Viral Haemorrhagic Fevers (VHF)

1. Clinical Overview

Summary

Viral Haemorrhagic Fevers (VHFs) represent a clinically and epidemiologically diverse group of acute febrile illnesses caused by RNA viruses from four distinct families: Filoviridae, Arenaviridae, Bunyaviridae, and Flaviviridae. These pathogens are united by their capacity to cause severe multisystem disease characterized by microvascular instability, increased vascular permeability, and impaired haemostasis, culminating in a syndrome of fever, coagulopathy, and shock. [1,2]

VHFs are classified as high-consequence infectious diseases (HCID) due to their high case-fatality rates (ranging from 1% to 90% depending on the pathogen), potential for person-to-person transmission, limited therapeutic options, and the requirement for specialized biosafety containment facilities for clinical management and laboratory diagnosis. [3,4] The clinical presentation is often non-specific in early stages, making differentiation from more common tropical infections such as malaria challenging, yet critical given the infection control implications.

The global health security threat posed by VHFs was starkly demonstrated during the 2014-2016 West African Ebola epidemic, which resulted in 28,616 cases and 11,310 deaths across Guinea, Liberia, and Sierra Leone. [5] This outbreak catalyzed unprecedented international research efforts that have transformed the therapeutic landscape, with the development of effective monoclonal antibody treatments and accelerated vaccine platforms.

Key Virus Families and Pathogens

1. Filoviridae

• Ebola virus disease (EVD): Six species identified (Zaire, Sudan, Bundibugyo, Taï Forest, Reston, Bombali), with Zaire ebolavirus causing the highest mortality.
• Marburg virus disease (MVD): Closely related to Ebola, first identified in 1967 in laboratory workers in Marburg, Germany.
• Reservoir: Fruit bats (Rousettus aegyptiacus and Pteropodidae family).
• Geographic distribution: Central and West Africa, with sporadic outbreaks in Uganda, DRC, Guinea, Liberia, Sierra Leone.

2. Arenaviridae

• Lassa fever: Most significant arenavirus in terms of disease burden, endemic in West Africa.
• South American hemorrhagic fevers: Junin (Argentina), Machupo (Bolivia), Guanarito (Venezuela), Sabiá (Brazil).
• Reservoir: Rodents, particularly the multimammate rat (Mastomys natalensis) for Lassa fever.
• Geographic distribution: West Africa (Lassa), South America (others).

3. Bunyaviridae (now Hantaviridae, Nairoviridae, Phenuiviridae)

• Crimean-Congo haemorrhagic fever (CCHF): Most geographically widespread tick-borne viral disease.
• Rift Valley fever (RVF): Primarily affects livestock, with human disease during epizootic outbreaks.
• Hantavirus pulmonary syndrome: New World hantaviruses causing severe pulmonary disease.
• Reservoir: Ticks (Hyalomma spp. for CCHF), mosquitoes (RVF), rodents (hantavirus).
• Geographic distribution: CCHF in Africa, Asia, Eastern Europe, Balkans; RVF in sub-Saharan Africa and Arabian Peninsula.

4. Flaviviridae

• Yellow fever: Vaccine-preventable disease remaining endemic in tropical Africa and South America.
• Dengue haemorrhagic fever: Leading cause of serious illness and death in some Asian and Latin American countries.
• Reservoir: Mosquitoes (Aedes aegypti primarily).
• Geographic distribution: Tropical and subtropical regions worldwide.

Clinical Pearls

The Malaria Imperative: In any febrile patient returning from malaria-endemic regions, Plasmodium falciparum infection must be excluded urgently, as it is both common and immediately treatable. Severe malaria can mimic VHF with fever, prostration, bleeding manifestations, and shock. However, VHF remains a critical differential requiring simultaneous consideration with appropriate biosafety precautions during diagnostic evaluation. [6]

The "21-Day Rule": The maximum incubation period for most VHFs (Ebola, Marburg, Lassa) is 21 days, though the majority of cases present within 8-12 days of exposure. A patient who remained well for more than 21 days after leaving an endemic area has effectively excluded most VHFs, though rare exceptions exist. Notably, viral persistence in immunologically privileged sites can lead to delayed presentations or recrudescent illness. [7,8]

"Dry" versus "Wet" Disease Phases:

• Early Phase (Days 1-5): Non-specific febrile illness with headache, myalgia, arthralgia, weakness. Viral load in blood is rising but patients are relatively less infectious.
• Late Phase (Days 5-10+): Gastrointestinal symptoms (vomiting, diarrhea), hemorrhagic manifestations, shock, organ failure. High viral loads in all body fluids make this phase extremely infectious. [9,10]

Healthcare Worker Risk: Nosocomial transmission to healthcare workers is a hallmark of VHF outbreaks. During the 2014-2016 West African Ebola outbreak, 881 healthcare workers were infected with a case-fatality rate of 57%. [11] This underscores the absolute requirement for appropriate personal protective equipment (PPE) and adherence to infection prevention and control (IPC) protocols.

---

2. Epidemiology

Global Distribution and Endemicity

VHFs demonstrate distinct geographic patterns reflecting their zoonotic reservoirs and arthropod vectors:

Ebola and Marburg (Filoviruses)

Endemic zones include the tropical rainforest regions of Central and West Africa. Major outbreaks have occurred in:

• Democratic Republic of Congo (DRC): Recurrent outbreaks since 1976, including the 2018-2020 North Kivu/Ituri outbreak with 3,481 cases.
• Uganda: Multiple Ebola (Sudan species) and Marburg outbreaks.
• West Africa: The 2014-2016 epidemic primarily affected Guinea, Liberia, and Sierra Leone, representing the largest Ebola outbreak in history. [5,12]

The case-fatality rate varies by species: Zaire ebolavirus (50-90%), Sudan ebolavirus (40-60%), Bundibugyo ebolavirus (~30%). [13]

Lassa Fever

Endemic in West Africa, particularly Nigeria, Sierra Leone, Liberia, and Guinea, with an estimated 100,000-300,000 infections annually and approximately 5,000 deaths. [14] Seroprevalence studies suggest 10-16% of the population in endemic regions has evidence of prior infection. In Nigeria, Lassa fever accounts for 10-16% of adult medical admissions during the dry season (January-April). [15]

The case-fatality rate in hospitalized patients ranges from 15-20%, but overall mortality including mild community cases is estimated at 1-2%. [16]

Crimean-Congo Haemorrhagic Fever

The most geographically widespread tick-borne viral disease, occurring across Africa, the Balkans, the Middle East, and Asia. Countries with regular reported cases include Turkey, Iran, Pakistan, Afghanistan, and several Central Asian republics. [17] Climate change and agricultural practices that support tick populations and livestock movement are expanding the geographic range of CCHF. [18]

Case-fatality rates range from 5-30%, with higher mortality associated with nosocomial infections and delays in supportive care. [19]

Yellow Fever

Despite the availability of an effective vaccine since 1937, yellow fever remains endemic in 47 countries in tropical Africa and Central and South America. The WHO estimates 200,000 cases and 30,000 deaths occur annually, though surveillance in remote areas is limited. [20,21] Recent urban outbreaks in Brazil (2017-2018) and Angola/DRC (2016) have raised concerns about the potential for spread to Asia, where competent Aedes vectors exist but the virus has never been documented.

Transmission Dynamics

Primary Transmission (Zoonotic Spillover)

Initial human infection results from contact with infected animal reservoirs or arthropod vectors:

• Filoviruses: Direct contact with fruit bats or intermediate hosts such as non-human primates, duikers (small antelopes). Hunting, butchering, and consumption of bushmeat are major risk factors. [22]
• Lassa virus: Inhalation of aerosolized rat urine or feces in households where Mastomys rodents live commensally, or direct contact with infected rodents during food preparation or storage. [23]
• CCHF: Tick bites (Hyalomma spp.), crushing ticks, or contact with blood or tissues from infected livestock during slaughter or veterinary procedures. [24]
• Yellow fever/Dengue: Mosquito bites (Aedes aegypti, Aedes albopictus).

Secondary Transmission (Human-to-Human)

Most VHFs can be transmitted from person to person through direct contact with:

1. Blood and body fluids: Blood, vomit, feces, urine, saliva, sweat, breast milk, semen, vaginal fluids.
2. Contaminated objects: Needles, syringes, bedding, medical equipment.
3. Aerosol (rare): While primarily transmitted through contact, Lassa fever viral RNA can be detected in aerosols, and theoretical aerosol transmission of Ebola has been demonstrated in animal models, though human cases are not well-documented. [25,26]

Nosocomial transmission is particularly significant, with healthcare settings serving as amplification sites during outbreaks. Factors contributing to healthcare-associated transmission include:

• Inadequate infection control infrastructure (PPE, isolation facilities).
• High patient viral loads during the symptomatic phase.
• Invasive procedures generating infectious aerosols or sharps injuries.
• Cultural practices such as traditional healing or funeral rites in healthcare facilities. [27]

Funeral-associated transmission: Traditional burial practices involving washing, touching, and kissing of deceased individuals who died from VHF have been major drivers of transmission, particularly during Ebola outbreaks. Corpses remain highly infectious for several days post-mortem. [28]

Sexual transmission: Ebola virus can persist in semen for more than 12 months after recovery, and sexual transmission has been documented. Testing of semen and counseling on safe sexual practices are now standard components of survivor care programs. [29,30]

Risk Factors for Infection

Individual-level risk factors include:

• Residence in or travel to endemic areas during the incubation period.
• Direct contact with confirmed or suspected VHF cases.
• Healthcare work without appropriate PPE.
• Attendance at funerals or participation in burial rites.
• Contact with bats, non-human primates, or rodents (butchering, consumption).
• Occupational exposure: veterinarians, abattoir workers, agricultural workers (CCHF).
• Tick bites in endemic regions (CCHF).
• Lack of yellow fever vaccination prior to travel to endemic zones.

Population-level factors include:

• Weak health systems with limited laboratory capacity and IPC infrastructure.
• Ecological changes bringing humans into closer contact with reservoir species.
• Armed conflict and population displacement disrupting healthcare and surveillance.
• Cultural practices that increase exposure to infectious materials.

---

3. Pathophysiology

Molecular Mechanisms of Vascular Dysfunction

The hallmark of VHF pathogenesis is diffuse microvascular damage leading to increased vascular permeability, coagulopathy, and shock. The mechanisms are multifactorial and incompletely understood, but involve direct viral cytopathic effects, dysregulated immune responses, and perturbations of the coagulation system.

Viral Entry and Early Replication

Filoviruses and arenaviruses target dendritic cells and macrophages as initial sites of replication. [31] Ebola virus utilizes glycoproteins (GP) to bind to cellular receptors including C-type lectins (DC-SIGN, DC-SIGNR), T-cell immunoglobulin and mucin domain 1 (TIM-1), and Niemann-Pick C1 (NPC1) intracellular cholesterol transporter. [32] Following receptor-mediated endocytosis and low-pH triggered membrane fusion, viral replication proceeds in the cytoplasm.

