What is Ebola virus disease, including its virology, reservoir, epidemiology, transmission, pathogenesis, clinical features, diagnosis, treatment, and prevention?

Ebola Virus Disease: Comprehensive Overview

Virology

Ebola virus (EBOV) is an enveloped, nonsegmented, negative-stranded RNA virus belonging to the family Filoviridae, encoding seven viral structural proteins including a critical glycoprotein that mediates host cell attachment and membrane fusion. 1

• The genome encodes one glycoprotein, one nucleoprotein, one RNA-dependent RNA polymerase, and four virion proteins 1
• The glycoprotein is the only transmembrane surface protein and is essential for viral entry into host cells 1
• EBOV is the most lethal of four viruses in the Filoviridae family causing EVD in humans, with untreated case-fatality rates of 70-90% 1
• EBOV is responsible for 59% (19 of 32) of all reported EVD outbreaks in humans, including the two largest outbreaks in history 1

Reservoir and Epidemiology

Fruit bats are strongly implicated as the natural reservoir for EBOV, though the virus has never been cultured from naturally infected bats. 1

Animal Reservoirs

• EBOV has been detected by rRT-PCR and serology in three fruit bat species: Hypsignathus monstrosus, Epomops franqueti, and Myonycteris torquata in Gabon and Democratic Republic of Congo 1
• Experimentally infected fruit and insectivorous bats (Tadarida condylura, Tadarida pumila, Epomophorus wahlbergi) support viral replication without apparent illness 1
• EBOV has been cultured from sera and viscera of experimentally infected fruit bats 1
• Exposure to fruit bats was implicated in the 2007 outbreak in Luebo, Democratic Republic of Congo 1

Intermediate Hosts

• Nonhuman primates (chimpanzees, gorillas) and duikers are susceptible to EBOV infection resulting in disease and death 1
• Contact with infected animal carcasses has been directly implicated in several human outbreaks 1
• For many outbreaks, the animal source remains unknown 1

Geographic Distribution

• EVD occurs predominantly in African countries 2
• Recent outbreaks include Uganda (September 2022, Sudan ebolavirus) with 136 confirmed cases and 53 deaths, and Democratic Republic of Congo (August-September 2022) with one case 2

Transmission Dynamics

Human-to-human transmission occurs through direct contact with blood, bodily fluids, and secretions from infected individuals, with transmission risk beginning after symptom onset. 2

Primary Transmission Routes

• Direct contact with blood, body fluids, and secretions from symptomatic infected individuals 2
• Contact with virally contaminated objects and equipment 2
• Sexual transmission through semen has been documented 1

Viral Persistence and Sexual Transmission

• EBOV has been cultured from semen up to 82 days after illness onset 1
• EBOV RNA detected by rRT-PCR in semen within 3 months of discharge from Ebola treatment units in most men 1
• Viral persistence in semen documented up to 965 days after illness onset in some cases 1
• Older men (>40 years) more likely to have persistent EBOV RNA in semen after 3 months of recovery 1
• No documented transmission through female-to-male sexual contact 1

Immune-Privileged Sites

• EBOV persists in eye, placenta, testes, and central nervous system 1
• EBOV cultured from ocular aqueous humor at 3 months after illness onset 1
• EBOV crosses the placenta and detected in amniotic fluid, fetal meconium, umbilical cord, and neonatal buccal swabs 1
• EBOV persists in amniotic fluid for unknown duration after clearance from maternal blood 1

Pathogenesis and Immune Response

EBOV demonstrates broad cell tropism with monocytes, macrophages, and dendritic cells as early preferred targets, leading to immune dysregulation through virus-induced cytokine release. 1

Cellular Pathogenesis

• Monocytes, macrophages, and dendritic cells are early targets with important roles in viral dissemination 1
• Virus-induced release of cytokines and chemokines results in immune system dysregulation 1
• Increased vascular permeability occurs from cytokine-mediated endothelial damage 3

Coagulopathy Mechanism

• Disseminated intravascular coagulation (DIC) develops from immune dysregulation and endothelial damage 3
• Elevated prothrombin time, partial thromboplastin time, and detectable fibrin-split products occur in fatal cases 3
• Combined vascular permeability and coagulopathy lead to hemorrhagic manifestations 3

Terminal Events

• Multisystem organ failure occurs 7-10 days after illness onset due to combined vascular instability, coagulopathy, and immune dysregulation 3

Clinical Features

EVD typically begins with "dry symptoms" (fever, headache, myalgia, joint pain) followed by "wet symptoms" (nausea, vomiting, diarrhea) at approximately day 4 of illness. 1

Early Phase (Days 1-4)

• Fever, headache, muscle aches, joint pain 1
• Sudden onset of flu-like symptoms 4

Progressive Phase (Day 4 onwards)

• Nausea, vomiting, and diarrhea 1
• Severe diarrhea with outputs up to 10 L/day leading to severe metabolic derangements 1
• Cough, shortness of breath 1
• Conjunctival injection 1
• Erythematous maculopapular rash 1

Late Phase (Hemorrhagic Manifestations)

• Hemorrhage occurs in approximately half of patients, appearing late in disease course 1, 3
• Bleeding from injection sites, epistaxis, hematemesis, hematochezia, melena, gingival bleeding 1, 3

Fatal Outcome

• Death typically occurs 7-10 days after illness onset from multisystem organ failure 1, 3

Laboratory Findings and Diagnostics

Laboratory diagnosis relies on rRT-PCR detection of EBOV RNA, with characteristic findings including leukopenia, lymphopenia, and elevated transaminases. 1

Hematologic Findings

• Leukopenia and lymphopenia 1, 3
• Elevated prothrombin time and partial thromboplastin time in DIC 1, 3
• Detectable fibrin-split products 1, 3

