Ebola: The Evolving Catastrophe

This educational program will review the current Ebola outbreak, discuss epidemiology pathophysiology, signs and symptoms, patient assessment, prevention, and supportive care for Ebola victims. We will concentrate specifically on the 2014 Ebola virus (EBOV) (Zaire Ebolavirus) epidemic currently raging in the West African countries of Guinea, Liberia, Nigeria, Senegal and Sierra Leone.

After completing this course, the learner will be able to meet the following 30 objectives:

1. Define Ebola virus disease (EVD) or Ebola Hemorrhagic Fever (Ebola HF).
2. Discuss the evolving catastrophe of the current ebola outbreak
3. Relate the "hypothesized" modes of transmission of the Ebola virus from bats to various animal populations to humans.
4. List five ways EVD is transmitted from human-to-human.
5. State the signs and symptoms of EVD including time from exposure to the ebola virus and onset of symptomology.
6. Describe the pathophysiology underlying EVD.
7. Relate a minimum of three key questions which should be asked during the medical history which would lead the healthcare worker to suspect EVD.
8. Discuss prevention.
9. Describe the supportive care which should be provided to every individual with EVD.
10. Discuss the overall mortality rate and its meaning to the countries and the entire world.
11. List some long-term problems which may persist after surviving EVD.
12. Discuss the economic effects on the Ebola ravaged countries and the global implications of these effects.

As of August 2014, the World Health Organization (WHO) also reported an outbreak of Ebola Virus Disease in the Democratic Republic of the Congo (DRC) which lies in Central Africa. The WHO confirmed that the current strain of the virus is the Zaire Ebola species, which is common in the DRC. The virology results and epidemiological findings indicate no connection to the current epidemic in West Africa (i.e. the index case and her contacts had no history of travel to the Ebola ravaged countries in Western Africa or history of contact with individuals from the affected areas). This is the DRC's seventh Ebola outbreak since 1976.

Ebola virus disease (EVD) or Ebola hemorrhagic fever (Ebola HF) is the human disease caused by the Ebola virus-one of numerous Viral Hemorrhagic Fevers. It is a severe, often fatal disease in humans and nonhuman primates such as monkeys, gorillas, and chimpanzees.

Basic understanding of these countries may help to facilitate understanding of the roadblocks faced in undertaking the eradication of these Ebola outbreaks.

In general, there are inherent problems with containing and controlling the Ebola epidemics in the affected countries.

• Lack of an adequate infrastructural base such as running water, plumbing, schools, hospitals, clinics, roads etc.
• Culture of corruption limiting development of the countries resources.
• Maldistribution of wealth resulting in many of the affected areas being extremely poor with limited access to running water or soap.
• Low literacy rates due to lack of schools or poor school attendance.
• Poor economic conditions resulting in a "bushmeat" problem, which is a major environmental, as well as, socio-economic crisis. (Bushmeat is typically obtained by trapping wild animals, usually with wire snares, or otherwise with shotguns, poisoned arrows or arms). The "bushmeat crisis" has emerged as a result of poor living conditions and a lack of education about the dangers of eating it. Deplorable economic conditions force many families to become dependent on bushmeat, either as a means of acquiring income (hunting the meat and selling it), or becoming dependent on it for food. Unemployment and urbanization have exacerbated the problem further by turning cities with their urban sprawl into a prime market for commercial bushmeat.
• In some areas, people have become suspicious of both the government and hospitals. Some hospitals have been attacked by angry protestors who believe that the disease is a hoax or that the hospitals are responsible for the disease.
• Distrust of western countries due to past history of colonialism.
• History of political disruptions in the forms of military coups, civil wars etc. which left death and destruction in their wake. This caused recovery to be slow and, in some cases, elusive.
• Multilingual, multicultural ethnic groups in any given country.
• Belief in traditional folk remedies.
• Cultural practices that predispose people to physical contact with the deceased, especially death customs such as washing the body of the deceased.
• Some hospitals lack basic supplies and are understaffed which has increased the chance of staff catching the virus themselves. In August, the WHO reported that ten percent of the dead were health care workers.

