MED-NERD
Ebola Virus
Outline:
- Introduction
- Epidemiology
- Transmission
- Symptoms
- Diagnosis
- Differential diagnosis
- Management and treatment
- Prognosis and mortality rate
- Prevention
- References
Introduction:
Ebola virus, known as Ebola Haemorrhagic Fever (EHF), was first detected in 1976 near Ebola River (the Democratic Republic of Congo).
Ebola virus belongs to Ebola genus and is a member of Filoviridae family which is derived from a Latin word (filum) that means thread. It is a filamentous virus as it has a twisted thread shape. It is a large non segmented, negative-strand RNA virus. Ebola virus genus includes five species : Reston ebolavirus (RESTV), Taï Forest ebolavirus (TAFV), Sudan ebolavirus (SUDV), Bundibugyo ebolavirus (BDBV), the newly identified Bombali ebolavirus (BOMV), and Zaire
ebolavirus which is usually known as Ebola virus (EBOV). These viruses consist of about 19 kp encoding nucleoproteins, glycoproteins, virion proteins, and RNA dependent RNA polymerase.
All species cause endemic West African Ebola Virus Disease (EVD) except RESTV which was detected only in the Philippines. The Filoviridae family also includes the genus Marburgvirus (Marburg virus (MARV) and Ravn virus (RAVV), and the most virulent virus of the family is MARV. Ceuvavirus was detected in bats in Spain.
Epidemiology:
-In 1976, EBOV was first detected in the Democratic Republic of Congo by Dr. Peter Piot.
-Since the discovery of EBOV, more than 17 EVD outbreaks have occurred mostly in six African countries, the Republic of the Congo, Gabon, Sudan, Uganda, Gabon, Guinea, and about 43 FVD outbreaks reported in Africa.
-About 15,000 deaths and 34,000 cases were caused by these outbreaks, approximately 5000 cases were among women of childbearing age.
-Some outbreaks occurred due to laboratory contamination.
-Until 1989, the virus was considered an African virus (occurring only in Africa).
-After 1989, Reston virus (RESTV) was discovered in the Philippines non-human primate (NHP) breeding facilities.
-Until 2013, outbreaks emerged mainly from middle Africa.
From 2013 to 2016, the largest outbreak of EBOV have occurred , it was caused by novel EBOV variant, Makona (EBOV/Mak) spreading from Guinea to Western Africa, ended in March 2016 causing about 28,652 human infections and 11,325 deaths. On August 8th, 2014, the WHO declared EBOV a public health emergency of International Concern. Cases were reported mainly in Guinea, Liberia, and Sierra Leone.
-In December 2013, complete sequence of 65 Marburg viruses and 29 ebolaviruses genome were detected.
-Natural filovirus disease caused about 35 outbreaks.
-In 2018, Bombali virus was detected in bats.
-On June 1, 2020, the most recent outbreak has occurred in the Democratic Republic of the Congo and is considered ongoing.
-Most cases that were reported outside Africa were in healthcare workers working in in regions with an active outbreak.
-On September 20, 2022, The Uganda Ministry of health announced the first positive case of EVD caused by Sudan virus. Until now, no confirmed cases reported in the United States or other countries and the outbreak is still small in Uganda.
-On October 19, 2022, 65 confirmed cases of EVD were reported according to the WHO with 25 deaths, about 11 healthcare providers were infected with 5 deaths.
-On October 20, 2022, one case of EVD was detected in Mityana District, Uganda due to contact with other infected cases.
Transmission:
Transmission of EBOV occurs in different ways. The typical human to human transmission occurs through direct contact with infected body fluids (blood, urine, faeces, saliva, vomit, semen, breast milk, fomites), and tissues of infected human. The exact reservoir of EBOV is unknown, however bats are considered the main source of infection. According to the World Health Organization (WHO), fruit bats of Pteropodidae family (e.g., Epomops franqueti, Hypsignathus monstrous, Myonycteris torquata) may be the natural reservoirs of EBOV in Africa. Pteropodidae family of fruit bats is highly found in India, which represents a threat to EBOV infection. Contact with infected secretions from dead individuals and unsafe conventional burials caused approximately 68% of EVD cases in 2014 in Guinea.
Nonhuman primates may transmit the disease to humans by eating the partly eaten fruits. Oral transmission of EVD is caused by
eating infected uncooked animal meat like bats or chimpanzees. In 2008, EBOV was detected in Filipino pigs which increased the possibility of animal hosts. Ebola virus was detected in breastmilk, amniotic fluid, and placental and foetal tissue representing a greater risk of infection during pregnancy. Transmission of EBOV during pregnancy is associated with higher rate of mortality.
The RNA of EBOV can be detected in semen, vaginal and rectal discharge up to 3 months. In 1996, an asymptomatic carrier case was reported in North Gabon. Poor hygiene and sterilization were considered main factors in transmission of EVD as in 1976 in Sudan and Zaire, and 1967 Yambuku outbreaks. The clothes and medical utensils of infected patients are usually burned to avoid spreading the virus.
