Crimean-Congo hemorrhagic fever is a tick-borne viral hemorrhagic fever caused by a Nairovirus (Bunyaviridae family), transmitted primarily by Hyalomma ticks, with a case fatality rate of 10–40% (as low as 5% with high-quality supportive care). [1-2] It is the most geographically widespread tick-borne viral disease, endemic across Africa, Eastern Europe, the Middle East, and Asia, and has emerged in new European regions including Spain. [1-3]
1. History
- Tick exposure: Direct bite, crushing a tick with bare hands, or manual tick removal — ask about timing (incubation 1–14 days, typically 3–7 days after tick bite) [4-5]
- Occupational exposure: Farmers, veterinarians, slaughterhouse workers — contact with blood/tissues of viraemic livestock [5-6]
- Healthcare exposure: Contact with blood or body fluids of an infected patient (nosocomial transmission is well-documented) [7]
- Travel history: Residence in or travel to endemic areas (Turkey, Iran, Pakistan, Afghanistan, Central Asia, Balkans, Africa, Spain) [1-2]
- Outdoor activities: Hiking, camping, picnicking in endemic rural areas [5]
- Symptom characterization: Sudden onset of high fever (39–41°C), severe headache, myalgia, dizziness, followed by GI symptoms (nausea, vomiting, diarrhea, abdominal pain), then hemorrhagic manifestations [5]
- Progression: Four distinct phases — incubation → prehemorrhagic (avg 3 days) → hemorrhagic (days 3–5, lasting 2–3 days) → convalescence (day 10–20) [5]
- Important negatives: No respiratory symptoms early, no rash initially (petechiae appear in hemorrhagic phase)
2. Alarm Features
- Hemorrhagic manifestations: Petechiae, ecchymoses, epistaxis, hematemesis, melena, hematuria, gingival bleeding, menometrorrhagia, hemoptysis [5]
- Cerebral hemorrhage — can be rapidly fatal [5]
- DIC — an early and prominent feature of severe disease [5]
- Multiorgan failure: Hepatorenal insufficiency, shock [8]
- Altered mental status: Changes in mood and sensory perception in severe cases [4]
- Rapid platelet decline with active bleeding
- Hemophagocytic lymphohistiocytosis (HLH) — elevated ferritin, hypofibrinogenemia, hypertriglyceridemia [5][9]
3. Medications
- Ribavirin (WHO-recommended antiviral):
- Dosing: 30 mg/kg loading dose, then 15 mg/kg q6h × 4 days, then 7.5 mg/kg q8h × 6 days (oral or IV) [5]
- Most effective when started ≤96 hours from symptom onset; odds of death increase 2.4-fold per day without treatment [10-11]
- Adverse effects: hemolytic anemia, arrhythmia, bone marrow suppression, deranged liver function [2]
- Contraindicated in pregnancy (though some guidelines recommend use given high maternal mortality risk) [1]
- Evidence base remains debated — a 2018 Cochrane review found insufficient reliable evidence, but a meta-analysis showed a 1.7-fold reduction in mortality [2][12]
- Corticosteroids: May be beneficial alongside ribavirin, particularly in hemorrhagic/severe phases and HLH (~2.3-fold mortality reduction when combined with ribavirin) [9][12]
- Avoid: Aspirin, NSAIDs, IM injections, anticoagulants (unless specifically indicated, e.g., portal vein thrombosis), and any drugs affecting coagulation [5]
- Post-exposure prophylaxis: Oral ribavirin for healthcare workers with medium-to-high risk exposure [5][11]
4. Diet
- NPO or clear liquids during active hemorrhagic phase if GI bleeding is present
- Aggressive IV fluid and electrolyte replacement — crystalloids (normal saline or Ringer's lactate) are first-line [1]
- Avoid oral intake that could obscure GI hemorrhage assessment
- Nutritional support as tolerated during convalescence
5. Review of Systems
- Constitutional: Fever, fatigue, malaise, myalgia, arthralgia
- GI: Nausea, vomiting, diarrhea, abdominal pain, hematemesis, melena
- Hematologic: Bleeding from any site, easy bruising, petechiae
- Neurologic: Headache, dizziness, altered mental status, somnolence (severity marker) [13]
- Hepatic: Jaundice, RUQ pain (hepatomegaly in 20–40%) [5]
- Cardiac: Palpitations, chest pain (myocarditis possible) [14-15]
- Urinary: Hematuria
- Respiratory: Hemoptysis
- Gynecologic: Menometrorrhagia
6. Collateral History and Family History
- Household contacts: Other family members with tick exposure or febrile illness
- Occupational contacts: Co-workers in livestock/agricultural settings
- Healthcare contacts: Any recent hospitalization or medical procedures in endemic areas — nosocomial transmission accounts for a significant proportion of cases [7]
- Funeral attendance: Contact with deceased CCHF patients is a transmission risk
