral tick-borne illnesses

›Bourbon virus disease

›Same vector (Amblyomma americanum), similar presentation

›ICD-10: A93.8 (other specified arthropod-borne viral fevers)

›No specific treatment; supportive care only

›Differentiation

05Laboratory Tests/lt78

Complete blood count

›CBC with differential

›Leukopenia

›Hallmark finding in HRTV infection

›Neutropenia with ANC potentially < 700 cells/mm^3

›Nadir around days 6–7 of hospitalization

›Thrombocytopenia

›Hallmark finding alongside leukopenia

›Monitor platelet trend for bleeding risk stratification

›Rising platelets signal clinical improvement

›Serial monitoring

›At least daily CBC during hospitalization

›Monitor trajectory toward nadir then recovery

Hepatic panel

›Liver function tests

›AST and ALT elevation

›Mild-to-moderate elevation typical

›Peak expected around days 7–8 of illness

›Recovery expected with viral clearance

›Total bilirubin and alkaline phosphatase

›Less prominently elevated than aminotransferases

›Jaundice uncommon but possible in severe cases

›Clinical significance

›Elevated transaminases confirm hepatic involvement

›Worsening values suggest progressive disease

Coagulation studies

›DIC workup

›Prothrombin time and INR

›Prolongation suggests DIC or severe hepatic dysfunction

›Monitor in hemorrhagic presentations

›Partial thromboplastin time

›Additional coagulopathy marker

›Obtain if DIC suspected

›Fibrinogen and D-dimer

›Decreased fibrinogen and elevated D-dimer confirm DIC

›Note: coagulopathy was not prominent in index cases unlike SFTS

Pathogen-specific testing

›HRTV confirmatory testing

›RT-PCR for viral RNA

›Most useful in first 2 weeks of illness

›Available through state health departments and CDC only

›No commercial assays currently exist

›HRTV IgM and IgG serology

›Microsphere-based immunoassays developed at CDC

›Sensitivity and specificity > 95%

›IgM indicates recent infection

›Plaque reduction neutralization test (PRNT)

›Confirmatory serologic test

›Gold standard for antibody confirmation

›Bacterial tick-borne illness exclusion

›Ehrlichia chaffeensis PCR and serology

›Critical to rule out treatable bacterial illness

›Order simultaneously with HRTV testing

›Anaplasma phagocytophilum PCR

›Similar clinical presentation to HRTV

›Rapid PCR result guides antibiotic decisions

›RMSF serology (Rickettsia rickettsii)

›IFA serology; early serology may be negative

›Treat empirically if clinically suspected

Additional workup

›Peripheral blood smear

›Morphologic evaluation

›Exclude babesiosis (ring forms, Maltese cross)

›Exclude TTP (schistocytes)

›Exclude hematologic malignancy (blast cells)

›Neutrophil morphology

›Morulae (intracellular inclusions) suggest ehrlichiosis

›Absent morulae do not exclude ehrlichiosis

›Metabolic panel

›Electrolytes

›Hyponatremia common with systemic viral illness

›Correct electrolyte abnormalities

›Renal function (creatinine, BUN)