West Africa, also called Western Africa and the West of Africa, is the westernmost subregion of the African continent. West Africa is inhabited by West Africans, and in line with the current membership of the Economic Community of West African States (ECOWAS), established in May 1975, West Africa has been defined in Africa as including fifteen states Benin, Burkina Faso, Island of Cape Verde, Gambia, Ghana, Guinea, Guinea-Bissau, Ivory Coast, Liberia, Mali, Niger, Nigeria, Senegal, Sierra Leone, and Togo. (Diagram 1).

Diagram 1: EBOLA VIRUS EPIDEMIC IN WEST AFRICA 2014

Situation map of the outbreak

Date December 2013 – present Location Liberia, Sierra Leone, Guinea, Nigeria, Senegal

Casualties Reported Cases / Deaths (as of 25 September 2014) Total: 6,808 / 3,159 Liberia: 3,564 / 1,922 Sierra Leone: 2,120 / 564 Guinea: 1,103 / 668 Nigeria: 20 / 8 Senegal: 1 / 0

The Democratic Republic of the Congo, also known as DR Congo, DRC, Congo, Congo-Kinshasa, DROC, or RDC, is a country located in Central Africa. (Diagram 2)

Diagram 2: EBOLA VIRUS EPIDEMIC in the DEMOCRATIC REPUBLIC OF THE CONGO-2014

DRC Ebola area as of 6 September 2014

Casualties Cases / Deaths (as of 23 September 2014) DR Congo: 70 / 42

Ebola virus disease (EVD) or Ebola hemorrhagic fever (Ebola HF) is caused by four of five identified subspecies of Ebolavirus classified in the genus Ebolavirus, family Filoviridae, order Mononegavirales. The four identified subspecies of the Ebolavirus that have caused disease in humans are:

• Bundibugyo virus (BDBV) (Bundibugyo ebolavirus) (Ebola-Bundibugyo)
• Ebola virus (EBOV) (Zaire ebolavirus)
• Sudan virus (SUDV) (Sudan ebolavirus)
• Taï Forest virus (TAFV) (Taï Forest ebolavirus formerly Cote d'Ivoire ebolavirus)

The fifth virus, Reston virus (RESTV) (Reston ebolavirus), has caused disease in nonhuman primates such as monkeys, gorillas and chimpanzees but is not thought to cause disease in humans. A host of similar species are probably associated with Reston virus, which was isolated from infected cynomolgous monkeys that were imported to the United States and Italy from the Philippines. Several workers in the Philippines and in US holding facilities became infected with the virus, but did not become ill.

The International Committee on Taxonomy of Viruses currently recognizes four subspecies of the Ebolavirus: Zaire ebolavirus (EBOV), Sudan ebolavirus (SUDV), Reston ebolavirus (RESTV), and Taï Forest ebolavirus (TAFV). The World Health Organization (WHO) and Centers for Disease Control and Prevention (CDC) added an additional subspecies of Ebola, the Bundibugyo ebolavirus (BDBV) or Ebola-Bundibugyo, following an outbreak in Uganda in 2007.

Ebola outbreaks have been restricted to Africa with the exception of the Reston ebolavirus. (Table 2)

The first Ebolavirus subspecies was discovered in 1976 in what is now the Democratic Republic of the Congo (DRC), formerly Zaire, near the Ebola River. Since then, outbreaks have appeared sporadically.

August 2014

• An outbreak of Ebola Virus in the Democratic Republic of Congo (DRC) was reported. The index case and the 80 contacts had no history of travel to the Ebola-affected countries or history of contact with individuals from the affected areas. It is believed that the outbreak in the DRC is unrelated to the ongoing outbreak in West Africa.
• Several people, including four health care workers, were reported to have died of Ebola-like symptoms in the remote northern Équateur province, a province that lies about 750 miles north of the capital Kinshasa.
• 13 people were reported to have died with similar symptoms.
• The Équateur Province Ministry of Health confirmed an outbreak of Ebola to the WHO. The initial case was a woman from Ikanamongo Village who became ill with symptoms of Ebola after she had butchered a bush animal that her husband had killed. She was treated in a private clinic, but on 11 August she died of a then-unidentified hemorrhagic fever. The following week, relatives of the woman, several health-care workers who had treated the woman, and individuals with whom they had been in contact came down with similar symptoms. Five health care workers subsequently died.