- Family history is not a major factor (no hereditary predisposition), but household clustering from shared tick exposure can occur
7. Risk Factors
- Tick bite (Hyalomma species) — identified in 68% of cases [10]
- Rural residence (87% of cases in one large Turkish cohort) [10]
- Occupational exposure: Farmers, herders, veterinarians, slaughterhouse workers [6]
- Healthcare workers: Nurses and physicians most affected; splashes with blood/body fluids (OR 4.2), treating patients who died (OR 3.8) [7][11]
- Age ≥50 years (OR 3.1 for mortality) [10]
- Comorbidities: Diabetes mellitus (OR 4.49 for mortality), chronic heart disease, hypertension [10]
- Male sex (65.7% of cases) [10]
- Seasonal: Peak during spring/summer months when ticks are active
8. Differential Diagnosis
The differential varies by geographic location: [5]
- Malaria — most likely diagnosis in febrile travelers; must be ruled out urgently with blood films [16]
- Dengue hemorrhagic fever — similar thrombocytopenia and hemorrhagic features
- Other viral hemorrhagic fevers: Ebola, Marburg, Lassa fever, Rift Valley fever [4]
- Hantavirus hemorrhagic fever with renal syndrome
- Bacterial: Meningococcemia, leptospirosis, rickettsial diseases (Mediterranean spotted fever), typhoid
- Thrombotic thrombocytopenic purpura (TTP) / HUS
- Acute leukemia — can mimic with pancytopenia and bleeding
- Scrub typhus — important in South Asian endemic overlap areas [17]
- HLH from other causes [9]
9. Past Medical History
- Prior tick bites or CCHF exposure (IgG positivity indicates prior infection but does not confirm acute disease) [5]
- Diabetes mellitus — strongest comorbidity predictor of mortality [10]
- Chronic liver disease — may worsen coagulopathy
- Immunosuppression — may alter disease course
- Peptic ulcer disease — increased GI bleeding risk; use H2 blockers prophylactically [5]
- Pregnancy — associated with high maternal and fetal mortality; ribavirin use is controversial [1]
10. Physical Exam
- Vitals: High fever (39–41°C), tachycardia (resting HR >96 bpm associated with severe disease in children), hypotension in shock; bradycardia may occur during convalescence or with ribavirin [5][18-19]
- Skin: Petechiae, ecchymoses, large hematomas, injection site bleeding [5]
- Face/neck/chest: Hyperemia, flushing [5]
- Eyes: Conjunctival injection, congested sclera, subconjunctival hemorrhage [5]
- Abdomen: Hepatomegaly (20–40%), splenomegaly (14–23%), tenderness [5]
- Oropharynx: Gingival bleeding, palatal petechiae
- Neurologic: Somnolence (a severity criterion in the Swanepoel/SSI scoring) [13]
- Tick search: Examine scalp, axillae, groin, behind ears
11. Lab Studies
- CBC: Thrombocytopenia (hallmark — platelet cutoff <21.5 × 10⁹/L has 82% sensitivity/specificity for confirmed CCHF), leukopenia, lymphopenia (lymphocyte <1.19 × 10⁹/L is an early marker with AUC 0.976) [20-21]
- Liver enzymes: Elevated AST, ALT (AST often disproportionately elevated) [5][22]
- LDH and CK: Elevated — useful early diagnostic clues [5-6]
- Coagulation: Prolonged PT, aPTT, elevated D-dimer, low fibrinogen (DIC panel) [6][13]
- Ferritin: Markedly elevated in HLH complication [9]
- Triglycerides: Elevated in HLH [9]
- Renal function: Elevated creatinine in severe cases
- Potassium: Elevated K is a predictor of CCHF in ED [22]
- Blood type and crossmatch: Essential given transfusion needs
12. Imaging
- Imaging is not primary for diagnosis but is used to evaluate complications
- Abdominal CT: To assess for intra-abdominal hemorrhage, hepatosplenomegaly, portal vein thrombosis (rare complication) [9]
- Chest X-ray: Pleural effusion, pulmonary hemorrhage
- Echocardiography: Indicated in severe cases — may show reduced LVEF, pericardial effusion, segmental wall motion abnormalities (all more common in fatal cases) [15][23]
- CT head: If altered mental status or suspected cerebral hemorrhage
13. Special Tests
- RT-PCR (gold standard for early diagnosis): Positive during viremic phase (first ~7 days of illness) [5][24]
- ELISA: IgM positivity confirms acute infection (appears later in disease); IgG alone does not confirm acute disease [5]
- Severity Scoring Index (SSI): Includes platelet count, bleeding, fibrinogen, aPTT, and somnolence — accurate predictor of death (OR 3.27 per point increase) [13]
- Swanepoel criteria (revised): Used to define severe cases and guide ribavirin initiation [5]
- DIC score: Correlates with cytokine levels and mortality [5]