›Renal involvement not typical but monitor in severe cases

›Prerenal azotemia with dehydration

›Lactate

›Elevated lactate indicates hypoperfusion

›Guides fluid resuscitation

›Blood cultures

›Bacterial sepsis exclusion

›Obtain before empiric antibiotics

›Two sets from separate sites

›Negative cultures support viral etiology

06Diagnostic Tests/dt62

Scoring Systems

›Clinical severity assessment

›No validated HRTV-specific severity score exists

›Severity stratification based on clinical and lab parameters

›CDC case definition guides classification

›High-risk features for mortality

›Age > 70 years with comorbidities

›Altered mental status at presentation

›Platelet count < 50 x10^9/L

›Multiorgan failure

›SOFA score for organ failure quantification

›Respiratory, coagulation, hepatic, cardiovascular, renal, neurologic domains

›Score >= 2 organ dysfunction supports ICU admission

Scoring Systems additional

›HRTV epidemiologic case classification

›Confirmed case definition

›RT-PCR positive for HRTV RNA, OR

›Seroconversion or 4-fold rise in neutralizing antibody titer

›Suspected case definition

›Compatible illness with tick exposure in endemic region during tick season

›Leukopenia and thrombocytopenia without alternative explanation

MRI

›Brain MRI in encephalopathy

›Indications

›Persistent or worsening confusion not explained by metabolic cause

›Focal neurologic deficits

›CT head negative but encephalopathy persists

›Expected findings

07Disposition/dispo50

Admission criteria

›Hospital admission indications

›Significant cytopenias

›WBC < 3.0 x10^9/L or platelets < 100 x10^9/L

›88% of confirmed HRTV cases required hospitalization

›Inability to tolerate oral intake

›Persistent vomiting or diarrhea with dehydration

›Inability to take oral medications

›Confusion or altered mental status

›Any degree of encephalopathy

›High-risk feature for severe disease and mortality

›Hemodynamic instability

›Hypotension, tachycardia, signs of poor perfusion

›Requires IV fluid resuscitation

ICU criteria

›ICU admission indications

›Multiorgan failure

›Two or more organ systems affected

›SOFA score escalation

›Hemorrhagic disease or DIC

›Active bleeding with thrombocytopenia

›DIC confirmed on coagulation studies

›Hemodynamic instability not responding to fluids

›Vasopressor requirement

›Septic shock physiology

›Respiratory failure

›Uncommon in HRTV but possible

›SpO2 < 90% requiring supplemental oxygen or ventilation

08Treatment/t79

Empiric antibiotics

›Doxycycline empiric therapy

›Indication

›Start empirically when tick-borne illness suspected

›Covers ehrlichiosis and anaplasmosis while awaiting HRTV testing

›Dosing

›Doxycycline 100 mg PO or IV every 12 hours

›IV formulation preferred if unable to tolerate oral

›Duration and reassessment

›Continue until bacterial tick-borne illness excluded

›Discontinue if HRTV confirmed and no bacterial co-infection

›Failure to improve within 48 hours raises viral etiology suspicion

›Contraindications

›Allergy to tetracyclines

›Pregnancy (relative contraindication — see Special Populations)