The virus enters the host mucosal membrane or skin cracks and persists for an asymptomatic period lasting up to few weeks. A person presenting with typical viral illness signs is considered infectious.
Ebola virus is considered a biosafety level 4 and category A bioterrorism pathogen, according to the Centers for Disease Control and Prevention (CDC), with massive transmission worldwide.
Symptoms:
-The incubation period of EBOV ranges from 2 to 21 days. Symptoms usually develop 8-11 after infection. EVD or Ebola haemorrhagic fever is associated with constitutional non-specific symptoms ( flu-like syndrome) including: sudden high fever, headache, myalgias, malaise, nausea, vomiting, abdominal pain, and diarrhoea. EBOV is characterized by high progression and mortality rate leading to multiple organ failure, mental disorder, coma and death.
The initial disease includes dry symptoms and the advanced disease includes wet symptoms.
The most frequent symptom is high-grade fever >38°C ( 85%-95%). General malaise occurs in about (85–95%) of cases, headaches (52–74%), sore throat (56–58%), dysphagia, and dry cough. In more progressive cases, patients experience diarrhoea (84–86%), myalgia (50–79%), abdominal pain (62–68%), nausea, and vomiting.
Maculopapular exanthema occurs nearly in 25–52% from day 5 to day 7 of the disease.
The late phase disease presents with haemorrhagic manifestations such as petechiae, conjunctival bleeding, Gum bleeding, intraperitoneal bleeding, petechiae, contusion, epistaxis, melena, haematuria, venipuncture site bleeding, and clot formation.
Advanced stages include multiorgan dysfunction, myocarditis, pulmonary oedema, confusion, stupor, dehydration, hypotension, leading to shock, coma, and eventually death.
Survivors experience the following symptoms in the convalescence phase that lasts several months: joint pain, fatigue, loss of appetite and memory. After resolution, EBOV RNA may be found in some organs (e.g., testis) for more than 1 year.
Diagnosis:
Diagnosis of EBOV is based of clinical picture, history of exposure, and is confirmed by laboratory tests especially molecular test. Clinical presentation and laboratory values differ according to the stage of the disease.
History of exposure:
1-Primary exposure: working in or travelling to Ebola-endemic country.
2-Secondary exposure: Human-to-human transmission including Family and medical care providers, exposure to infected blood or body fluids, exposure to semen from an EVD survivor, people prepared burial for infected patients. Primate-to-human exposure including animal care providers.
Laboratory testing:
Laboratory tests include: complete blood count (CBC), comprehensive metabolic panel (CMP), urine analysis (UA), Basic coagulation profile, PCR, Ebola virus antibody, enzyme-linked immunoassay (ELISA) which is less sensitive than reverse transcriptase polymerase chain reaction (RT-PCR).
Other tests may be used to confirm the diagnosis: electron microscopy, virus isolation by cell culture, and antigen-capture detection tests.
RT-PCR has high sensitivity (nearly 100%) and is used to detect serum viral RNA, despite being negative up to 72 hours after the onset of symptoms. Results of PCR depend on the amount of virus presents in the blood which is increased in active infection.
ELISA is less sensitive (91% sensitivity) and less commonly used detecting immunoglobulin M (IgM) and IgG specific to the virus. Positive results may be delayed up to 3 weeks in acute cases.
Novel rapid diagnostic tests are still under research and is not available yet.
Diagnosis should be made as rapid as possible in pregnancy due to the high risk of mortality in pregnant females and the need for obstetric interventions.
According to the WHO, the following tests are recommended:
-Automated or semi-automated nucleic acid tests (NAT): for routine diagnosis.
-Rapid antigen detection tests: For screening, surveillance, and if NATs are not available.
For collection of specimens:
-In 2014, the WHO recommended collecting samples (blood samples and oral swabs) at Ebola treatment centres.
-Samples represent a severe biohazard risk, therefore extreme biological containment conditions must be used in laboratory testing.
-Triple packaging system must be used to package all samples being transported.
-Blood sample in ethylene-diamine-tetra-acetic acid (EDTA): In case of active infection.
-Oral specimen in universal transport medium: If blood samples are not available.
According to the CDC recommendations regarding healthcare professionals:
-Patients presenting with fever, abdominal pain, diarrhoea, vomiting, severe headache, bruising, unexplained bleeding, should be considered Ebola cases until prove otherwise.
-History must be taken regarding travelling to Ebola-endemic area in 21 days preceding the onset of symptoms.
-Suspected cases should be isolated in private room with private bathroom with implementation of standard precautions in addition to notification to public health authorities. After the disease is confirmed, investigations must be done to detect all possible contacts.
People at high risk of Ebola infection include:
-Direct contact with Ebola infected blood or body fluids.
-Physical contact with Ebola case.
-Living or travelling to Ebola-endemic area, or visiting Ebola patient.
Differential diagnosis:
The diagnosis of EVD is difficult due to the non-specific symptoms experienced early in the disease.