- Specimens must be handled under BSL-4 conditions; notify the laboratory before sending samples [16][24]
14. ECG
- Tachycardia: Common; resting HR >96 bpm is an independent risk factor for severe disease [18]
- Bradycardia: Reversible bradycardia reported, particularly in pediatric patients — may be disease-related or ribavirin-associated [19]
- Supraventricular tachycardia: Reported as an uncommon presentation [17]
- T-wave changes, bundle branch block: Described as cardiac complications [14]
- Myocarditis pattern: ST changes, low voltage — consider if troponin elevated or echo abnormal [14-15]
- ECG monitoring is recommended in all hospitalized patients, especially those receiving ribavirin (risk of arrhythmia) [2]
15. Assessment
CCHF progresses through four clinical phases: [5]
- Incubation (1–14 days, typically 3–7 days post-tick bite)
- Prehemorrhagic phase (1–7 days): Nonspecific febrile illness — fever, headache, myalgia, GI symptoms
- Hemorrhagic phase (days 3–5 of illness, lasting 2–3 days): Petechiae → ecchymoses → mucosal/visceral bleeding → DIC → multiorgan failure
- Convalescence (begins day 10–20 in survivors): Labile pulse, alopecia, polyneuritis
Severity stratification using the SSI (platelet count, bleeding, fibrinogen, aPTT, somnolence) guides treatment decisions. [13] Children generally have milder disease and lower mortality (~2%) compared with adults (~5–13%). [10][25] Many infections are subclinical. [2]
16. Treatment Plan
Initial stabilization
- Isolate immediately — single-patient room, closed door [4]
- Strict barrier precautions and PPE (see Infection Control below)
- IV access (minimize invasive procedures; avoid IM injections) [5]
Supportive care (cornerstone of management)
- IV crystalloid resuscitation (NS or Ringer's lactate) [1]
- Blood product replacement: Platelets, FFP, packed RBCs, cryoprecipitate — guided by CBC checked 1–2 times daily [5]
- Fluid and electrolyte monitoring [5]
- GI prophylaxis: H2 blockers for peptic ulcer prevention [5]
Antiviral therapy
- Ribavirin: Start as early as possible (ideally ≤96 hours from symptom onset) [10-11]
- Loading dose: 30 mg/kg IV/PO
- Days 1–4: 15 mg/kg q6h
- Days 5–10: 7.5 mg/kg q8h [5]
- Mild cases may not require ribavirin [2][5]
Adjunctive therapy
- Corticosteroids: Consider in severe/hemorrhagic cases and suspected HLH — prednisolone or methylprednisolone [9][12-13]
- IVIG: Experimental; some evidence of benefit [26]
Infection control
- Suspected stable patients: Fluid-resistant gown, face shield, facemask, double gloves [4]
- Confirmed or unstable patients (bleeding/vomiting/diarrhea): Impermeable gown, PAPR or N95, double gloves, boot covers, apron [4]
- Avoid aerosol-generating procedures when possible; use AIIR if AGPs are necessary [4][27]
- Post-exposure prophylaxis: Oral ribavirin for healthcare workers with medium-to-high risk exposure (blood/body fluid splash, needlestick) [5][11]
17. Disposition
- All confirmed or suspected CCHF cases require hospital admission with isolation [5]
- ICU admission criteria: Active hemorrhage, DIC, hemodynamic instability, multiorgan failure, altered mental status, need for blood product resuscitation — ICU required in ~8% of cases [10]
- Infectious disease and public health notification are mandatory — CCHF is a notifiable disease and a CDC Category C bioterrorism agent [8]
- Contact tracing: All healthcare and household contacts must be identified, monitored for 14 days, and offered PEP if high-risk [5][11][28]
- Discharge criteria: Afebrile, no active bleeding, rising platelet count, improving transaminases, clinically stable — typical hospital stay ~7–10 days [5][25]
18. Follow Up / Return Precautions
- Follow-up: Infectious disease clinic within 1–2 weeks of discharge; repeat CBC, LFTs, coagulation studies
- Convalescent symptoms: Patients should be counseled about possible labile pulse, tachycardia, temporary alopecia, polyneuritis, fatigue, memory difficulties, xerostomia, and visual/hearing changes [5]
- Return immediately for: Recurrent fever, any new bleeding (gums, nose, stool, urine), worsening abdominal pain, confusion, dizziness/syncope, chest pain
- Avoid pregnancy for at least 6 months after ribavirin therapy [1]
- Expected recovery: Convalescence begins 10–20 days after illness onset; most symptoms resolve, though some neurologic sequelae may persist [5]
- No known relapse of infection [5]
- Serology follow-up: IgG seroconversion confirms prior infection and likely confers immunity
References
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