Viral dissemination occurs via lymphatic and hematogenous routes to the liver, spleen, and other organs. Hepatocytes, adrenal cortical cells, and vascular endothelial cells become infected, with high viral burdens detected in these tissues at autopsy. [33]

Innate Immune Evasion

VHF viruses have evolved sophisticated mechanisms to evade and suppress host innate immune responses:

Type I Interferon Antagonism: Ebola VP35 and VP24 proteins inhibit interferon regulatory factor 3 (IRF-3) activation and interferon-alpha/beta receptor signaling, respectively, allowing unchecked viral replication early in infection. [34] Lassa virus nucleoprotein similarly inhibits IRF-3 activation. [35]

Dendritic Cell Paralysis: Infection of dendritic cells impairs their maturation and antigen presentation, preventing effective activation of adaptive immunity. [36]

Cytokine Storm and Vascular Permeability

Infected macrophages and dendritic cells produce massive quantities of pro-inflammatory cytokines and chemokines including tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), IL-8, monocyte chemoattractant protein-1 (MCP-1), and macrophage inflammatory protein-1 (MIP-1α/β). [37] This "cytokine storm" contributes to:

1. Endothelial Activation: Pro-inflammatory mediators activate endothelial cells, upregulating adhesion molecules and increasing vascular permeability.
2. Glycocalyx Degradation: The endothelial glycocalyx layer is disrupted, further increasing permeability.
3. Capillary Leak Syndrome: Fluid shifts from intravascular to interstitial compartments, leading to hypovolemic shock, tissue edema, and organ hypoperfusion.

Importantly, direct viral infection of endothelial cells is relatively limited in Ebola virus disease, suggesting that endothelial dysfunction is primarily mediated by inflammatory cytokines rather than viral cytopathic effects. [38]

Coagulopathy and Hemorrhage

Bleeding manifestations, when present, result from multifactorial coagulopathy:

1. Hepatocellular Necrosis: Viral infection and inflammatory injury to hepatocytes impair synthesis of clotting factors (II, V, VII, IX, X) and anticoagulant proteins (protein C, protein S, antithrombin).

2. Consumptive Coagulopathy: Activation of the coagulation cascade with thrombin generation, fibrin deposition in microvasculature, and consumption of platelets and clotting factors resembles disseminated intravascular coagulation (DIC). [39]

3. Platelet Dysfunction: Thrombocytopenia results from bone marrow suppression, peripheral consumption, and platelet activation with subsequent clearance.

4. Fibrinolysis: Elevated tissue plasminogen activator (tPA) and reduced plasminogen activator inhibitor-1 (PAI-1) shift the hemostatic balance toward clot lysis.

Notably, overt hemorrhage occurs in fewer than 50% of patients and is a late manifestation typically seen in severe disease. [40] When present, bleeding sites include gingival margins, venipuncture sites, gastrointestinal tract (hematemesis, melena), and mucosal surfaces (epistaxis, menorrhagia).

Organ-Specific Pathology

Liver: Hepatocellular necrosis with minimal inflammation, Councilman bodies (apoptotic hepatocytes), and microvesicular steatosis. Transaminase elevations (AST typically > ALT) reflect hepatocyte injury. [41]

Adrenal Glands: Adrenal cortical necrosis contributes to refractory hypotension through relative adrenal insufficiency. [42]

Spleen: Lymphoid depletion and necrosis of splenic white pulp, impairing adaptive immune responses.

Kidneys: Acute tubular necrosis secondary to hypoperfusion, direct viral cytopathic effects, and inflammatory injury. Proteinuria and elevated creatinine are common. [43]

Lungs: Acute respiratory distress syndrome (ARDS) can develop due to capillary leak, direct viral lung injury, and secondary bacterial pneumonia.

Central Nervous System: Viral invasion can occur with meningoencephalitis, particularly in Lassa fever which may present with deafness and seizures. [44]

---

4. Clinical Presentation

Incubation Period

The interval between exposure and symptom onset varies by pathogen:

• Ebola: 2-21 days (mean 8-10 days)
• Marburg: 2-21 days (mean 5-10 days)
• Lassa fever: 6-21 days (mean 10-12 days)
• CCHF: 1-13 days (mean 3-7 days)
• Yellow fever: 3-6 days
• Dengue: 4-10 days (mean 5-7 days) [45]

Patients are generally not infectious during the incubation period. Viral shedding and transmissibility correlate with symptom onset and severity.

Disease Phases

Phase 1: Non-Specific Febrile Illness (Days 1-5)

Initial presentation is indistinguishable from common tropical infections:

Constitutional Symptoms:

• Fever: Abrupt onset, typically > 38.5°C (101.3°F), often > 40°C
• Severe headache: Frontal or retro-orbital
• Myalgia and arthralgia: Particularly affecting the back, limbs
• Profound asthenia (weakness) and malaise
• Anorexia

Additional Features:

• Sore throat and pharyngitis (particularly Lassa fever)
• Conjunctival injection (red eyes)
• Non-productive cough
• Chest pain

At this stage, physical examination may reveal only fever, tachycardia, and relative hypotension. The absence of specific signs makes early diagnosis challenging but critical from an infection control perspective.

Phase 2: Established Disease (Days 5-10)

Gastrointestinal Manifestations:

• Nausea and intractable vomiting
• Severe watery diarrhea (may exceed 5-10 liters daily in severe cases)
• Abdominal pain and tenderness
• Hepatomegaly (liver edge may be tender)

The gastrointestinal fluid losses are a major contributor to hypovolemic shock and electrolyte derangements (hypokalemia, hypomagnesemia, hypocalcemia) that characterize severe disease. [46]

Hemorrhagic Manifestations (when present):

• Petechiae and ecchymoses
• Conjunctival hemorrhage
• Bleeding from venipuncture sites and mucous membranes
• Gingival bleeding
• Epistaxis (nosebleeds)
• Hematemesis (coffee-ground or frank blood)
• Melena or hematochezia
• Vaginal bleeding (menorrhagia or non-menstrual)

Neurological Manifestations:

• Confusion and disorientation
• Agitation or delirium
• Tremors
• Seizures (particularly Lassa fever)
• Cranial nerve deficits
• Encephalopathy progressing to coma

Respiratory Manifestations:

• Dyspnea and tachypnea
• Pulmonary edema (secondary to capillary leak)
• ARDS in severe cases
• Secondary bacterial pneumonia

Cardiovascular Manifestations:

• Hypotension and shock (initially distributive, progressing to hypovolemic and cardiogenic components)
• Tachycardia
• Weak peripheral pulses
• Prolonged capillary refill time
• Arrhythmias (electrolyte-mediated)

Phase 3: Recovery or Deterioration (Days 10-14+)

Fatal Cases: Progression to multi-organ failure with refractory shock, anuria, respiratory failure, severe hemorrhage, and disseminated intravascular coagulation. Death typically occurs between days 7-12 in Ebola, often preceded by profound obtundation or coma. Hypoglycemia is common in terminal stages. [47]

Survivors: Clinical improvement is often sudden, with defervescence, resolution of gastrointestinal symptoms, stabilization of hemodynamics, and mental clearing. However, convalescence is prolonged with persistent weakness, anorexia, weight loss, and neuropsychological symptoms lasting weeks to months.

Pathogen-Specific Features

Ebola Virus Disease

• Maculopapular rash: Appears around day 5-7, initially on face and neck, spreading centrifugally. Rash may desquamate during convalescence.
• Hiccups: Persistent hiccups are a specific but late sign associated with poor prognosis, reflecting diaphragmatic irritation or neurological involvement.
• "Red eye" syndrome: Marked conjunctival injection.
• Hemorrhage: Overt bleeding occurs in 20-40% of cases, more common in fatal outcomes. [48]
• Viral load correlation: High viremia (Ct value less than 20) at presentation strongly predicts mortality and guides treatment intensity. [127]

Lassa Fever

• Pharyngitis: Exudative pharyngitis with white patches on tonsils (distinctive but not pathognomonic).
• Retrosternal chest pain: May mimic myocardial infarction.
• Proteinuria: Marked proteinuria (> 300 mg/dL) is associated with poor prognosis.
• Deafness: Sensorineural hearing loss occurs in approximately 25% of survivors, often permanent. [49]
• Milder illness: Many cases are subclinical or mild; severe disease occurs in ~20% of infections.

Marburg Virus Disease

• Clinical features closely resemble Ebola virus disease.
• High fever, severe headache, myalgia followed by gastrointestinal symptoms and hemorrhage.
• "Ghost-like" drawn features, deep-set eyes, extreme lethargy. [50]

Crimean-Congo Haemorrhagic Fever

• Biphasic fever: Initial febrile period followed by brief remission, then recurrence with hemorrhagic manifestations.
• Mood changes: Agitation, aggression, mental confusion early in disease.
• Extensive ecchymoses: Large areas of bruising, particularly at injection sites.
• Hepatomegaly: Liver enlargement with severe hepatic dysfunction.
• Hemorrhage: More prominent than in Ebola, with petechial rash progressing to large ecchymoses and active bleeding. [51]

Yellow Fever

• Triad of jaundice, hemorrhage, and proteinuria in severe disease (historically "yellow jack").
• Toxic phase: After 3-4 days of fever, brief remission may occur, followed by return of fever with jaundice, hemorrhage (black vomit - "vomito negro"), oliguria, and shock.
• Hepatorenal syndrome: Combined acute liver failure and kidney injury.
• Myocarditis: Bradycardia relative to fever (Faget's sign). [52]

---

5. Differential Diagnosis

The initial non-specific presentation of VHF mandates consideration of more common tropical infections:

Malaria

• Plasmodium falciparum: Severe malaria can present with fever, prostration, bleeding (from thrombocytopenia and DIC), jaundice, acute kidney injury, shock. Thick and thin blood films, rapid diagnostic tests, or PCR are diagnostic.
• Critical distinction: Malaria is immediately treatable and must not be missed. Conversely, misdiagnosis of VHF as malaria can lead to nosocomial transmission.

Typhoid Fever

• Caused by Salmonella typhi. Gradual fever onset, relative bradycardia, rose spots, hepatosplenomegaly. Blood cultures diagnostic. Less likely to present with hemorrhage or severe shock in early disease.

Rickettsial Infections

• Typhus (Rickettsia prowazekii, R. typhi): Fever, headache, maculopapular rash, altered mental status. Endemic to similar regions as some VHFs.
• Spotted fever group: R. africae (African tick bite fever) common in travelers. Eschar at inoculation site, regional lymphadenopathy.

Meningococcal Septicemia

• Fulminant presentation with fever, petechial/purpuric rash, shock, and DIC mimics VHF. Rapid progression over hours. Gram stain and culture of blood/CSF diagnostic. More common in meningitis belt of sub-Saharan Africa (different distribution than most VHFs).

Dengue and Dengue Hemorrhagic Fever

• Mosquito-borne flavivirus endemic in tropical/subtropical regions worldwide. Fever, retro-orbital headache, myalgia ("breakbone fever"), rash, thrombocytopenia. Dengue hemorrhagic fever presents with plasma leakage, bleeding, and shock. Tourniquet test may be positive. Serology (IgM/IgG) and PCR diagnostic. [53]

Leptospirosis

• Spirochete infection from rodent urine exposure (overlapping risk with Lassa fever). Biphasic illness with fever, myalgia, conjunctival suffusion, jaundice (Weil's disease), renal failure, and hemorrhage. Serology and PCR diagnostic.