The initial phase of EVD resembles malaria, dengue fever, Influenza, typhoid fever meningococcaemia, gastroenteritis, cholera, shigella, Norovirus, Rotavirus, and some other bacterial infections. Moreover, EVD resembles other Haemorrhagic Fevers including Lassa fever, Crimean-Congo haemorrhagic fever, Marburg virus, and Bunya virus.
Management and treatment:
-The most effective management is prevention.
-Quarantine and isolation of patients.
-The main line of EVD treatment is supportive and symptomatic treatment.
-Rehydration with repeated Intravenous (IV) fluid and electrolyte and oral rehydration solution administration.
-Antipyretics, analgesics.
-Adequate oxygen (intubation and ventilation) and maintaining a stabilized blood pressure.
-Adequate nutrition and blood transfusion.
-Glucose and vasopressor support.
-Antiemetics and antidiarrheal drugs in case of vomiting and diarrhoea.
-Prophylactic antibiotics (third generation I.V. cephalosporins) in case of septicaemia and secondary bacterial infections.
-Monitoring coagulopathies and multiorgan dysfunction.
-Renal replacement therapy in case of renal dysfunction.
-Contact tracing, epidemiological surveillance.
-Recovery usually requires months.
-Weight gain and returning to normal daily activities take some time.
-EBOV persists and can be detected for weeks even after recovery.
Management with Monoclonal antibodies (mAbs):
Monoclonal antibodies (mAbs) are synthetic proteins resembling the action of natural antibodies in order to stop replication of organisms such as viruses. mAbs can bind to glycoproteins on the surface of EBOV preventing its entrance to the host cell.
Currently, there are two mAbs drugs approved by the U.S. Food and Drug Administration (FDA) to treat EVD caused by EBOV in both adults and children. Both drugs were evaluated during 2018-2020 Ebola outbreak in the Democratic Republic of the Congo in a randomized controlled trial.
-Inmazeb: Approved in October 2020. It is a combination of three monoclonal antibodies.
-Ebanga: Approved in December 2020. It is single monoclonal antibody.
Management in pregnancy:
According to the 2020 WHO guidelines for management of EVD in pregnant females:
-Care should be given in a private, high-risk facility.
-Maternal condition should be prioritized in management of pregnant women over foetal condition.
-Extreme fluid resuscitation of up to 10 L per day is necessary in pregnant females.
-In case of high viral load, delaying delivery may be useful due to the risk of coagulopathy.
-Pregnant women with severe infection may not survive in surgical delivery instead, uterotonics and fundal massage should be done for fear of postpartum haemorrhage.
-Regular prenatal care is highly recommended for pregnant women who survived from EVD.
Prognosis and mortality rates:
Mortality rates range from 25% to 90%; 50% on average depending on the strain of EBOV, early detection of the disease, and access to medical care. Zaire ebolavirus is associated with the highest mortality rate. SUDV cases fatality rates ranging between (41% and 65%), whereas Bundibugyo virus (40%). Less mortality with TAFV and RESTV mainly causes asymptomatic cases.
Pregnancy mortality rates range from 74% to 93%. Abortion and foetal loss occur almost in 100% of infected pregnant females. Neonates born to infected mothers , approximately 100% of them died within 3 weeks of life.
Prevention:
Preventive measures include proper case management, contact tracing, surveillance safe burials.
-It is critical to implement screening and international travel bans on departure from Ebola-endemic areas to prevent the spread of the virus.
-Increasing awareness about Ebola virus infection and its protective methods.
According to the WHO:
-Handling animals (e.g., monkeys, fruit bats, forest antelope, porcupines, apes) with gloves and protective clothing, proper cooking of animal products (meat) before eating.
-Regular hand washing after visiting patients, wearing gloves and protective clothing.
-Follow up of individuals who contacted infected people for 21 days with their isolation in a clean environment.
-Males survived from EVD should practice safer sex for up to 12 months after the onset of disease, their semen tests results should be negative twice for EBOV.
-Avoid contact with body fluids.
-Proper frequent antenatal care (ANC) visits for pregnant females survived from EVD to prevent possible pregnancy complications.
According to the CDC guidelines:
-Healthcare professionals should wear personal protective equipment (PPE), including surgical hood, single-use full face shield, N95 mask, powered air-purifying respirator.
-Gloves should be disinfected using alcohol-based hand rub (ABHR) after handling body fluids and during patient care.
Vaccination:
In December 2020, Ervebo vaccine was approved by the FDA and prequalified by the WHO for individuals 18 years of age or older (excluding pregnant and breastfeeding women) for effective protection against the species Zaire ebolavirus.
In 2018-2020 Ebola virus disease outbreaks in the Democratic Republic of the Congo, the vaccine had been received by more than 350 000 people in Guinea.
The European Medicines Agency in May 2020, requested granting marketing authorization for a vaccine called Zabdeno-and-Mvabea which is formed of 2-components for individuals 1 year and older.
The vaccine is given in two doses:
First dose: Zabdeno is administered
Second dose: After nearly 8 weeks, Mvabea is administrated.
Therefore in outbreaks, the vaccine is not suitable due to long duration between the first and second doses and immediate protection is crucial.
See: Reye Syndrome ( Fatty Liver With Encephalopathy)
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