Challenges with Ebola outbreak in West Africa

Background

Ebola belongs to the family Filoviridae, in which most members cause severe hemorrhagic fever in humans. There are five species: Zaire ebolavirus, Sudan ebolavirus, Bundibugyo ebolavirus, Tai forest ebolavirus, and Reston ebolavirus. Each species contains one virus (Table 1) ^{Footnote 2 Footnote 3}.

Table 1: Species of Genus Ebolavirus ^{Footnote 3 Footnote 4}

Species	Virus	Region	Fatality Rate
Zaire ebolavirus	EBOV	Africa	60-90%
Sudan ebolavirus	SUDV	Africa	40-60%
Bundibugyo ebolavirus	BDBV	Africa	25%, based on one outbreak
Tai forest ebolavirus	TAFV	Africa	Unknown, only one known infection in Ivory Coast
Reston ebolavirus	RESTV	Asia	Not known to cause lethal infections in humans. Lethal in non-human primates.

The current outbreak is caused by a new variant of EBOV, the species most virulent in humans ^{Footnote 5}.

The natural reservoir of EBOV is unknown, but is thought to be fruit bats ^{Footnote 6}. EBOV is known to cause disease in humans, non-human primates, and other mammals ^{Footnote 4 Footnote 7}. EBOV is thought to enter the human population through exposure to the bodily fluids of an infected fruit bat or mammal, especially non-human primates. Human infection with EBOV has been associated with hunting and processing bushmeat ^{Footnote 8 Footnote 9 Footnote 10}.

Following an incubation period of 2 to 21 days (and is usually 8-10 days), Ebola initially presents with non-specific symptoms (e.g. headaches, fever, and muscle pain). This progresses to a rash, diarrhea and vomiting typically followed by multi-organ failure, hemorrhaging and death. Person-to-person transmission occurs through direct contact with the bodily fluids and tissues of an infected person ^{Footnote 2}. Those most at risk of infection during outbreaks are family members and caregivers of infected individuals, individuals in contact with dead bodies during funeral preparations and rituals, and health care personnel through safety protocol breaches (e.g. needlestick injury) ^{Footnote 11}.

Although treatment options to date have been limited, outbreak control measures are effective in arresting transmission when they can be executed properly. These measures include barrier and quarantine methods to limit exposure, early identification, isolation of cases, contact tracing, communication strategies to decrease risky behaviours, and epidemiologic surveillance ^{Footnote 11 Footnote 12 Footnote 13}.

Outbreak control measures for Ebola are effective. Why then, has the West Africa outbreak been so challenging to control?

The Challenges

The Ebola virus has deadly attack mechanisms

The Ebola virus enters the host through small skin lesions and mucosal surfaces facilitated by its surface glycoprotein (GP). Upon cell entry the virus replicates and, as progeny virus buds from the host cell membrane, the infected cell is destroyed ^{Footnote 14 Footnote 15 Footnote 16}. Analysis of tissues from infected human and non-human primates have demonstrated that viral replication occurs initially in leukocytes, epithelial cells, hepatocytes, splenic, adrenal cortical, and endothelial cells ^{Footnote 4}.

Leukocytes

Leukocytes - macrophages, monocytes and dendritic cells - are the primary cell targets of infection ^{Footnote 17}; this has a profound effect on the immune response. Macrophages and monocytes are part of the innate immune response and the body's first line of defense against infections. Cell death of monocytes and macrophages lead to a massive release of proinflammatory cytokines, thus attracting more macrophages to be infected ^{Footnote 18 Footnote 19 Footnote 20}. This causes a positive feedback loop between macrophages and cytokines which can lead to a dysregulated inflammatory response or cytokine storm ^{Footnote 3 Footnote 19 Footnote 20 Footnote 23}.

The death of infected dendritic cells means they are incapable of activating the adaptive immune response. Patients with fatal EBOV virus disease show almost no viral antigen specific antibodies due to suppressed B- and T-cell immunity ^{Footnote 21}. This is caused by anti-inflammatory cytokines released by macrophages, such as interleukin-10 (IL-10) ^{Footnote 22}. Thus, EBOV hyperstimulates the innate immune response and suppresses the adaptive immune response.