Biochemical Findings

• Elevated transaminase levels 1, 3
• Severe metabolic derangements depending on fluid losses 1

Diagnostic Methods

• Real-time reverse transcriptase-polymerase chain reaction (rRT-PCR) for EBOV RNA detection 1
• Nucleic acid amplification, immunohistochemical staining, or antigen detection 1
• Serology for antibody detection 1

Differential Diagnosis

EVD must be differentiated from other viral hemorrhagic fevers and severe febrile illnesses endemic to Africa, particularly malaria, typhoid fever, and other causes of acute gastroenteritis with hemorrhagic features. 5

Key distinguishing features include:

• Epidemiologic exposure history (contact with infected individuals or animals) 2
• Progression from dry to wet symptoms over 4 days 1
• Severe volume depletion from massive diarrhea 1
• Late-onset hemorrhagic manifestations in approximately 50% of cases 3

Complications and Prognosis

EVD survivors face significant long-term morbidity with a five-fold increased risk of death within one year after recovery, with renal failure contributing to approximately 60% of post-recovery deaths. 1

Acute Complications

• Multisystem organ failure 1, 3
• Disseminated intravascular coagulation 3
• Severe metabolic derangements from fluid losses 1
• Case-fatality rate of 70-90% when untreated, approximately 50% with supportive care 1, 2

Post-Recovery Sequelae

• Urinary frequency, headache, fatigue, muscle pain, memory loss, joint pain reported significantly more in survivors than controls 1
• Ocular complications: photophobia, hyperlacrimation, conjunctivitis, uveitis with subsequent cataract formation 1
• Age-standardized mortality ratio of 5.2 (95% CI: 4.0-6.8) at 1 year post-recovery compared to general population 1
• Renal failure contributing to approximately 60% of post-recovery deaths 1

Treatment

Treatment of EVD centers on aggressive supportive care including intravenous fluids, electrolyte replacement, and management of secondary infections, with experimental monoclonal antibodies showing promise. 6, 7

Supportive Care

• Intravenous fluids and electrolyte replacement for severe volume depletion 6
• Treatment of secondary infections 6
• Management of metabolic derangements 1
• Early detection and supportive care enhance survival likelihood 6

Experimental Therapies

• Monoclonal antibodies have shown promising results in animal studies and clinical trials 6
• Antiviral drugs under investigation 6
• No specific FDA-approved treatment for EVD beyond supportive care 7

Vaccines

The rVSVΔG-ZEBOV-GP Ebola vaccine (Ervebo) is FDA-approved for prevention of EVD caused by Zaire ebolavirus in adults aged ≥18 years, recommended for highest-risk occupational groups. 1

Ervebo Vaccine Characteristics

• Replication-competent, live attenuated vaccine approved December 19,2019 1
• Contains rice-derived recombinant human serum albumin and live attenuated recombinant vesicular stomatitis virus 1
• Recombinant virus created by replacing VSV glycoprotein gene with EBOV-Kikwit 1995 strain glycoprotein gene 1
• Contraindicated in persons with severe allergic reaction to rice protein 1

ACIP Recommendations (2020)

ACIP recommends preexposure vaccination with Ervebo for adults aged ≥18 years at highest risk for occupational exposure to EBOV. 1

Specific populations include:

• Persons responding to an EVD outbreak 1
• Healthcare personnel at federally designated Ebola treatment centers in the United States 1
• Laboratorians or other staff at biosafety level 4 facilities in the United States 1

Vaccine Implementation

• Some African countries have implemented EVD vaccines, but long-term effectiveness and safety still under study 6

Infection Control and Public Health Measures

Effective EVD outbreak control requires stringent contact tracing, isolation of cases, safe burial practices, and comprehensive infection prevention measures across healthcare settings. 7

Healthcare Infection Control

• Standard, contact, and droplet precautions for all suspected or confirmed EVD cases 7
• Personal protective equipment for all healthcare personnel with potential exposure to patients or infectious materials 1
• Safe handling of contaminated medical supplies, devices, equipment, and environmental surfaces 1
• Proper decontamination of facilities and equipment 7

Public Health Response

• Stringent contact tracing and surveillance 2, 7
• Border control measures 2
• Case isolation and management 7
• Safe and dignified burial practices 7
• Social and community mobilization 7
• Laboratory service support for rapid diagnosis 7

Prevention of Transmission

• Avoid direct contact with blood, bodily fluids, and secretions from infected individuals 2
• Avoid contact with virally contaminated objects 2
• Sexual abstinence or condom use for male survivors due to prolonged viral shedding in semen 1
• Avoid contact with infected animal carcasses or bush meat 4

Outbreak History

The 2014-2016 West Africa outbreak was the largest EVD outbreak in history, emphasizing the critical need for effective control and prevention measures. 6

Historical Context

• First identified in 1976 in Zaire (now Democratic Republic of Congo) near the Ebola River 4, 6
• Simultaneous outbreaks in Sudan and Democratic Republic of Congo in 1976 6
• Intermittent outbreaks in several African nations since 1976 6

Major Outbreaks

• 2014-2016 West Africa outbreak: largest in history, highlighting need for effective control measures 6
• 2022 Uganda outbreak (Sudan ebolavirus): 136 confirmed cases, 53 deaths including 18 healthcare workers with 7 deaths 2
• 2022 Democratic Republic of Congo outbreak: one confirmed case (ended September 27,2022) 2

Epidemiologic Patterns

• EBOV responsible for 19 of 32 (59%) reported EVD outbreaks in humans 1
• Case-fatality rates vary from 30-90% depending on outbreak and treatment availability 2, 5
• Healthcare workers at significant risk during outbreaks 2