Supportive care

›Antipyretic therapy

›Acetaminophen preferred

›650–1000 mg PO or IV every 6–8 hours as needed

›Maximum 4 g/24 hours in healthy adults; reduce dose in hepatic impairment

›NSAIDs contraindicated

›Increased bleeding risk with thrombocytopenia

›Avoid ibuprofen, naproxen, ketorolac

›Antiemetic therapy

›First-line antiemetics for nausea and vomiting

›Ondansetron 4 mg IV or PO every 6–8 hours as needed

›Metoclopramide 10 mg IV every 6–8 hours as alternative

›Avoid prochlorperazine in elderly patients

›Extrapyramidal side effects

›Anticholinergic burden in geriatric patients

›Fluid resuscitation

›IV fluid therapy

›0.9% NaCl or Lactated Ringer 1–2 L IV for dehydration

›Titrate to urine output 0.5 mL/kg/hour

›Oral rehydration if tolerated

›Oral hydration solutions for mild dehydration

›Encourage frequent small volumes if persistent nausea

Hematologic management

›Platelet transfusion

›Thresholds for transfusion

›Platelet count < 10 x10^9/L prophylactically

›Platelet count < 50 x10^9/L with active bleeding or invasive procedures

›Transfusion strategy

›One apheresis unit typical initial dose

›Recheck platelet count 1 hour post-transfusion

›Hematology consultation for refractory thrombocytopenia

›Packed red blood cell transfusion

›Indications for transfusion

›Hemoglobin < 70 g/L in stable patients

›Hemoglobin < 80 g/L in cardiac disease or active hemorrhage

›Transfusion considerations

›Type and screen on admission

›Irradiated products in immunocompromised patients

›DIC management

›Treat underlying cause

›Supportive care for HRTV as primary management

›No specific antiviral accelerates DIC resolution

›Component therapy

›Fresh frozen plasma 10–15 mL/kg for coagulopathy with bleeding

›Cryoprecipitate for fibrinogen < 1.5 g/L

›Platelet transfusion per thresholds above

Antiviral considerations

›No approved antiviral therapy

›No FDA-approved antiviral exists for HRTV

›Management is entirely supportive

›Investigational agents are not available outside research settings

›Investigational agents

›Favipiravir: RNA polymerase inhibitor; efficacy demonstrated in mouse models

›4'-fluorouridine (EIDD-2749): In vitro and murine efficacy data

›Ribavirin: Studied in IFNAR knockout mouse model; not routinely used

›Role of investigational access

›Compassionate use or expanded access protocols not established

›Contact CDC for guidance in critically ill patients

Electrolyte management

›Electrolyte correction

›Sodium

›Hyponatremia common with systemic viral illness and poor oral intake

›Correct sodium deficit at rate < 8–10 mmol/L per 24 hours

›Potassium

›Hypokalemia with vomiting and diarrhea

›Potassium chloride 20–40 mmol IV or PO per dose as needed

›Magnesium

›Replete magnesium sulfate 2 g IV over 20 minutes if < 0.6 mmol/L

›Oral magnesium for mild deficiency if tolerating PO

09Special Populations/sp59

Pregnancy

›Pregnancy considerations for HRTV

›Epidemiology in pregnancy

›No published series of HRTV in pregnancy; case data limited

›Theoretical concerns about maternal cytopenias and fetal risk

›Antibiotic considerations

›Doxycycline is FDA category D; avoid after first trimester if possible

›If ehrlichiosis cannot be excluded, doxycycline benefits likely outweigh risks

›Short courses of doxycycline acceptable for serious maternal illness

›Management priorities

›Maternal stabilization is primary priority

›Fetal monitoring per obstetric guidance

›Obstetrics consultation for all pregnant patients with suspected HRTV

›Hemorrhagic risk

›Thrombocytopenia increases obstetric hemorrhage risk

›Platelet transfusion thresholds may be higher in pregnancy

›Target platelets > 75 x10^9/L near term or delivery

Geriatric

›Geriatric considerations

›Epidemiology

›Median age of confirmed cases 71 years

›Mortality concentrated in elderly with comorbidities

›Mortality rate approximately 10–13% overall

›Altered presentation

›Confusion may be attributed to baseline cognitive impairment

›Lower physiologic reserve leads to faster decompensation

›Fever may be blunted in elderly with frailty

›Medication safety

10Background/b73

Epidemiology

›Disease burden and demographics

›Case counts

›Over 60 confirmed cases spanning 14 US states reported to CDC as of 2020

›First identified in Missouri in 2009 (McMullan et al., NEJM 2012)

›Likely underreported given lack of commercial testing

›Demographics

›Median age 71 years (range 43–80)

›75% male

›Mortality approximately 10–13%, concentrated in elderly with comorbidities

›Geographic distribution

›Midwest and southern US within Amblyomma americanum distribution range

›States with confirmed cases include Missouri, Tennessee, Kansas, Oklahoma, and others

›Seasonal pattern

›April through September corresponding to peak Lone Star tick activity

›No documented winter cases

›Vector and transmission

›Primary vector

›Lone Star tick (Amblyomma americanum)

›Tick attachment significantly associated with infection (P = 0.03)

›88% of confirmed cases reported a tick on themselves before illness

›Reservoir hosts

›White-tailed deer and small mammals serve as reservoir hosts

›Seroprevalence data in wildlife demonstrate broad animal exposure

›Human-to-human transmission not documented

Pathophysiology

›Viral classification and structure

›Taxonomy

›Heartland bandavirus (formerly Heartland phlebovirus)

›Family Phenuiviridae, genus Bandavirus

›Negative-sense, trisegmented RNA virus

›Genomic segments

›Large (L) segment encodes RNA-dependent RNA polymerase

›Medium (M) segment encodes glycoproteins Gn and Gc

›Small (S) segment encodes nucleocapsid protein and NSs protein

›Disease mechanism

›Viral entry and tropism

›HRTV infects mononuclear phagocytes, dendritic cells, lymph nodes

›HRTV antigen detected in lymph nodes on autopsy

›Hepatic involvement with transaminase elevation

›Immune evasion

›NSs (non-structural) protein suppresses type I interferon response

›Interferon antagonism allows viral replication to proceed

›IFNAR knockout mice have markedly increased susceptibility

›Cytopenia mechanism

›Leukopenia and thrombocytopenia result from viral suppression of hematopoiesis

›Direct viral infection of bone marrow progenitors suspected

›Recovery of cytopenias parallels viral clearance

›Severe disease pathway

›Multiorgan failure in fatal cases

›Hemorrhagic disease with DIC (less prominent than SFTS)

›Encephalopathy mechanism may involve direct CNS viral invasion or inflammatory mediators

Therapeutic Considerations

›Evidence base for management

›Antiviral research status

›No FDA-approved antiviral; management is supportive

›Favipiravir inhibits HRTV replication in vitro and in vivo murine models

›4'-fluorouridine (EIDD-2749) demonstrated efficacy in mouse models (Westover et al., 2024)

›Ribavirin studied in IFNAR knockout mouse model (Fujii et al., 2022)