September 2014

• The WHO said that there were currently 31 deaths in the Northern Boende area in the province of Équateur and 53 confirmed, suspected or likely cases. The WHO confirmed that the current strain of the virus in the Boende District is the Zaire Ebola species. This strain is common in the country and similar to the 1995 Kikwit outbreak in the DRC. The virology results and epidemiological findings indicated no connection to the current epidemic in West Africa.
• The WHO raised the number of cases to 62 and the death toll to 35 from possible or confirmed Ebola cases. Included in this number are 9 health-care workers with 7 deaths among them. In total 386 contacts have been listed and 239 contacts are being followed up. The outbreak is still contained in Jeera County in the Boende region.
• The WHO raised the number of cases to 71 and the death toll to 40 from possible or confirmed Ebola cases.

The natural reservoir host of ebolaviruses remains unknown. However, on the basis of available evidence and the nature of similar viruses, researchers believe that the virus is animal-borne with bats, particularly fruit bats, being considered the most likely natural reservoir of the Ebola virus (EBOV).

In the 1976 and 1979 outbreaks in the cotton factory where the first cases of EBOV were employed, bats were known to roost. Only bats became infected when 24 plant species and 19 vertebrate species were experimentally inoculated with EBOV. The absence of clinical signs in these bats is characteristic of a reservoir species. In a 2002–2003 survey of 1,030 animals including 679 bats from Gabon and the Republic of the Congo, 13 fruit bats were found to contain EBOV RNA fragments. As of 2005, three types of fruit bats (Hypsignathus monstrosus, Epomops franqueti, and Myonycteris torquata) have been identified as being in contact with EBOV. They are now suspected to represent the EBOV reservoir hosts. Antibodies against Ebola Zaire and Reston viruses have been found in fruit bats in Bangladesh, thus identifying potential virus hosts and signs of the filoviruses in Asia.

Between 1976 and 1998, in 30,000 mammals, birds, reptiles, amphibians, and arthropods sampled from outbreak regions, no ebolavirus was detected apart from some genetic traces found in six rodents (Mus setulosus and Praomys) and one shrew (Sylvisorex ollula) collected from the Central African Republic. Traces of EBOV were detected in the carcasses of gorillas and chimpanzees during outbreaks in 2001 and 2003, which later became the source of human infections. However, the high lethality from infection in these species makes them unlikely as a natural reservoir.

Bushmeat

Bushmeat being prepared for cooking. Human consumption of equatorial animals in Africa in the form of bushmeat has been linked to the transmission of diseases to people, including Ebola.

Because the natural reservoir of ebolaviruses has not yet been proven, the manner in which the virus first appears in humans at the start of an outbreak remains unknown. EVD outbreaks are usually traceable to a single individual who has handled an infected animals body fluids while skinning the carcass of a gorilla, chimpanzee, or duiker.

Bats drop partially eaten fruits and pulp onto the ground then land mammals such as gorillas and duikers feed on these fallen fruits. This chain of events forms a possible indirect means of transmission from the natural host to animal populations, which has led to research towards viral shedding in the saliva of bats. Fruit bats are also eaten by people in parts of West Africa where they are smoked, grilled or made into a spicy soup. (Diagram 3).

Fruit production, animal behavior, and other factors vary at different times and places that may trigger outbreaks among animal populations.

Diagram 3: LIFE CYCLES OF THE EBOLA VIRUS

Human-to-human transmission of EVD infections is considered low as the disease is only spread by direct contact with the secretions from an individual who is showing the signs and symptoms of infection. EVD is spread by:

• Direct contact with blood or bodily fluids (urine, feces, vomit, semen) from an infected person (including embalming of an infected dead person).
• Through broken skin or mucus membranes.
• Contact with contaminated medical equipment, particularly needles and syringes
• Sexual intercourse with a male since semen is infectious in survivors for up to 7 weeks.
• Oral exposure and exposure to conjunctival secretions since these have been confirmed in non-human primates.

The quick onset of symptoms makes it easier to identify sick individuals and limits an infected individual's ability to spread the disease by traveling. Because dead bodies are still infectious, some doctors dispose of them by cremation, despite local traditional burial rituals.