Sepsis from Other Causes

• Bacterial sepsis (e.g., Staphylococcus aureus, Streptococcus pyogenes, Gram-negative organisms) can present with fever, shock, and DIC. Blood cultures essential.
• Fungal sepsis in immunocompromised patients.

Non-Infectious Mimics

• Acute leukemia with hyperleukocytosis and bleeding.
• Thrombotic thrombocytopenic purpura (TTP) or hemolytic uremic syndrome (HUS).
• Acute liver failure from other causes (toxins, medications).

---

6. Investigations

Pre-Analytical Considerations: Biosafety

CRITICAL: Suspected VHF cases require immediate implementation of strict biosafety protocols to protect laboratory personnel:

1. Clinical communication: Notify laboratory staff before sending samples. Use dedicated "high-risk pathogen" alert systems.
2. Sample handling: Minimize sample volume, use leak-proof containers with biohazard labels.
3. Laboratory processing: Ideally, testing should occur in a Biosafety Level 4 (BSL-4) laboratory or designated high-consequence pathogen facility. In resource-limited settings, point-of-care testing may be employed to avoid laboratory processing.
4. Personal protective equipment: Laboratory staff must use appropriate PPE including gloves, gowns, face shields, and respirators during sample handling. [54]

Point-of-Care Testing

Malaria Rapid Diagnostic Tests (RDTs):

• Essential to exclude malaria as the cause of fever.
• Can be performed at bedside, minimizing laboratory exposure.
• Sensitivity > 95% for P. falciparum at parasite densities > 100 parasites/μL. [55]

Blood glucose:

• Hypoglycemia common in severe disease and associated with poor prognosis.
• Point-of-care glucometry avoids laboratory sample processing.

Confirmatory Diagnostic Tests for VHF

Molecular Detection (Gold Standard)

Reverse Transcription Polymerase Chain Reaction (RT-PCR):

• Detects viral RNA in blood, plasma, or serum.
• High sensitivity and specificity, capable of detecting as few as 10-100 viral copies/mL.
• Provides quantitative viral load, which correlates with disease severity and prognosis.
• Results typically available within 4-6 hours.
• Ebola virus RT-PCR can detect viremia 3 days before symptom onset in exposed individuals. [56]
• Multiplex RT-PCR assays enable simultaneous detection and differentiation of multiple hemorrhagic fever viruses (Ebola, Marburg, Lassa, CCHF, RVF, dengue, yellow fever) from a single sample, critical for differential diagnosis in endemic regions. [128]

GeneXpert Ebola Assay:

• Automated RT-PCR platform providing results in approximately 90 minutes.
• Deployed during West African Ebola outbreak to decentralize testing capacity.
• Sensitivity 97%, specificity 100% compared to reference RT-PCR. [57]

Antigen Detection

Ebola Virus Antigen Rapid Tests:

• Detect viral proteins (VP40, GP, NP) in blood.
• Results in 15-30 minutes.
• Lower sensitivity than RT-PCR (sensitivity ~70-90%), particularly in early infection or low viral loads.
• Useful for rapid screening in outbreak settings but negative results should be confirmed by RT-PCR. [58]

Serology

IgM and IgG Antibodies:

• IgM appears around day 7-10 of illness, indicating acute or recent infection.
• IgG appears later and persists, indicating past infection or convalescence.
• ELISA (enzyme-linked immunosorbent assay) is the standard serological method.
• Less useful for acute diagnosis due to delayed antibody response; primarily for seroprevalence studies and confirming past infection in survivors. [59]

Supportive Laboratory Investigations

Hematology

Full Blood Count (FBC):

• Leukopenia (low white blood cells, particularly lymphopenia) in early disease.
• Leukocytosis with left shift in later stages, often secondary bacterial infection.
• Thrombocytopenia (platelet count less than 100,000/μL) common in all VHFs.
• Anemia: May develop due to bleeding or hemolysis. [60]

Biochemistry

Urea and Electrolytes:

• Acute kidney injury: Elevated creatinine and urea.
• Electrolyte derangements: Hyponatremia, hypokalemia, hypocalcemia, hypomagnesemia (from GI losses).

Liver Function Tests:

• Transaminitis: AST typically exceeds ALT (AST:ALT ratio > 1), reflecting hepatocellular necrosis and muscle breakdown.
• AST levels > 1,000 IU/L associated with poor prognosis in Ebola. [61]
• Hyperbilirubinemia in yellow fever and severe Lassa fever.

Lactate and Metabolic Acidosis:

• Elevated lactate reflects tissue hypoperfusion and anaerobic metabolism.
• Predictor of mortality in severe disease.

Blood Glucose:

• Hypoglycemia (less than 3.0 mmol/L or less than 54 mg/dL) common in children and terminal stages.

Coagulation Studies

• Prothrombin time (PT) and activated partial thromboplastin time (aPTT): Prolonged, reflecting consumption of clotting factors.
• Fibrinogen: Decreased (consumed in DIC).
• D-dimer: Elevated (marker of ongoing fibrinolysis).
• Platelet count: Thrombocytopenia. [62]

Urinalysis

• Proteinuria: Quantitative urine protein > 300 mg/dL is a poor prognostic marker in Lassa fever. [63]
• Hematuria: May indicate glomerular or urinary tract hemorrhage.

Prognostic Laboratory Markers

Several laboratory parameters correlate with disease severity and mortality risk:

Ebola Virus Disease:

• Viral load (RT-PCR Ct value less than 20, corresponding to > 10^7 copies/mL): Strongly associated with mortality.
• AST > 1,000 IU/L
• Creatinine > 180 μmol/L (> 2.0 mg/dL)
• Viremia at time of death can exceed 10^10 copies/mL. [64]

Lassa Fever:

• Viremia > 10^3 TCID50/mL
• AST > 150 IU/L
• Proteinuria > 300 mg/dL [65]

---

7. Management

Immediate Actions: Recognition and Isolation

Case Definition - Suspect VHF: A person presenting with:

1. Fever (≥38.0°C or 100.4°F) AND
2. Epidemiological risk factor (travel to endemic area, contact with case, occupational exposure) AND
3. No alternative diagnosis that fully explains the clinical presentation

Immediate Steps (do not delay):

1. Isolate: Place patient in single room with dedicated toilet/bathroom. Use negative pressure room if available.
2. Alert: Notify infection prevention and control (IPC) team, infectious diseases specialist, microbiology, and public health authorities immediately.
3. PPE: All healthcare workers entering room must don full PPE before contact:
   • Fluid-resistant gown or coverall
   • Double gloves
   • Face shield or goggles
   • FFP3 respirator (or N95 if FFP3 unavailable)
   • Waterproof apron for procedures with splash risk
   • Boot covers if extensive contamination anticipated
4. Risk assessment: Document detailed exposure history, contact tracing information.
5. Minimize procedures: Avoid aerosol-generating procedures (intubation, bronchoscopy, nebulizers) unless essential. [66]

Transfer to High-Level Isolation Unit (HLIU)

Patients with confirmed or high suspicion of VHF should be transferred to designated high-level isolation units equipped with:

• Negative pressure rooms with anteroom for donning/doffing PPE.
• Dedicated critical care equipment.
• Effluent waste treatment systems.
• Trained multidisciplinary teams experienced in high-consequence infectious disease management.
• Biosafety level 3/4 laboratory support on-site or rapid transport.

Examples:

• United Kingdom: Royal Free Hospital (London), Royal Victoria Infirmary (Newcastle)
• United States: Emory University Hospital, University of Nebraska Medical Center, NIH Clinical Center, Bellevue Hospital
• Europe: Robert Koch Institute (Germany), National Institute for Infectious Diseases (Italy) [67]

Infection Prevention and Control (IPC)

Standard, Contact, and Droplet Precautions

All VHF management requires strict adherence to enhanced IPC protocols:

Environmental Controls:

• Dedicated or disposable medical equipment (stethoscopes, blood pressure cuffs, thermometers).
• Limit room entries; consolidate care activities.
• Minimum number of healthcare workers assigned to patient care.
• Daily cleaning with hospital-grade disinfectant (10% bleach solution or EPA-registered product with viricidal activity).
• Safe sharps disposal and minimization of sharps use. [68]

Waste Management:

• All waste from VHF patients is Category A infectious waste.
• Double bagging, clearly labeled biohazard containers.
• Incineration or autoclaving before disposal.

Linen and Laundry:

• Minimal handling, placed directly in biohazard bags at point of removal.
• Laundered separately with hot water and bleach.

Body Fluid Management:

• Use bedpan/urinal with lid, direct disposal into toilet, flush with lid closed.
• For diarrhea, consider rectal tube with closed collection system to reduce contamination.

Post-Mortem Care:

• Deceased patients remain highly infectious.
• Minimize handling, wrap body in impermeable shroud.
• No embalming.
• Cremation preferred where culturally acceptable; if burial, sealed casket with family counseling on transmission risk. [69]

PPE Donning and Doffing

Critical: Breaches in PPE protocol are the leading cause of healthcare worker infections. [70]

Donning Sequence (under supervision):

1. Hand hygiene
2. Gown/coverall
3. Respirator (fit check)
4. Face shield/goggles
5. Inner gloves
6. Outer gloves (over gown cuff)
7. Boot covers (if used)

Doffing Sequence (highest risk, requires trained observer):

1. Remove outer gloves (roll off, inside-out)
2. Hand hygiene (gloved)
3. Remove face shield/goggles (touch only straps)
4. Hand hygiene
5. Remove gown (roll inside-out, touching only inside surface)
6. Hand hygiene
7. Remove respirator (touch only straps)
8. Hand hygiene
9. Remove inner gloves
10. Final hand hygiene
11. Exit anteroom, shower if protocol requires

Supportive Care: The Foundation of Treatment

High-quality supportive care is the most important determinant of survival across all VHFs. [71,72] A 2025 systematic review of immuno-inflammatory dysfunction in Ebola and Lassa fever highlights the critical role of early, aggressive supportive measures in modulating dysregulated immune responses and improving clinical outcomes. [123]

Fluid and Electrolyte Management

Aggressive Fluid Resuscitation:

• Hypovolemic shock from gastrointestinal losses (diarrhea, vomiting) is the primary driver of mortality in Ebola and other VHFs.
• Goal: Restore intravascular volume, maintain adequate organ perfusion.
• Intravenous crystalloids: Lactated Ringer's or normal saline, guided by clinical assessment (blood pressure, heart rate, capillary refill, urine output) and laboratory markers (lactate, creatinine).
• Patients may require 5-10 liters or more of IV fluid daily in severe diarrhea.
• Monitor for fluid overload, particularly in those developing ARDS or renal failure. [73]

Electrolyte Replacement:

• Potassium: Supplement aggressively (oral or IV) to maintain > 3.5 mmol/L. Hypokalemia causes arrhythmias and worsens muscle weakness.
• Magnesium: Replace to maintain > 0.75 mmol/L; critical for cardiac stability.
• Calcium: Monitor ionized calcium; correct hypocalcemia.
• Daily or twice-daily electrolyte monitoring essential in severe cases. [74]

Oral Rehydration:

• Oral rehydration solution (ORS) for conscious patients able to drink.
• May reduce need for IV access and associated infection risk.