Epithelial, hepatic, splenic and adrenal cells

Infected leukocytes are thought to spread the virus systemically through the lymphatic system and blood. The virus then preferentially attacks epithelial, hepatic, splenic and adrenal cells ^{Footnote 4}. Infected epithelial cells lining the gut cause gastrointestinal symptoms during the early stages of infection (e.g. vomiting and diarrhea) ^{Footnote 4}. Infected hepatocytes lead to increased liver enzyme levels and impaired liver function. This may decrease the synthesis of coagulation factors, contributing to coagulation abnormalities ^{Footnote 24}. Infected splenic cells can lead to necrosis and hemorrhage into the abdominal cavity. Necrosis of adrenal cortical cells affects the regulation of blood pressure, and appears to contribute to septic shock during the later stages of infection ^{Footnote 25}. The virus eventually reaches all vital organs, leading to progressive organ failure and shock ^{Footnote 4 Footnote 20}.

Endothelial cells

Endothelial cells lining the blood vessels are targeted during later stages of infection. Endothelial impairment is thought to increase vascular permeability that can lead to hemorrhage, a prominent feature of infection in approximately 40-50% of patients ^{Footnote 5 Footnote 14}.

How this pathology links with clinical signs and symptoms are highlighted in Table 2.

Table 2: Pathophysiology and clinical signs and symptoms of Ebola virus infection

	Clinical signs and symptoms	Pathophysiology
Early symptoms	Abrupt onset of fever, chills, malaise, myalgia Severe sore throat	Infected monocytes and macrophages release cytokines
First week	Systemic: Prostration, lethargy	Cytokines contribute to systemic symptoms
	Gastrointestinal: Anorexia, nausea, vomiting, abdominal pain, diarrhea (and progressively bloody diarrhea and hematemesis)	Viral replication in epithelial and endothelial cells lead to gastrointestinal symptoms and bleeding
	Cardiac: Chest pain dyspnea, shortness of breath, cough, nasal discharge	Viral replication and necrosis in cardiac tissues
	Splenic: Fever, abdominal pain, hemorrhage, if rupture into peritoneal cavity	Viral replication and necrosis
	Hepatic: Elevated liver enzymes and coagulation abnormalities	Liver cells are infected leading to cell death and affecting clotting factor production
	Vascular: Conjunctival injection, postural hypotension, edema	Endothelial cells are taken over and cytokines released, leading to increased vascular permeability
	Neurologic: Headache, confusion, encephalitis, seizure, coma	Viral replication in brain tissue and vascular dysfunction
	Skin: Maculopapular rash with varying degrees of erythema and desquamation	Endothelial leakage
Complications	Hemorrhage Petechiae, ecchymoses, uncontrolled bleeding from venipuncture sites, epistaxis, visceral hemorrhagic effusions and other mucosal hemorrhages	Infected hepatic cells result in elevated liver enzymes and coagulation abnormalities Damaged endothelial cells lead to increased vascular permeability
	Shock and hypotension Severe metabolic disturbances Disseminated intravascular coagulation and hypovolemic shock	Direct viral damage of tissues and organs may lead to organ failure and shock. Infected adrenal cells fail to regulate blood pressure, contributing to hypotension and septic shock. Diffuse coagulopathy
Laboratory findings	Early leucopenia, lymphopenia and subsequent neutrophilia, thrombocytopenia, prolonged prothrombin and partial thromboplastin times High serum aminotransferase levels Hyperproteinemia and proteinuria	Infected dendritic cells impair immune response Uncontrolled upregulation of cytokines and chemokines (cytokine storm) Widespread viral replication and cell death in spleen, kidney, liver, gonads, etc.

Elimination of the reservoir is not feasible

The prevalence and extent of the EBOV reservoir amongst wild animals is unknown, so sporadic cases of transmission from animals to humans cannot be prevented.

Treatment is supportive, not curative

There are currently no approved therapeutic treatments for Ebola. Until recently, treatment focused on rehydration, electrolyte management, antibiotics and antivirals to treat secondary infections and medications to control pain, fever and gastrointestinal distress ^{Footnote 2}.

The outbreak has reached urban areas

Historically, Ebola virus disease has been responsible for smaller outbreaks in the remote forests of Sub-Saharan Africa that have typically involved animal-to-human transmission and sporadic human-to-human transmission. This outbreak marks the first time EBOV has appeared in a capital city and has been imported by an infected person into Africa's most populous country, Nigeria. The unprecedented size and location of the outbreak, combined with the fact that the virus is now circulating in densely populated urban centers, sets up the conditions for sustaining human-to-human transmission making the outbreak even more challenging to control ^{Footnote 1}.