Healthcare workers have also contracted EVD. In these cases, transmission has occurred because:

• Appropriate protective clothing including masks, goggles, face shields, gowns and gloves have not been worn
• Needles and syringes have been reused without being appropriately sterilized
• Improper sterilization of instruments before being used again occurred
• There is a lack of use of universal precautions

Airborne transmission has not been documented during previous EVD outbreaks. The Ebola virus is, however, infectious as breathable 0.8–1.2 micrometre laboratory generated droplets. Because of this potential route of infection, ebolaviruses have been classified as Category A biological weapons.

Healthcare workers, family and friends in close contact with Ebola patients are at the highest risk of contracting EVD because they may come in contact with infected blood or body fluids.

The average time between exposure to the Ebola virus thus contracting EVD and the onset of symptoms may range anywhere from 2 to 21 days, although 8-10 days is most common.

Signs and symptoms of EVD usually begin suddenly with a flu-like stage characterized by (Diagram 4):

• fatigue
• fever (greater than 38.6°C or 101.5°F)
• headaches
• joint and muscle pain
• abdominal (stomach) pain
• vomiting
• diarrhea
• loss of appetite

Less common symptoms include the following: sore throat

• chest pain
• hiccups
• shortness of breath
• trouble swallowing
• decreased functioning of the liver and kidneys

Skin manifestations may include a maculopapular rash (in about 50% of cases). Not all infected individuals show hemorrhagic symptoms.

All infected individuals show some symptoms of circulatory system involvement, including impaired blood clotting. In 40–50% of cases, bleeding from puncture sites and mucous membranes (e.g. gastrointestinal tract, nose, vagina and gums) have been reported.

In the bleeding phase, which typically starts 5 to 7 days after first symptoms:

• internal and subcutaneous bleeding may present itself through reddening of the eyes and bloody vomit
• bleeding into the skin may create petechiae, purpura, ecchymoses, and hematomas (especially around needle injection sites)
• types of bleeding known to occur with EVD include: vomiting blood, coughing up blood, bloody stools
• Heavy bleeding is rare and is usually confined to the gastrointestinal tract

In general, the development of bleeding symptoms often indicates a worse prognosis and this blood loss can result in death. If the infected individual does not recover, death due to multiple organ dysfunction syndrome occurs within 7 to 16 days (usually between days 8 and 9) after the onset of first symptoms.

Some who become sick with EVD recover. Why this occurs is unknown. However, individuals who die usually have not developed a significant immune response to the virus at the time of death.

Diagram 4: SYMPTOMS OF EBOLA

Endothelial cells, mononuclear phagocytes, and hepatocytes are the main targets of the Ebola virus. After infection, a secreted glycoprotein (sGP) known as the Ebola virus glycoprotein (GP) is synthesized. Ebola replication overwhelms protein synthesis of infected cells and host immune defenses. The GP forms a trimeric complex, which binds the virus to the endothelial cells lining the interior surface of blood vessels. The sGP forms a dimeric protein that interferes with the signaling of neutrophils, a type of white blood cell, which allows the virus to evade the immune system by inhibiting early steps of neutrophil activation. These white blood cells also serve as carriers to transport the virus throughout the entire body to places such as the lymph nodes, liver, lungs, and spleen.

The presence of viral particles and cell damage resulting from budding causes the release of cytokines (to be specific, TNF-a, IL-6, IL-8, etc.), which are the signaling molecules for fever and inflammation. The cytopathic effect, from infection in the endothelial cells, results in a loss of vascular integrity. This loss in vascular integrity is furthered with synthesis of GP, which reduces specific integrins responsible for cell adhesion to the inter-cellular structure, and damage to the liver, which leads to coagulopathy. (Diagram 5).

Diagram 5: PATHOGENESIS SCHEMATIC

Early symptoms of EVD may be similar to those of dengue fever, Marburg virus disease, viral hemorrhagic fever, falciparum malaria, typhoid fever, shigellosis, rickettsial diseases such as typhus, cholera, gram-negative septicemia, borreliosis such as relapsing fever or EHEC enteritis.

Other infectious diseases that should be included in the differential diagnosis include: leptospirosis, scrub typhus, plague, Q fever, candidiasis, histoplasmosis, measles, trypanosomiasis, visceral leishmaniasis, hemorrhagic smallpox, and fulminant viral hepatitis.