Nutritional Support

• Anorexia and catabolism lead to severe malnutrition during illness.
• Early enteral nutrition (oral or nasogastric) improves outcomes.
• High-calorie, high-protein formulations.
• Vitamin supplementation (particularly vitamin K for coagulopathy, though evidence is limited). [75]

Hemodynamic Support

Vasopressors:

• Norepinephrine first-line for refractory hypotension despite adequate fluid resuscitation.
• Requires central venous access (increased risk in coagulopathic patients) and intensive monitoring.

Blood Products:

• Packed red blood cells: For significant anemia (hemoglobin less than 7 g/dL or symptomatic).
• Platelets: For severe thrombocytopenia with active bleeding or prior to essential invasive procedures (threshold often less than 20,000/μL, though evidence limited).
• Fresh frozen plasma (FFP) or cryoprecipitate: For coagulopathy with active bleeding, though efficacy uncertain and administration carries risks. [76]

Respiratory Support

• Supplemental oxygen: Maintain SpO2 > 94%.
• Mechanical ventilation: For respiratory failure (ARDS, severe pneumonia). Intubation is an aerosol-generating procedure requiring enhanced PPE and experienced operator. High mortality in mechanically ventilated Ebola patients (> 80%). [77]

Renal Replacement Therapy

• Acute kidney injury is common; continuous renal replacement therapy (CRRT) or hemodialysis may be required.
• Challenging in VHF due to infection control (extracorporeal circuit contamination, dialysate disposal) and coagulopathy (anticoagulation for circuit patency vs bleeding risk).
• Associated with improved survival in adequately resourced settings. [78]

Antimicrobials

Empiric Antibiotics:

• Broad-spectrum antibacterial coverage to treat or prevent secondary bacterial infections (pneumonia, bacteremia, catheter-associated infections).
• Ceftriaxone + metronidazole or piperacillin-tazobactam commonly used.
• Adjust based on local resistance patterns and culture results.

Antimalarials:

• Empiric antimalarial treatment (e.g., IV artesunate) often initiated pending definitive malaria testing in endemic regions, given overlapping presentation and high malaria prevalence.

Specific Antiviral and Immunotherapeutic Agents

Ebola Virus Disease

Monoclonal Antibodies (Standard of Care): The PALM (Pamoja Tulinde Maisha, "Together Save Lives") randomized controlled trial conducted during the 2018-2020 DRC outbreak established monoclonal antibodies as standard of care for EVD. [79]

mAb114 (Ansuvimab, Ebanga®):

• Single human monoclonal antibody targeting Ebola virus glycoprotein.
• PALM trial: 35% mortality vs 49% with ZMapp (p=0.007).
• Dosed as single IV infusion of 50 mg/kg.
• FDA approved October 2020. [80]

REGN-EB3 (Inmazeb®):

• Cocktail of three monoclonal antibodies (atoltivimab, maftivimab, odesivimab).
• PALM trial: 34% mortality vs 49% with ZMapp (p=0.004).
• Greater benefit seen in patients with lower viral loads at presentation.
• Dosed as single IV infusion of 150 mg/kg.
• FDA approved October 2020. [81]

Mechanism: Monoclonal antibodies bind to Ebola virus glycoprotein, neutralizing the virus and preventing cellular entry. Early administration (within 3-5 days of symptom onset, before viral loads peak) provides maximal benefit.

Other Investigational Agents:

• Remdesivir: Nucleotide analogue inhibiting viral RNA polymerase. PALM trial showed 53% mortality, not superior to standard care. [82]
• ZMapp: Cocktail of three chimeric monoclonal antibodies; superseded by mAb114 and REGN-EB3 which showed superior efficacy.

Lassa Fever

Ribavirin:

• Nucleoside analogue with broad antiviral activity.
• Most effective when initiated within first 6 days of illness.
• Dosing: Loading dose 30 mg/kg IV (max 2 g), then 16 mg/kg IV every 6 hours for 4 days, then 8 mg/kg IV every 8 hours for 6 days (total 10 days).
• Reduces mortality from ~50% to ~10% in severe cases when given early. [83,84]
• Side effects: Hemolytic anemia (dose-dependent), reversible on discontinuation.
• Oral ribavirin may be used for post-exposure prophylaxis in high-risk contacts.

Supportive Evidence:

• Observational studies from Sierra Leone and Nigeria demonstrated mortality benefit, particularly when combined with supportive care. [85]
• No randomized controlled trials due to ethical challenges, but extensive clinical experience supports use.

Crimean-Congo Haemorrhagic Fever

Ribavirin:

• Observational data suggest benefit, though quality of evidence is lower than for Lassa fever.
• Dosing: Similar to Lassa fever regimen (30 mg/kg loading, then 16 mg/kg q6h x 4 days, then 8 mg/kg q8h x 6 days).
• Recommended by WHO and CDC for CCHF, particularly if initiated within first 5 days. [86,87]
• A 2025 expert review confirmed ribavirin's role for CCHF alongside monoclonal antibodies for Ebola and Marburg, representing the current evidence-based therapeutic armamentarium for VHFs. [124]

Hyperimmune Globulin:

• Convalescent plasma or hyperimmune globulin from CCHF survivors has been used in some outbreaks with anecdotal success, but no controlled trials exist.

Yellow Fever

No Specific Antiviral Treatment:

• Management is entirely supportive.
• Vaccine is highly effective for prevention but of no benefit once disease is established.

Experimental Therapies and Clinical Trials

Favipiravir (T-705):

• Broad-spectrum RNA polymerase inhibitor.
• Showed potential benefit in animal models and early Ebola observational studies. [88]
• Requires further randomized trials.

Convalescent Plasma:

• Plasma from VHF survivors containing neutralizing antibodies.
• Historical use with inconsistent results; largely superseded by specific monoclonal antibodies for Ebola.

Interferon Therapy:

• Type I interferons (IFN-α, IFN-β) have been explored but limited efficacy and significant side effects.

Obstetric Considerations

Pregnancy and VHF: Pregnant women with VHF have markedly elevated mortality rates:

• Ebola: ~70% maternal mortality, near 100% fetal/neonatal mortality. [89]
• Lassa fever: 30% mortality in pregnant women vs 10-15% in general hospitalized population. Third-trimester infection associated with > 50% maternal mortality.

Management Principles:

• Aggressive supportive care.
• Antiviral therapy (ribavirin for Lassa/CCHF, mAbs for Ebola) should not be withheld; theoretical teratogenic concerns are outweighed by maternal mortality risk.
• Obstetric complications include spontaneous abortion, stillbirth, premature labor, postpartum hemorrhage.
• Neonates born to infected mothers are at high risk of vertical transmission and require isolation. [90]

Pediatric Considerations

Children have similar disease manifestations but:

• Higher risk of hypoglycemia.
• Greater fluid requirements relative to body weight.
• Different dosing for ribavirin and monoclonal antibodies (weight-based).
• Behavioral challenges with isolation and PPE may increase transmission risk to caregivers. [91]

---

8. Complications

Acute Complications

Multi-Organ Failure:

• Acute kidney injury: Prerenal (hypovolemia) progressing to intrinsic renal injury (acute tubular necrosis). Oliguria or anuria portends poor prognosis.
• Acute liver failure: Hepatocellular necrosis with synthetic dysfunction, encephalopathy. AST/ALT > 1,000-10,000 IU/L in severe cases.
• Acute respiratory distress syndrome: Non-cardiogenic pulmonary edema from capillary leak. Requires mechanical ventilation with high mortality.
• Myocarditis: Cardiac dysfunction with reduced ejection fraction, arrhythmias.

Neurological:

• Encephalopathy: Altered mental status, confusion, coma.
• Seizures: Particularly in Lassa fever and pediatric cases.
• Cerebral edema: Rare but fatal complication.

Hemorrhagic:

• Gastrointestinal bleeding: Hematemesis, melena leading to severe anemia and hypovolemic shock.
• Intracranial hemorrhage: Rare but catastrophic.
• Hemorrhagic shock: From combined coagulopathy and vascular leak.

Secondary Infections:

• Bacterial sepsis: Nosocomial infections (pneumonia, catheter-associated bloodstream infections, urinary tract infections) in critically ill patients.
• Fungal infections: In prolonged critical illness with broad-spectrum antibiotic use.

Post-Recovery Complications ("Post-Viral Syndromes")

Survivors of VHF, particularly Ebola, experience a constellation of persistent or delayed symptoms:

Post-Ebola Syndrome: Affects 50-75% of survivors with symptoms including: [92,93]

Musculoskeletal:

• Arthralgia (joint pain): Most common complaint, affecting large joints (knees, shoulders, hips). May be debilitating.
• Myalgia (muscle pain).
• Weakness and fatigue limiting activities of daily living.

Ocular:

• Uveitis: Intraocular inflammation (anterior or posterior uveitis) occurring weeks to months post-recovery. Can lead to vision loss if untreated. Viral antigen and RNA detected in aqueous humor. [94]
• Cataracts, glaucoma, retinal scarring.
• Survivors should undergo ophthalmologic screening.

Neuropsychiatric:

• Headaches.
• Memory impairment, difficulty concentrating ("brain fog").
• Depression, anxiety, post-traumatic stress disorder (PTSD).
• Sleep disturbances.

Auditory:

• Sensorineural hearing loss: Occurs in ~25% of Lassa fever survivors. Often bilateral and permanent. Mechanism unclear (direct viral cochlear damage vs immune-mediated). [95]

Reproductive:

• Viral persistence in semen: Ebola virus RNA can be detected in semen for > 12 months after recovery. Sexual transmission documented. [96]
• Testicular pain, epididymo-orchitis.
• Menstrual irregularities in female survivors.

Other:

• Alopecia (hair loss).
• Anorexia, weight loss.
• Abdominal pain.

Management of Post-VHF Complications

Survivor Clinics: Multidisciplinary follow-up clinics established during and after outbreaks to provide:

• Regular clinical assessment.
• Ophthalmologic screening and treatment (topical or systemic steroids for uveitis).
• Audiometric testing.
• Mental health support and counseling.
• Sexual health counseling, provision of condoms, semen testing.
• Social support and stigma reduction programs. [97]

Semen Testing:

• Male survivors should have semen tested by RT-PCR at 3, 6, 9, and 12 months post-recovery.
• Abstinence or condom use until two consecutive negative tests at least one month apart. [98]

---

9. Prognosis and Outcomes

Case-Fatality Rates

VHF mortality varies widely by pathogen, quality of supportive care, and patient factors:

Ebola Virus Disease:

• Zaire ebolavirus: 50-90% (historical outbreaks without optimal supportive care).
• With modern supportive care and monoclonal antibody therapy: 30-40%.
• PALM trial (with mAb114 or REGN-EB3): 34-35% overall mortality, but less than 10% in those presenting with low viral loads. [99]
• Sudan ebolavirus: 40-60%.
• Bundibugyo ebolavirus: ~30%.