›Doxycycline rationale

›Indicated empirically to cover bacterial mimics (ehrlichiosis, anaplasmosis)

›No direct antiviral activity against HRTV

›Should be reassessed once diagnostic results available

›Immune modulation considerations

›Corticosteroids not routinely recommended

›Immunosuppression may worsen viral replication based on animal data

›Avoid immunosuppressive agents unless compelling alternative indication

›Natural history

›Clinical course

›Illness typically lasts 2–4 weeks in survivors

›Cytopenias recover after viral clearance

›Full recovery expected in most immunocompetent patients

›Prognostic factors

›Age > 70 years with comorbidities most strongly associated with mortality

›Multiorgan failure portends poor prognosis

›Immunosuppression likely increases severity

11Patient Discharge Instructions/pdi34

copy discharge instructions

›Heartland virus discharge instructions

›About your illness

›Heartland virus is a rare tick-borne viral infection with no specific antiviral treatment

›Recovery takes weeks; fatigue and weakness are common during convalescence

›You will need follow-up blood tests to confirm your counts are recovering

›Follow-up appointments

›Blood recheck (CBC and liver tests) within 3–5 days of leaving hospital

›Return to your doctor if results are not improving

›Notify your doctor of any new symptoms during recovery

›Activity and diet

›Rest as needed; gradually increase activity as energy returns

›Drink plenty of fluids; aim for clear, pale urine

›Bland diet if nausea persists; avoid alcohol during recovery

›No contact sports or activities with bleeding risk until platelets fully recovered

›Medications to avoid

›Do not take ibuprofen, naproxen, aspirin, or any NSAID until blood counts are normal

›Avoid blood-thinning medications unless specifically directed by your physician

›Acetaminophen (Tylenol) is safe for fever and pain at recommended doses

›Return to emergency department immediately for

›Fever returning after discharge

›New or worsening confusion, difficulty thinking, or unusual behaviour

›Any bleeding: gums, nose, urine (pink or red), stool (black or red), unusual bruising

›Inability to keep fluids down

›Worsening fatigue, dizziness, or feeling faint

›Severe headache or stiff neck

›Tick prevention after recovery

›Wear long sleeves and pants in wooded or grassy areas

12References/r33

Guidelines and key sources

›Primary literature

›McMullan LK, Folk SM, Kelly AJ, et al. A New Phlebovirus Associated with Severe Febrile Illness in Missouri. N Engl J Med. 2012

›Index case description of Heartland virus

›Characterized temporal evolution of cytopenias and transaminases

›Staples JE, Pastula DM, Panella AJ, et al. Investigation of Heartland Virus Disease Throughout the United States, 2013-2017. Open Forum Infect Dis. 2020

›60+ cases across 14 states

›88% hospitalization rate; 10–13% mortality

›Pastula DM, Turabelidze G, Yates KF, et al. Notes From the Field: Heartland Virus Disease - United States, 2012-2013. MMWR. 2014

›Early surveillance data

›Epidemiologic characteristics of early confirmed cases

›Muehlenbachs A, Fata CR, Lambert AJ, et al. Heartland Virus-Associated Death in Tennessee. Clin Infect Dis. 2014

›Fatal case pathology and autopsy findings

›HRTV antigen in lymph nodes

›Westover JB, Jung KH, Alkan C, et al. Modeling Heartland Virus Disease in Mice and Therapeutic Intervention With 4'-Fluorouridine. J Virol. 2024

›EIDD-2749 efficacy in murine model

›Characterizes nadir and recovery of cytopenias

›Serologic and diagnostic references

›Basile AJ, Horiuchi K, Goodman CH, et al. Development of Diagnostic Microsphere-Based Immunoassays for Heartland Virus. J Clin Virol. 2021

›CDC microsphere immunoassays with > 95% sensitivity and specificity

›IgM and IgG detection methodology

›Brault AC, Savage HM, Duggal NK, Eisen RJ, Staples JE. Heartland Virus Epidemiology, Vector Association, and Disease Potential. Viruses. 2018

›Vector competence data for Amblyomma americanum

›Reservoir host seroprevalence

›Clinical practice guidelines

›Ho BM, Davis HE, Forrester JD, et al. Wilderness Medical Society Clinical Practice Guidelines for the Prevention and Management of Tick-Borne Illness in the United States. Wilderness Environ Med. 2021

›Tick-borne illness prevention and management framework

›Doxycycline empiric therapy guidance

Evidence & Review