Non-infectious diseases that can be confused with EVD include: acute promyelocytic leukemia, hemolytic uremic syndrome, snake envenomation, clotting factor deficiencies/platelet disorders, thrombotic thrombocytopenic purpura, hereditary hemorrhagic telangiectasia, Kawasaki disease, and even warfarin poisoning.

No vaccine is currently available for humans. The most promising candidates are DNA vaccines or vaccines derived from adenoviruses, vesicular stomatitis Indiana virus (VSIV) or filovirus-like particles (VLPs) because these candidates could protect nonhuman primates from ebolavirus-induced disease. DNA vaccines, adenovirus-based vaccines, and VSIV-based vaccines have entered clinical trials.

Vaccines have protected nonhuman primates such as crab-eating macaques and mice but the development and rigorous testing and trials on humans remains a long way off.

No proven ebolavirus-specific treatment exists. Treatment is primarily supportive in nature and includes:

• either oral rehydration therapy (slightly sweet and salty water to drink) or intravenous fluids
• balancing fluids and electrolytes to counter dehydration
• minimizing invasive procedures
• administration of anticoagulants early in infection to prevent or control disseminated intravascular coagulation        administration of procoagulants late in infection to control bleeding
• maintaining oxygen levels
• pain management
• the use of medications to treat bacterial or fungal secondary infections

Early treatment may increase the chance of survival. Timely treatment of EVD is important but challenging because the disease is difficult to diagnose clinically in the early stages of infection. Because early symptoms, such as headache and fever, are nonspecific to Ebola viruses, cases of EVD may be initially misdiagnosed.

The lack of treatments in the most-affected regions has spurred controversy. Some individuals are demanding that experimental drugs be made more widely available in Africa on a humanitarian basis. Other individuals warn that making unproven drugs widely available would be unethical, especially in light of past experimentation conducted in developing countries by Western drug companies. As a result of the controversy, on August 12, 2014 an expert panel of the WHO endorsed the use of interventions with as-yet-unknown effects for both treatment and prevention of EVD. The WHO expert panel also stated that deciding which treatments should be used and how to distribute them equitably were matters that needed further discussion.

Subsequently the WHO Assistant Director-General for Health Systems and Innovation said on September 5, 2014 that transfusion of whole blood or purified serum from Ebola survivors is the therapy with the greatest potential to be implemented immediately on a large scale in West Africa, although there is little information on the efficacy of such treatment.

In mid-September the sale of black market blood from survivors of the disease had become a new trend in the Ebola-affected regions. Serum derived blood from surviving victims has been used under strict control in certain cases. This trend in an uncontrolled manner could potentially lead to other infectious diseases. This treatment must be properly implemented as a medical treatment under strict control and screening of possible donors. Margaret Chan of the WHO has criticized the use of this practice in a black market environment, noting concerns over "storage and collection methods".

A number of experimental treatments are being studied or will undergo trials:

• ZMapp, being developed by Mapp Biopharmaceuticals, Inc., is a monoclonal antibody vaccine. It is still in the experimental stage and randomized controlled clinical trials still need to be conducted. The limited supply of the drug has been used to treat a small number of individuals infected with the Ebola virus. Although some of these have recovered the outcome is not considered statistically significant. ZMapp has proved highly effective in a trial involving rhesus macaque monkeys.
• TKM-Ebola, an RNA interference drug.
• Favipiravir, a drug approved in Japan for stockpiling against influenza pandemics. The drug appears to be useful in a mouse model of the disease. Japan has offered to supply the drug if requested by the WHO.
• In September, an experimental vaccine, currently known as the NIAID/GSK vaccine, commenced simultaneous Phase 1 trials in Oxford and Bethesda. The vaccine was developed jointly by GlaxoSmithKline and the NIH. If this phase is completed successfully, the vaccine will be fast tracked for use in West Africa. In preparation for this, GSK is preparing a stockpile of 10,000 doses.