Marburg Virus Disease:

• 25-80% depending on outbreak and supportive care. Recent Rwanda outbreak (2024): 58 cases, 15 deaths (26% mortality). [120]
• Tanzania outbreak (2023): 9 cases, 6 deaths (67% mortality). [121]
• Equatorial Guinea outbreak (2023): 17 cases, 12 deaths (71% mortality). [122]

Lassa Fever:

• Overall case-fatality: 1-2% (includes mild/subclinical cases).
• Hospitalized severe cases: 15-20%.
• Pregnant women (third trimester): > 50%.
• With early ribavirin and optimal supportive care: less than 10%. [100]

Crimean-Congo Haemorrhagic Fever:

• 5-30% overall, higher in nosocomial outbreaks (up to 50%). [101]

Yellow Fever:

• Overall: 3-7.5% (includes mild cases).
• Severe toxic phase: 20-50% mortality.
• With intensive supportive care: 15-20%. [102]

Prognostic Factors

Viral Load:

• Higher viremia at presentation strongly predicts mortality.
• Ebola: Ct value less than 20 (> 10^7 copies/mL) associated with > 80% mortality vs less than 30% for Ct > 25. [103]

Laboratory Markers:

• AST > 1,000 IU/L (Ebola, Lassa).
• Creatinine > 180 μmol/L (> 2 mg/dL).
• Proteinuria > 300 mg/dL (Lassa).
• Lactate > 4 mmol/L.
• Severe thrombocytopenia less than 50,000/μL.

Clinical Factors:

• Age: Extremes of age (infants, elderly) have higher mortality.
• Pregnancy: Markedly increased risk.
• Comorbidities: Diabetes, immunosuppression, chronic kidney disease.
• Hemorrhagic manifestations: Active bleeding associated with worse outcomes.
• Time to treatment: Early antiviral/immunotherapy administration improves survival. [104]

Long-Term Outcomes

Ebola Survivors:

• PREVAIL III study (Liberia): 75% of survivors reported at least one symptom at 12 months post-infection, most commonly arthralgias, headache, and ocular problems. [105]
• Persistent immune activation and inflammation detected for months after viral clearance.

Lassa Survivors:

• 25% develop permanent sensorineural hearing loss.
• Recovery otherwise generally complete, though fatigue may persist for weeks. [106]

Quality of Life:

• Significant psychosocial impacts including stigma, loss of family members (often multiple), economic hardship from prolonged illness.
• PTSD and depression common.
• Rehabilitation and community reintegration support critical. [107]

---

10. Prevention and Control

Pre-Exposure Prophylaxis: Vaccination

Yellow Fever Vaccine (17D)

• Efficacy: > 95% protective efficacy with single dose, likely conferring lifelong immunity. [108]
• Indications: All travelers to endemic regions (sub-Saharan Africa, South America). Required for entry to some countries.
• Contraindications: Severe immunosuppression (HIV with CD4 less than 200, immunosuppressive therapy), age less than 6 months, severe egg allergy, thymic disorders.
• Adverse effects: Generally well-tolerated. Rare but serious: yellow fever vaccine-associated viscerotropic disease (YEL-AVD, 0.4 per 100,000 doses), yellow fever vaccine-associated neurologic disease (YEL-AND, 0.8 per 100,000 doses). Higher risk in age > 60 years. [109]
• A 2022 retrospective cohort study across three US healthcare databases found neurotropic disease incidence ranging from 0 to 3.04 per 100,000 vaccinees, with no viscerotropic cases identified, confirming the vaccine's excellent safety profile. [125]
• A 2023 French National Reference Center case series (10-year data) provided detailed clinical and immunological insights into YEL-AND and YEL-AVD, emphasizing the importance of screening for thymic disorders and immunodeficiency before vaccination. [126]

Ebola Vaccines

rVSV-ZEBOV (Ervebo®):

• Recombinant vesicular stomatitis virus-based vaccine expressing Ebola Zaire glycoprotein.
• Efficacy: 97-100% protective efficacy demonstrated in Guinea ring vaccination trial (2015). [110]
• Single-dose intramuscular injection.
• FDA and EMA approved (2019) for individuals ≥18 years at risk of exposure.
• Indications: Healthcare workers in outbreak settings, laboratory personnel working with live Ebola virus, responders deployed to outbreak areas.
• Adverse effects: Injection site pain, fever, headache, arthralgia (generally mild and self-limited). Vesiculoviral arthritis in ~5% (transient).

Ad26.ZEBOV, MVA-BN-Filo (Zabdeno® and Mvabea®):

• Two-dose heterologous prime-boost regimen.
• Ad26.ZEBOV (adenovirus 26 vector) given first, followed by MVA-BN-Filo (modified vaccinia Ankara vector) 56 days later.
• Approved by EMA (2020) for pre-exposure prophylaxis.
• Induces broader immune response (covers multiple Ebola species and Marburg). [111]

Vaccination Strategies:

• Ring vaccination: Vaccinate contacts and contacts-of-contacts of confirmed cases to create protective "ring" around case, preventing onward transmission. Highly effective during outbreaks. [112]
• Pre-exposure prophylaxis: For at-risk populations (healthcare workers, laboratory staff) in endemic or outbreak-prone areas.

Lassa Fever Vaccine

• No licensed vaccine currently available.
• Several candidates in development including recombinant vesicular stomatitis virus (rVSV) platforms and DNA vaccines in early-phase trials. [113]

CCHF Vaccine

• No licensed vaccine available for human use.
• Experimental vaccines under development.

Post-Exposure Prophylaxis (PEP)

High-Risk Exposure Definition:

• Percutaneous injury (needlestick) with blood or body fluids from confirmed/suspected VHF case.
• Mucous membrane exposure (splash to eyes, nose, mouth).
• Direct skin contact with blood/body fluids with breach in skin integrity (cuts, abrasions).
• Unprotected direct contact during high-risk activities (e.g., intubation without appropriate PPE). [114]

Management of Exposed Healthcare Workers:

Ebola Exposure:

1. Immediate decontamination: Wash exposed area with soap and water for 15 minutes. Irrigate eyes/mucous membranes copiously.
2. Risk assessment: Document exact nature of exposure, PPE status, source patient viral load.
3. Active monitoring: Twice-daily temperature and symptom checks for 21 days post-exposure.
4. Investigational PEP: Monoclonal antibodies (mAb114, REGN-EB3) have been used for high-risk exposures in outbreak settings under compassionate use/expanded access protocols. Evidence from outbreak settings suggests potential prophylactic efficacy when administered within 72 hours of exposure, though randomized trial data remain limited. [115]
5. Restriction from patient care: Controversial; some protocols allow continued work with active monitoring, others mandate quarantine.

Lassa Fever Exposure:

1. Decontamination.
2. Oral ribavirin: Consider PEP with oral ribavirin for high-risk exposures (dosing not standardized; typically oral ribavirin 600 mg loading, then 400 mg q8h for 7-10 days).
3. Active monitoring for 21 days.

CCHF Exposure:

1. Decontamination.
2. Oral ribavirin: PEP recommended for high-risk exposures (similar dosing to Lassa).
3. Active monitoring for 13 days. [116]

Public Health Measures

Outbreak Detection and Response:

• Enhanced surveillance in at-risk regions.
• Rapid deployment of diagnostic capacity.
• Contact tracing and monitoring.
• Community engagement and risk communication.
• Safe burial practices to prevent funeral-associated transmission. [117]

Vector Control:

• Mosquito control (yellow fever, dengue): Insecticide spraying, removal of breeding sites, bed nets.
• Tick control (CCHF): Acaricides for livestock, protective clothing for agricultural/veterinary workers.
• Rodent control (Lassa, hantavirus): Improved food storage, household hygiene, rodent trapping. [118]

One Health Approach: Integration of human, animal, and environmental health surveillance to detect spillover events early and prevent outbreaks. [119]

---

11. Patient and Layperson Explanation

What are Viral Haemorrhagic Fevers?

Viral haemorrhagic fevers are a group of serious infections caused by viruses found in certain parts of the world, particularly Africa, South America, and parts of Asia. These viruses are normally carried by animals (like bats, rodents) or spread by insects (mosquitoes, ticks).

When humans get infected—usually by contact with infected animals or insects—the virus attacks blood vessels and the body's ability to form blood clots. This can lead to bleeding (haemorrhage), though not all patients develop visible bleeding. The main danger is severe illness with fever, vomiting, diarrhea, shock, and organ failure.

How do people catch these infections?

Most infections happen in specific ways:

• Ebola and Marburg: Handling or eating infected wild animals (bats, monkeys), or caring for someone who is sick with the disease (touching their blood, vomit, sweat, or other body fluids).
• Lassa fever: Breathing in dust contaminated with urine or droppings from infected rats, which are common in homes in West Africa.
• Crimean-Congo fever: Tick bites, or contact with blood from infected livestock during slaughter.
• Yellow fever: Mosquito bites.

What are the symptoms?

Early symptoms are similar to flu or malaria:

• High fever
• Severe headache
• Muscle and joint pain
• Extreme tiredness
• Sore throat

After several days, more serious symptoms may develop:

• Severe vomiting and diarrhea (losing large amounts of fluid)
• Bleeding from gums, nose, or in vomit/stool (though this doesn't happen in all cases)
• Confusion or unconsciousness
• Shock (very low blood pressure)

How are these infections treated?

For Ebola: We now have effective treatments called monoclonal antibodies (laboratory-made proteins that attack the virus). When given early, these medicines significantly improve survival. Intensive supportive care with intravenous fluids, nutrition, and treatment of complications is also crucial.

For Lassa fever and Crimean-Congo fever: An antiviral drug called ribavirin can help if given early. Supportive care with fluids and treatment of symptoms is essential.

For yellow fever: There is no specific treatment, but excellent intensive care support can help people survive while their immune system fights the virus.

Can these infections be prevented?

Yes:

• Yellow fever vaccine: A safe and highly effective vaccine exists. Anyone traveling to areas with yellow fever should get vaccinated.
• Ebola vaccine: Available for healthcare workers and people at high risk during outbreaks.
• Avoiding exposure: Don't touch sick or dead animals, use insect repellent and bed nets in areas with mosquitoes, avoid tick-infested areas, and practice good hygiene to keep rodents out of homes.

What should travelers know?

If you develop fever within 3 weeks of returning from tropical regions (particularly Africa, South America, or parts of Asia):

• Seek medical care immediately.
• Tell your doctor about your travel history, including specific countries and any animal or insect contact.
• Malaria is the most common cause, but your doctor may also test for other infections including haemorrhagic fevers if appropriate.

---

12. Examination Focus

High-Yield Exam Topics

MRCP, FRACP Written Examinations

SBA Question Stems:

1. "A 32-year-old aid worker returns from Sierra Leone with 5-day history of fever, headache, and myalgia. She had contact with Ebola patients but wore full PPE. Temperature 38.9°C. What is the most appropriate next step?"

   • Answer: Immediate isolation, alert IPC and public health, arrange Ebola RT-PCR testing with appropriate biosafety precautions.

2. "A patient with confirmed Ebola virus disease has AST 1,200 IU/L, creatinine 250 μmol/L, viral load 10^8 copies/mL. Which treatment has the strongest evidence for reducing mortality?"

   • Answer: Monoclonal antibodies (mAb114 or REGN-EB3) plus aggressive supportive care.

3. "Ribavirin is the recommended antiviral for which two viral haemorrhagic fevers?"

   • Answer: Lassa fever and Crimean-Congo haemorrhagic fever.

4. "A patient with suspected Lassa fever has proteinuria of 400 mg/dL. What does this indicate?"

   • Answer: Poor prognostic marker associated with increased mortality.

Data Interpretation:

• Laboratory results showing thrombocytopenia, transaminitis (AST > ALT), AKI, prolonged PT/aPTT in context of fever and travel history → recognize VHF as differential.

MRCS, FRCS, FRACS (Surgical Examinations)

Viva Scenarios:

1. "You are operating in a rural hospital in Uganda when a colleague develops fever and severe diarrhea 7 days after operating on a patient who later died of unknown cause. Discuss your approach."

   • Key points: Suspect VHF (Ebola endemic in Uganda), immediate isolation of colleague, contact tracing, alert authorities, assess own exposure risk and monitoring needs.

2. "Discuss the infection control measures required when managing a patient with suspected viral haemorrhagic fever in a UK hospital."

   • Key points: Immediate isolation, full PPE (double gloves, gown, FFP3 respirator, face shield), minimize procedures, alert IPC and ID teams, transfer to HLIU, strict waste management, contact tracing.

MRCOG, FRANZCOG (Obstetrics and Gynaecology)

Clinical Scenarios:

1. "A pregnant woman at 34 weeks gestation presents with fever and vaginal bleeding. She returned from Nigeria 8 days ago. Discuss differential diagnosis and management."
   • Differentials: Include Lassa fever (endemic in Nigeria, presents with fever ± bleeding). Also malaria, placental abruption, septic abortion.
   • Management: Immediate isolation with PPE, test for malaria and Lassa fever with appropriate biosafety, obstetric assessment, ribavirin should not be withheld if Lassa confirmed despite pregnancy, prepare for high risk of fetal loss and maternal mortality.

PLAB, AMC, USMLE

Clinical Vignettes:

• Recognize red flags: Fever + travel + bleeding/shock → VHF in differential.
• Know geographic distribution of specific VHFs.
• Understand infection control principles.
• Identify treatments: mAbs for Ebola, ribavirin for Lassa/CCHF.

Viva Voce Key Points

Ebola:

• Reservoir: Fruit bats (Pteropodidae).
• Transmission: Direct contact with blood/body fluids, nosocomial, funeral-associated.
• Diagnosis: RT-PCR (gold standard), rapid antigen tests (lower sensitivity).
• Treatment: Monoclonal antibodies (mAb114, REGN-EB3) plus aggressive supportive care.
• Vaccine: rVSV-ZEBOV (Ervebo), ring vaccination strategy.
• Viral persistence: Semen for > 12 months, causing sexual transmission risk and late complications (uveitis).

Lassa Fever:

• Reservoir: Multimammate rat (Mastomys natalensis).
• Endemic: West Africa (Nigeria, Sierra Leone, Liberia, Guinea).
• Clinical: Pharyngitis, retrosternal chest pain, deafness (25% of survivors).
• Diagnosis: RT-PCR, viral culture (BSL-4).
• Treatment: Ribavirin (most effective within 6 days of symptom onset).
• Prognosis: Proteinuria > 300 mg/dL predicts poor outcome.

CCHF:

• Vector: Hyalomma ticks.
• Transmission: Tick bite, contact with livestock blood/tissues.
• Geographic: Africa, Balkans, Middle East, Central Asia.
• Clinical: Biphasic fever, extensive ecchymoses, hepatomegaly.
• Treatment: Ribavirin.

Yellow Fever:

• Vector: Aedes aegypti mosquito.
• Endemic: Tropical Africa and South America.
• Clinical: "Yellow" (jaundice), "black vomit" (hematemesis), Faget's sign (bradycardia relative to fever).
• Prevention: Highly effective vaccine (17D), required for travel to endemic areas.
• Treatment: Supportive only.

Common Pitfalls to Avoid

1. Assuming all VHF patients bleed: Overt hemorrhage occurs in less than 50% of cases; absence of bleeding does not exclude VHF.
2. Forgetting malaria: Always exclude malaria first in febrile returned travelers—it's common and treatable.
3. Inadequate PPE: Healthcare worker infections from breaches in infection control are major amplifiers of outbreaks.
4. Delaying ribavirin in Lassa/CCHF: Efficacy highest when started early (less than 6 days of symptoms).
5. Not considering pregnancy as high-risk: Pregnant women have markedly elevated mortality from VHF.

---

13. References

Primary Sources

1. Feldmann H, Geisbert TW. Ebola haemorrhagic fever. Lancet. 2011;377(9768):849-862. doi:10.1016/S0140-6736(10)60667-8

2. Bray M, Geisbert TW. Viral hemorrhagic fevers. Harrison's Principles of Internal Medicine, 20th ed. McGraw-Hill; 2018.

3. Public Health England. Viral haemorrhagic fever: ACDP algorithm and guidance on management of patients. Updated 2019.

4. Centers for Disease Control and Prevention. Viral Hemorrhagic Fevers (VHFs). Updated 2021.

5. WHO Ebola Response Team. Ebola virus disease in West Africa — the first 9 months of the epidemic and forward projections. N Engl J Med. 2014;371(16):1481-1495. doi:10.1056/NEJMoa1411100

6. Checkley AM, Smith A, Smith V, et al. Risk factors for mortality from imported falciparum malaria in the United Kingdom over 20 years: an observational study. BMJ. 2012;344:e2116. doi:10.1136/bmj.e2116

7. Emond RT, Evans B, Bowen ET, Lloyd G. A case of Ebola virus infection. Br Med J. 1977;2(6086):541-544. doi:10.1136/bmj.2.6086.541

8. Varkey JB, Shantha JG, Crozier I, et al. Persistence of Ebola virus in ocular fluid during convalescence. N Engl J Med. 2015;372(25):2423-2427. doi:10.1056/NEJMoa1500306

9. Bah EI, Lamah MC, Fletcher T, et al. Clinical presentation of patients with Ebola virus disease in Conakry, Guinea. N Engl J Med. 2015;372(1):40-47. doi:10.1056/NEJMoa1411249

10. Schieffelin JS, Shaffer JG, Goba A, et al. Clinical illness and outcomes in patients with Ebola in Sierra Leone. N Engl J Med. 2014;371(22):2092-2100. doi:10.1056/NEJMoa1411680

11. Kilmarx PH, Clarke KR, Dietz PM, et al. Ebola virus disease in health care workers — Sierra Leone, 2014. MMWR Morb Mortal Wkly Rep. 2014;63(49):1168-1171.

12. Malvy D, McElroy AK, de Clerck H, Günther S, van Griensven J. Ebola virus disease. Lancet. 2019;393(10174):936-948. doi:10.1016/S0140-6736(18)33132-5

13. Kuhn JH, Becker S, Ebihara H, et al. Proposal for a revised taxonomy of the family Filoviridae: classification, names of taxa and viruses, and virus abbreviations. Arch Virol. 2010;155(12):2083-2103. doi:10.1007/s00705-010-0814-x

14. McCormick JB, Fisher-Hoch SP. Lassa fever. Curr Top Microbiol Immunol. 2002;262:75-109. doi:10.1007/978-3-642-56029-3_4

15. Ogbu O, Ajuluchukwu E, Uneke CJ. Lassa fever in West African sub-region: an overview. J Vector Borne Dis. 2007;44(1):1-11.

16. Richmond JK, Baglole DJ. Lassa fever: epidemiology, clinical features, and social consequences. BMJ. 2003;327(7426):1271-1275. doi:10.1136/bmj.327.7426.1271

17. Bente DA, Forrester NL, Watts DM, et al. Crimean-Congo hemorrhagic fever: history, epidemiology, pathogenesis, clinical syndrome and genetic diversity. Antiviral Res. 2013;100(1):159-189. doi:10.1016/j.antiviral.2013.07.006

18. Messina JP, Pigott DM, Golding N, et al. The global distribution of Crimean-Congo hemorrhagic fever. Trans R Soc Trop Med Hyg. 2015;109(8):503-513. doi:10.1093/trstmh/trv050

19. Ergonul O. Crimean-Congo haemorrhagic fever. Lancet Infect Dis. 2006;6(4):203-214. doi:10.1016/S1473-3099(06)70435-2

20. World Health Organization. Yellow Fever Fact Sheet. Updated 2021.

21. Garske T, Van Kerkhove MD, Yactayo S, et al. Yellow fever in Africa: estimating the burden of disease and impact of mass vaccination from outbreak and serological data. PLoS Med. 2014;11(5):e1001638. doi:10.1371/journal.pmed.1001638

22. Leroy EM, Kumulungui B, Pourrut X, et al. Fruit bats as reservoirs of Ebola virus. Nature. 2005;438(7068):575-576. doi:10.1038/438575a

23. Monath TP, Newhouse VF, Kemp GE, Setzer HW, Cacciapuoti A. Lassa virus isolation from Mastomys natalensis rodents during an epidemic in Sierra Leone. Science. 1974;185(4147):263-265. doi:10.1126/science.185.4147.263

24. Ergonul O, Celikbas A, Dokuzoguz B, Eren S, Baykam N, Esener H. Characteristics of patients with Crimean-Congo hemorrhagic fever in a recent outbreak in Turkey and impact of oral ribavirin therapy. Clin Infect Dis. 2004;39(2):284-287. doi:10.1086/422000

25. Stephenson EH, Larson EW, Dominik JW. Effect of environmental factors on aerosol-induced Lassa virus infection. J Med Virol. 1984;14(4):295-303. doi:10.1002/jmv.1890140402

26. Twenhafel NA, Mattix ME, Johnson JC, et al. Pathology of experimental aerosol Zaire ebolavirus infection in rhesus macaques. Vet Pathol. 2013;50(3):514-529. doi:10.1177/0300985812469636

27. Bausch DG, Towner JS, Dowell SF, et al. Assessment of the risk of Ebola virus transmission from bodily fluids and fomites. J Infect Dis. 2007;196 Suppl 2:S142-S147. doi:10.1086/520545

28. Francesconi P, Yoti Z, Declich S, et al. Ebola hemorrhagic fever transmission and risk factors of contacts, Uganda. Emerg Infect Dis. 2003;9(11):1430-1437. doi:10.3201/eid0911.030339

29. Sissoko D, Duraffour S, Kerber R, et al. Persistence and clearance of Ebola virus RNA from seminal fluid of Ebola virus disease survivors: a longitudinal analysis and modelling study. Lancet Glob Health. 2017;5(1):e80-e88. doi:10.1016/S2214-109X(16)30243-1

30. Christie A, Davies-Wayne GJ, Cordier-Lassalle T, et al. Possible sexual transmission of Ebola virus — Liberia, 2015. MMWR Morb Mortal Wkly Rep. 2015;64(17):479-481.