It is important to remember that vaccines are usually given to individuals before they are exposed to a virus that causes a disease. A vaccine stimulates the immune system to generate antibodies and cellular immunity that can fight off an infection should it occur. Typically, therapeutics are provided to individuals who are already infected with a virus. As can be seen, prevention of EVD is the best route to take while waiting for the development and rigorous testing of vaccines and other therapeutic treatments.

The disease has a high mortality rate: often between 50 percent and 90 percent. April 2014 information from the WHO across all occurrences to date puts the overall fatality rate at 60%-65%. There are indications based on variations in death rate between countries that early and effective treatment of symptoms (e.g., supportive care to prevent dehydration) may reduce the fatality rate significantly.

If an infected individual survives, recovery may be quick and complete. Prolonged cases are often complicated by the occurrence of long-term problems, such as:

• inflammation of the testicles
• joint pains
• muscle pains
• skin peeling
• hair loss
• eye symptoms may include: light sensitivity, excess tearing, iritis, iridocyclitis, choroiditis and blindness

EBOV and SUDV may be able to persist in the semen of some survivors for up to seven weeks, which could give rise to infections and disease via sexual intercourse.

In addition to the loss of life, the outbreak is having a number of significant economic impacts:

• Markets and shops are closing, due to travel restrictions, cordon sanitaire (fear of human contact), leading to loss of income for producers and traders.
• Movement of people away from affected areas has disturbed agricultural activities. The U.N. Food and Agriculture Organization (FAO) have warned that the outbreak could endanger harvest and food security in West Africa.
• Tourism is directly impacted in affected countries. Other countries in Africa which are not directly affected by the virus have also reported adverse effects on tourism.
• Foreign mining companies have withdrawn non-essential personnel, deferred new investment, and cut back operations.
• Many airlines have experienced reduced traffic. Some airlines have suspended flights to the area.
• Forecasts of economic growth have been reduced. A 4 August World Bank-IMF assessment for Guinea projected a full percentage point fall in GDP growth from 4.5 percent to 3.5 percent and on 17 September, they reported that if the epidemic continues to grow, the affected countries could see the economic impact grow eight-fold, "dealing a potentially catastrophic blow to the already fragile states."
• The outbreak is straining the finances of governments, with Sierra Leone using Treasury bills to fund the fight against the virus.
• The IMF is considering expanding assistance to Guinea, Sierra Leone, and Liberia as their national deficits balloon and their economies contract sharply.

International Organizations which have responded to the Ebola Epidemic in West Africa and the Democratic Republic of the Congo include the:

• World Health Organization
• US Centers for Disease Control
• Médecins Sans Frontières
• Economic Community of West African States (ECOWAS)
• European Union
• World Bank Group
• World Food Program
• United Nations Security Council
• US NIH's National Institute of Allergy and Infectious Diseases

Charitable Organizations, Foundations and Individuals include:

• Bill and Melinda Gates Foundation
• Paul G. Allen Family Foundation
• Samaritan's Purse
• Red Cross
• Aiko Dangote

It would be fair to say that most countries circling the globe have responded with:

• Money
• Health care supplies including medical protective clothing, disinfectants, thermodetectors and medicines
• Health Care Teams including Infectious Disease Specialists and research teams
• Initiated stepped up surveillance of all travelers entering or leaving the country by air or sea from Ebola-affected regions
• Issued travel advisories
• Food and water donations
• Sent healthcare personnel or other personnel i.e. military personnel to assist in the construction of hospitals/clinics to aid the volumes of ill individuals

Anxiety and fear now has struck the United States and other countries of the world since EVD is no longer being viewed as "just an African problem". Despite all the best intentions and best efforts the Ebola epidemic in West Africa continues to spread exponentially. The Ebola epidemic in the DRC is just beginning to pick up speed. Now the whole world feels threatened, so much so, that most average everyday people feel at risk.

Instead of feeling afraid and becoming paranoid use common sense: wash your hands, pay attention to those who seem to "have the flu", ask questions about recent travel, to what country, exposure to bushmeat etc. Remember, despite what you may think, African "bushmeat" is illegally sold here in America.

The Centers for Disease Control and Prevention offer protocols for diagnosis/testing, transportation/monitoring/movement, protecting healthcare workers, EVD information for clinicians in U.S. healthcare settings and other very valuable information for caring for the Ebola patient and keeping all others safe.