31. Geisbert TW, Hensley LE, Larsen T, et al. Pathogenesis of Ebola hemorrhagic fever in cynomolgus macaques: evidence that dendritic cells are early and sustained targets of infection. Am J Pathol. 2003;163(6):2347-2370. doi:10.1016/S0002-9440(10)63591-2

32. Carette JE, Raaben M, Wong AC, et al. Ebola virus entry requires the cholesterol transporter Niemann-Pick C1. Nature. 2011;477(7364):340-343. doi:10.1038/nature10348

33. Zaki SR, Goldsmith CS. Pathologic features of filovirus infections in humans. Curr Top Microbiol Immunol. 1999;235:97-116. doi:10.1007/978-3-642-59949-1_7

34. Basler CF, Wang X, Mühlberger E, et al. The Ebola virus VP35 protein functions as a type I IFN antagonist. Proc Natl Acad Sci U S A. 2000;97(22):12289-12294. doi:10.1073/pnas.220398297

35. Martínez-Sobrido L, Zuniga EI, Rosario D, García-Sastre A, de la Torre JC. Inhibition of the type I interferon response by the nucleoprotein of the prototypic arenavirus lymphocytic choriomeningitis virus. J Virol. 2006;80(18):9192-9199. doi:10.1128/JVI.00555-06

36. Mahanty S, Hutchinson K, Agarwal S, McRae M, Rollin PE, Pulendran B. Cutting edge: impairment of dendritic cells and adaptive immunity by Ebola and Lassa viruses. J Immunol. 2003;170(6):2797-2801. doi:10.4049/jimmunol.170.6.2797

37. Wauquier N, Becquart P, Padilla C, Baize S, Leroy EM. Human fatal zaire ebola virus infection is associated with an aberrant innate immunity and with massive lymphocyte apoptosis. PLoS Negl Trop Dis. 2010;4(10):e837. doi:10.1371/journal.pntd.0000837

38. Geisbert TW, Young HA, Jahrling PB, et al. Mechanisms underlying coagulation abnormalities in ebola hemorrhagic fever: overexpression of tissue factor in primate monocytes/macrophages is a key event. J Infect Dis. 2003;188(11):1618-1629. doi:10.1086/379724

39. Osterholm MT, Moore KA, Kelley NS, et al. Transmission of Ebola viruses: what we know and what we do not know. mBio. 2015;6(2):e00137-15. doi:10.1128/mBio.00137-15

40. Martines RB, Ng DL, Greer PW, Rollin PE, Zaki SR. Tissue and cellular tropism, pathology and pathogenesis of Ebola and Marburg viruses. J Pathol. 2015;235(2):153-174. doi:10.1002/path.4456

41. Bowen ET, Lloyd G, Harris WJ, Platt GS, Baskerville A, Vella EE. Viral haemorrhagic fever in southern Sudan and northern Zaire. Preliminary studies on the aetiological agent. Lancet. 1977;1(8011):571-573. doi:10.1016/s0140-6736(77)92001-3

42. Geisbert TW, Hensley LE, Gibb TR, Steele KE, Jaax NK, Jahrling PB. Apoptosis induced in vitro and in vivo during infection by Ebola and Marburg viruses. Lab Invest. 2000;80(2):171-186. doi:10.1038/labinvest.3780021

43. Rollin PE, Bausch DG, Sanchez A. Blood chemistry measurements and D-Dimer levels associated with fatal and nonfatal outcomes in humans infected with Sudan Ebola virus. J Infect Dis. 2007;196 Suppl 2:S364-S371. doi:10.1086/520613

44. Cummins D, McCormick JB, Bennett D, et al. Acute sensorineural deafness in Lassa fever. JAMA. 1990;264(16):2093-2096.

45. Paessler S, Walker DH. Pathogenesis of the viral hemorrhagic fevers. Annu Rev Pathol. 2013;8:411-440. doi:10.1146/annurev-pathol-020712-164041

46. Hunt L, Gupta-Wright A, Simms V, et al. Clinical presentation, biochemical, and haematological parameters and their association with outcome in patients with Ebola virus disease: an observational cohort study. Lancet Infect Dis. 2015;15(11):1292-1299. doi:10.1016/S1473-3099(15)00144-9

47. Chertow DS, Kleine C, Edwards JK, Scaini R, Giuliani R, Sprecher A. Ebola virus disease in West Africa — clinical manifestations and management. N Engl J Med. 2014;371(22):2054-2057. doi:10.1056/NEJMp1413084

48. Kortepeter MG, Bausch DG, Bray M. Basic clinical and laboratory features of filoviral hemorrhagic fever. J Infect Dis. 2011;204 Suppl 3:S810-S816. doi:10.1093/infdis/jir299

49. Cummins D, McCormick JB, Bennett D, et al. Acute sensorineural deafness in Lassa fever. JAMA. 1990;264(16):2093-2096.

50. Gear JSS, Cassel GA, Gear AJ, et al. Outbreak of Marburg virus disease in Johannesburg. Br Med J. 1975;4(5995):489-493. doi:10.1136/bmj.4.5995.489

51. Swanepoel R, Gill DE, Shepherd AJ, Leman PA, Mynhardt JH, Harvey S. The clinical pathology of Crimean-Congo hemorrhagic fever. Rev Infect Dis. 1989;11 Suppl 4:S794-S800. doi:10.1093/clinids/11.supplement_4.s794

52. Monath TP, Vasconcelos PFC. Yellow fever. J Clin Virol. 2015;64:160-173. doi:10.1016/j.jcv.2014.08.030

53. World Health Organization. Dengue: Guidelines for Diagnosis, Treatment, Prevention and Control. New edition. Geneva: WHO; 2009.

54. Connor MJ Jr, Kraft C, Mehta AK, et al. Successful delivery of RRT in Ebola virus disease. J Am Soc Nephrol. 2015;26(1):31-37. doi:10.1681/ASN.2014111057

55. Abba K, Deeks JJ, Olliaro PL, et al. Rapid diagnostic tests for diagnosing uncomplicated P. falciparum malaria in endemic countries. Cochrane Database Syst Rev. 2011;(7):CD008122. doi:10.1002/14651858.CD008122.pub2

56. Kortepeter MG, Dierberg K, Shenoy ES, Cieslak TJ. Marburg virus disease: a summary for clinicians. Int J Infect Dis. 2020;99:233-242. doi:10.1016/j.ijid.2020.07.042

57. Pang Z, Li A, Li J, et al. Comprehensive multiplex one-step real-time TaqMan qRT-PCR assays for detection and quantification of hemorrhagic fever viruses. PLoS One. 2014;9(4):e95635. doi:10.1371/journal.pone.0095635

58. Jansen van Vuren P, Grobbelaar A, Storm N, et al. Comparative evaluation of the diagnostic performance of the prototype Cepheid GeneXpert Ebola assay. J Clin Microbiol. 2016;54(2):359-367. doi:10.1128/JCM.02724-15

59. Boisen ML, Hartnett JN, Goba A, et al. Field validation of recombinant antigen immunoassays for diagnosis of Lassa fever. Sci Rep. 2018;8(1):5939. doi:10.1038/s41598-018-24246-w

60. Fausther-Bovendo H, Kobinger GP. Pre-exposure prophylaxis and prophylactic monoclonal antibody protection against Ebola virus. Curr Opin Immunol. 2016;42:45-49. doi:10.1016/j.coi.2016.05.003

61. Kerber R, Krumkamp R, Diallo B, et al. Analysis of diagnostic findings from the European Mobile Laboratory in Guéckédou, Guinea, March 2014 through March 2015. J Infect Dis. 2016;214(suppl 3):S250-S257. doi:10.1093/infdis/jiw269

62. Emond RT, Evans B, Bowen ET, Lloyd G. A case of Ebola virus infection. Br Med J. 1977;2(6086):541-544. doi:10.1136/bmj.2.6086.541

63. McCormick JB, King IJ, Webb PA, et al. Lassa fever. Effective therapy with ribavirin. N Engl J Med. 1986;314(20):20-26. doi:10.1056/NEJM198601023140104

64. Schieffelin JS, Shaffer JG, Goba A, et al. Clinical illness and outcomes in patients with Ebola in Sierra Leone. N Engl J Med. 2014;371(22):2092-2100. doi:10.1056/NEJMoa1411680

65. Johnson KM, McCormick JB, Webb PA, Smith ES, Elliott LH, King IJ. Clinical virology of Lassa fever in hospitalized patients. J Infect Dis. 1987;155(3):456-464. doi:10.1093/infdis/155.3.456

66. Uyeki TM, Mehta AK, Davey RT Jr, et al. Clinical management of Ebola virus disease in the United States and Europe. N Engl J Med. 2016;374(7):636-646. doi:10.1056/NEJMoa1504874

67. Isakov A, Miles W, Gibbs S, et al. Transport and management of patients with confirmed or suspected Ebola virus disease. Ann Intern Med. 2015;163(8):639-640. doi:10.7326/L15-5156

68. Fischer WA 2nd, Hynes NA, Perl TM. Protecting health care workers from Ebola: personal protective equipment is critical but is not enough. Ann Intern Med. 2014;161(10):753-754. doi:10.7326/M14-1953

69. Centers for Disease Control and Prevention. Guidance on Personal Protective Equipment (PPE) To Be Used By Healthcare Workers during Management of Patients with Confirmed Ebola or Persons under Investigation (PUIs) for Ebola who are Clinically Unstable or Have Bleeding, Vomiting, or Diarrhea in U.S. Hospitals, Including Procedures for Donning and Doffing PPE. Updated 2018.

70. Herstein JJ, Biddinger PD, Kraft CS, et al. Initial costs of Ebola treatment centers in the United States. Emerg Infect Dis. 2016;22(2):350-352. doi:10.3201/eid2202.151431

71. Chertow DS, Uyeki TM, DuPont HL. Lassa fever: another threat from West Africa. Ann Intern Med. 2016;164(8):560-561. doi:10.7326/M16-0181

72. Fowler RA, Fletcher T, Fischer WA 2nd, et al. Caring for critically ill patients with Ebola virus disease. Perspectives from West Africa. Am J Respir Crit Care Med. 2014;190(7):733-737. doi:10.1164/rccm.201408-1514CP

73. Sissoko D, Laouenan C, Folkesson E, et al. Experimental treatment with favipiravir for Ebola virus disease (the JIKI Trial): a historically controlled, single-arm proof-of-concept trial in Guinea. PLoS Med. 2016;13(3):e1001967. doi:10.1371/journal.pmed.1001967

74. Lyon GM, Mehta AK, Varkey JB, et al. Clinical care of two patients with Ebola virus disease in the United States. N Engl J Med. 2014;371(25):2402-2409. doi:10.1056/NEJMoa1409838

75. Kreuels B, Wichmann D, Emmerich P, et al. A case of severe Ebola virus infection complicated by gram-negative septicemia. N Engl J Med. 2014;371(25):2394-2401. doi:10.1056/NEJMoa1411677

76. Wolf T, Kann G, Becker S, et al. Severe Ebola virus disease with vascular leakage and multiorgan failure: treatment of a patient in intensive care. Lancet. 2015;385(9976):1428-1435. doi:10.1016/S0140-6736(14)62384-9

77. Florescu DF, Kalil AC, Hewlett AL, et al. Administration of brincidofovir and convalescent plasma in a patient with Ebola virus disease. Clin Infect Dis. 2015;61(6):969-973. doi:10.1093/cid/civ395

78. Connor MJ Jr, Kraft C, Mehta AK, et al. Successful delivery of RRT in Ebola virus disease. J Am Soc Nephrol. 2015;26(1):31-37. doi:10.1681/ASN.2014111057

79. Mulangu S, Dodd LE, Davey RT Jr, et al. A randomized, controlled trial of Ebola virus disease therapeutics. N Engl J Med. 2019;381(24):2293-2303. doi:10.1056/NEJMoa1910993

80. U.S. Food and Drug Administration. FDA approves treatment for Ebola virus. December 2020.

81. European Medicines Agency. Inmazeb. Summary of product characteristics. November 2020.

82. Mulangu S, Dodd LE, Davey RT Jr, et al. A randomized, controlled trial of Ebola virus disease therapeutics. N Engl J Med. 2019;381(24):2293-2303. doi:10.1056/NEJMoa1910993

83. McCormick JB, King IJ, Webb PA, et al. Lassa fever. Effective therapy with ribavirin. N Engl J Med. 1986;314(20):20-26. doi:10.1056/NEJM198601023140104

84. Bausch DG, Hadi CM, Khan SH, Lertora JJ. Review of the literature and proposed guidelines for the use of oral ribavirin as postexposure prophylaxis for Lassa fever. Clin Infect Dis. 2010;51(12):1435-1441. doi:10.1086/657315

85. Raabe VN, Kann G, Ribner BS, et al. Favipiravir and ribavirin treatment of epidemiologically linked cases of Lassa fever. Clin Infect Dis. 2017;65(5):855-859. doi:10.1093/cid/cix406

86. Ergonul O, Celikbas A, Dokuzoguz B, Eren S, Baykam N, Esener H. Characteristics of patients with Crimean-Congo hemorrhagic fever in a recent outbreak in Turkey and impact of oral ribavirin therapy. Clin Infect Dis. 2004;39(2):284-287. doi:10.1086/422000

87. Elaldi N, Bodur H, Ascioglu S, et al. Efficacy of oral ribavirin treatment in Crimean-Congo haemorrhagic fever: a quasi-experimental study from Turkey. J Infect. 2009;58(3):238-244. doi:10.1016/j.jinf.2009.01.014

88. Bai CQ, Mu JS, Kargbo D, et al. Clinical and virological characteristics of Ebola virus disease patients treated with favipiravir (T-705)—Sierra Leone, 2014. Clin Infect Dis. 2016;63(10):1288-1294. doi:10.1093/cid/ciw571

89. Jamieson DJ, Uyeki TM, Callaghan WM, Meaney-Delman D, Rasmussen SA. What obstetrician-gynecologists should know about Ebola: a perspective from the Centers for Disease Control and Prevention. Obstet Gynecol. 2014;124(5):1005-1010. doi:10.1097/AOG.0000000000000533

90. Price ME, Fisher-Hoch SP, Craven RB, McCormick JB. A prospective study of maternal and fetal outcome in acute Lassa fever infection during pregnancy. BMJ. 1988;297(6648):584-587. doi:10.1136/bmj.297.6648.584

91. Sissoko D, Keïta M, Diallo B, et al. Ebola virus persistence in breast milk after no reported illness: a likely source of virus transmission from mother to child. Clin Infect Dis. 2017;64(4):513-516. doi:10.1093/cid/ciw793

92. Qureshi AI, Chughtai M, Loua TO, et al. Study of Ebola virus disease survivors in Guinea. Clin Infect Dis. 2015;61(7):1035-1042. doi:10.1093/cid/civ453

93. Sneller MC, Reilly C, Badio M, et al. A longitudinal study of Ebola sequelae in Liberia. N Engl J Med. 2019;380(10):924-934. doi:10.1056/NEJMoa1805435

94. Mattia JG, Vandy MJ, Chang JC, et al. Early clinical sequelae of Ebola virus disease in Sierra Leone: a cross-sectional study. Lancet Infect Dis. 2016;16(3):331-338. doi:10.1016/S1473-3099(15)00489-2

95. Cummins D, McCormick JB, Bennett D, et al. Acute sensorineural deafness in Lassa fever. JAMA. 1990;264(16):2093-2096.

96. Deen GF, Knust B, Broutet N, et al. Ebola RNA persistence in semen of Ebola virus disease survivors — preliminary report. N Engl J Med. 2017;377(15):1428-1437. doi:10.1056/NEJMoa1511410

97. Etard JF, Sow MS, Leroy S, et al. Multidisciplinary assessment of post-Ebola sequelae in Guinea (Postebogui): an observational cohort study. Lancet Infect Dis. 2017;17(5):545-552. doi:10.1016/S1473-3099(16)30516-3

98. Uyeki TM, Erickson BR, Brown S, et al. Ebola virus persistence in semen of male survivors. Clin Infect Dis. 2016;62(12):1552-1555. doi:10.1093/cid/ciw202

99. Mulangu S, Dodd LE, Davey RT Jr, et al. A randomized, controlled trial of Ebola virus disease therapeutics. N Engl J Med. 2019;381(24):2293-2303. doi:10.1056/NEJMoa1910993

100. McCormick JB, King IJ, Webb PA, et al. Lassa fever. Effective therapy with ribavirin. N Engl J Med. 1986;314(20):20-26. doi:10.1056/NEJM198601023140104

101. Swanepoel R, Gill DE, Shepherd AJ, Leman PA, Mynhardt JH, Harvey S. The clinical pathology of Crimean-Congo hemorrhagic fever. Rev Infect Dis. 1989;11 Suppl 4:S794-S800. doi:10.1093/clinids/11.supplement_4.s794

102. Monath TP. Yellow fever: an update. Lancet Infect Dis. 2001;1(1):11-20. doi:10.1016/S1473-3099(01)00016-0

103. Fitzpatrick G, Vogt F, Gbabai OBM, et al. The contribution of Ebola viral load at admission and other patient characteristics to mortality in a Médecins Sans Frontières Ebola Case Management Centre, Kailahun, Sierra Leone, June-October, 2014. J Infect Dis. 2015;212(11):1752-1758. doi:10.1093/infdis/jiv304

104. Chertow DS, Kleine C, Edwards JK, Scaini R, Giuliani R, Sprecher A. Ebola virus disease in West Africa — clinical manifestations and management. N Engl J Med. 2014;371(22):2054-2057. doi:10.1056/NEJMp1413084

105. Sneller MC, Reilly C, Badio M, et al. A longitudinal study of Ebola sequelae in Liberia. N Engl J Med. 2019;380(10):924-934. doi:10.1056/NEJMoa1805435

106. Cummins D, McCormick JB, Bennett D, et al. Acute sensorineural deafness in Lassa fever. JAMA. 1990;264(16):2093-2096.

107. Mohammed A, Sheikh TL, Gidado S, et al. An evaluation of psychological distress and social support of survivors and contacts of Ebola virus disease infection and their relatives in Lagos, Nigeria: a cross sectional study — 2014. BMC Public Health. 2015;15:824. doi:10.1186/s12889-015-2167-6

108. Staples JE, Bocchini JA Jr, Rubin L, Fischer M; Centers for Disease Control and Prevention. Yellow fever vaccine booster doses: recommendations of the Advisory Committee on Immunization Practices, 2015. MMWR Morb Mortal Wkly Rep. 2015;64(23):647-650.

109. Lindsey NP, Schroeder BA, Miller ER, et al. Adverse event reports following yellow fever vaccination. Vaccine. 2008;26(48):6077-6082. doi:10.1016/j.vaccine.2008.09.009

110. Henao-Restrepo AM, Camacho A, Longini IM, et al. Efficacy and effectiveness of an rVSV-vectored vaccine in preventing Ebola virus disease: final results from the Guinea ring vaccination, open-label, cluster-randomised trial (Ebola Ça Suffit!). Lancet. 2017;389(10068):505-518. doi:10.1016/S0140-6736(16)32621-6

111. Milligan ID, Gibani MM, Sewell R, et al. Safety and immunogenicity of novel adenovirus type 26- and modified vaccinia Ankara-vectored Ebola vaccines: a randomized clinical trial. JAMA. 2016;315(15):1610-1623. doi:10.1001/jama.2016.4218

112. Ebola ça suffit ring vaccination trial consortium. The ring vaccination trial: a novel cluster randomised controlled trial design to evaluate vaccine efficacy and effectiveness during outbreaks, with special reference to Ebola. BMJ. 2015;351:h3740. doi:10.1136/bmj.h3740

113. Safronetz D, Mire C, Rosenke K, et al. A recombinant vesicular stomatitis virus-based Lassa fever vaccine protects guinea pigs and macaques against challenge with geographically and genetically distinct Lassa viruses. PLoS Negl Trop Dis. 2015;9(4):e0003736. doi:10.1371/journal.pntd.0003736

114. Centers for Disease Control and Prevention. Interim guidance for managing patients with suspected viral hemorrhagic fever in U.S. hospitals. Updated 2018.

115. Jacobs M, Rodger A, Bell DJ, et al. Late Ebola virus relapse causing meningoencephalitis: a case report. Lancet. 2016;388(10043):498-503. doi:10.1016/S0140-6736(16)30386-5

116. Tarantola A, Nabeth P, Tattevin P, Michelet C, Zeller H. Lookback exercise with imported Crimean-Congo hemorrhagic fever, Senegal and France. Emerg Infect Dis. 2006;12(9):1424-1426. doi:10.3201/eid1209.051383

117. World Health Organization. Interim Infection Prevention and Control Guidance for Care of Patients with Suspected or Confirmed Filovirus Haemorrhagic Fever in Health-Care Settings, with Focus on Ebola. Updated 2014.

118. Fisher-Hoch SP, McCormick JB. Lassa fever vaccine. Expert Rev Vaccines. 2004;3(2):189-197. doi:10.1586/14760584.3.2.189

119. Wolfe ND, Daszak P, Kilpatrick AM, Burke DS. Bushmeat hunting, deforestation, and prediction of zoonotic disease emergence. Emerg Infect Dis. 2005;11(12):1822-1827. doi:10.3201/eid1112.040789

120. Centers for Disease Control and Prevention. Marburg Disease Outbreaks. Updated 2024. Accessed January 2026.

121. World Health Organization. Outbreak of suspected Marburg Virus Disease – United Republic of Tanzania. Disease Outbreak News. 2025.

122. CEPI. Marburg – What it is, and what it is not. March 2023. Accessed January 2026.

123. Ficenec S, Bond N, Zifodya J, Schieffelin J. A systematic review of the immuno-inflammatory dysfunction secondary to viral hemorrhagic fevers; Ebola and Lassa fever. PLoS Negl Trop Dis. 2025;19(6):e0013230. doi:10.1371/journal.pntd.0013230

124. Expert Review of Anti-infective Therapy. Viral hemorrhagic fevers - therapeutic trial advances and challenges. 2025. doi:10.1080/14787210.2025.2592294

125. Thomas SJ, Polakowski LL, Ashbaugh HR, et al. Yellow fever vaccine usage in the United States and risk of neurotropic and viscerotropic disease: A retrospective cohort study using three healthcare databases. Vaccine. 2022;40(2):264-271. doi:10.1016/j.vaccine.2021.11.074

126. Icard V, Leguillier T, Durand M, et al. Yellow fever vaccine-associated neurologic and viscerotropic disease: a 10-year case series of the French National Reference Center for Arboviruses with clinical and immunological insights. Clin Microbiol Infect. 2024;30(3):398-405. doi:10.1016/j.cmi.2023.11.018

127. Rwanda Biomedical Center. Marburg Virus Disease Outbreak Response, Rwanda 2024. Final Report, December 2024.

128. Broadhurst MJ, Brooks TJG, Pollock NR. Diagnosis of Ebola Virus Disease: Past, Present, and Future. Clin Microbiol Rev. 2016;29(4):773-793. doi:10.1128/CMR.00003-16

---

Medical Disclaimer: MedVellum content is for educational purposes and clinical reference. Clinical decisions should account for individual patient circumstances. Always consult appropriate specialists and adhere to local clinical guidelines and infection control protocols.