Affected countries have challenges in health care infrastructure

Sierra Leone, Guinea and Liberia are small countries that have limited resources to respond to prolonged outbreaks, especially in rural areas. This is the first time that West Africa has had to deal with an EBOV outbreak, therefore most primary health workers did not have any prior experience dealing with this virus. Limited surveillance and reporting systems may have delayed outbreak identification and the subsequent global response. The WHO has identified these issues as gaps in the outbreak response ^{Footnote 1 Footnote 26}.

Health care workers are at risk of infection

The WHO has reported health-facility transmission as a central issue during the current outbreak ^{Footnote 1}. Health care workers are at risk of contracting EBOV while caring for infected patients through accidental exposure to infected bodily fluids. To date, more than 170 health care workers have been infected and at least 81 have died ^{Footnote 27}. These deaths have discouraged some health care workers and international organizations from participating in treatment and control efforts ^{Footnote 1}.

Outbreak control strategies have been met with distrust

Persistent community resistance has been identified as a major challenge in the health sector response to the outbreak ^{Footnote 1}. Effective prevention and control strategies have been undermined by fear, mistrust and misinformation within affected communities, leading some to believe that medical staff have brought the virus to the country. This has resulted in people refusing to cooperate with medical personnel, helping patients escape isolation wards, and exhibiting hostile behaviour ^{Footnote 1 Footnote 26 Footnote 28}. Traditional burial practices also pose a major risk to close relatives, since they typically involve the cleaning and rubbing of dead bodies that may have a high load of Ebola virus. The recommendation that these burial practices be performed by outbreak response team members has been perceived to conflict with beliefs and cultural practices ^{Footnote 26}.

Progress to date

The international response is building momentum

International aid and resources have been increasingly directed to West Africa to control the EBOV outbreak. The WHO has coordinated efforts to scale up the human and financial resources necessary to effectively conduct infection prevention and control activities and to implement infrastructure needed to manage future outbreaks, such as strengthening the surveillance and laboratory capacities. Numerous non-governmental organizations, including Médecins Sans Frontières, Save the Children, and religious organizations have been working on the ground to help stop the spread of this disease ^{Footnote 1}.

Based on the deliberations of an Emergency Committee, the WHO Director General has made a number of recommendations, including: affected states should declare the outbreak a national emergency and establish an emergency operation centre to coordinate support and response efforts; exit screening be conducted at all international airports, seaports and major land crossings to identify individuals with unexplained febrile illness; appropriate contact management; and all states should enhance their capacity to detect, investigate and manage Ebola cases through improved surveillance, laboratory diagnostic support and rapid response ^{Footnote 29}.

Canada has joined other nations, organizations, and the WHO by providing financial and technical support. As of August 8, 2014, Canada has contributed over $5 million towards humanitarian, infection control and security interventions in West Africa ^{Footnote 30}. As a member of the WHO Global Outbreak Alert and Response Network (GOARN), Canada provides technical and human resources towards the identification and response to significant international outbreaks ^{Footnote 31}.

The National Microbiology Laboratory (NML) of the Public Health Agency of Canada (PHAC) has worked closely with the WHO to provide rapid diagnostic support in mobile laboratory in Sierra Leone ^{Footnote 32}.

Within Canada, PHAC is taking the lead on national preparedness for Ebola cases, working closely with the provinces and territories and all affected stakeholders. Case definitions, infection control guidelines, public health management of cases and contacts associated with Ebola virus disease, environmental decontamination, biosafety guidelines and more are under development. The Agency is also facilitating the development of clinical care guidelines with the Association of Medical Microbiology and Infectious Diseases Canada, the Canadian Critical Care Society, and the Canadian Association of Emergency Physicians.

Communication strategies are being implemented to address fears and misconceptions

An assessment of the current outbreak led Dr. Luis Sambo, the WHO Regional Director for Africa, has recommended that affected governments scale up national resources to promote behavioural change while respecting cultural practices ^{Footnote 1}. Local collaborations (e.g. training community members to identify contacts, and working with local leaders to effectively disseminate the correct information on EBOV) are being used to dispel misconceptions and strengthen control strategies ^{Footnote 26}. Collaborations with religious, community and tribal leaders are being used to disseminate information ^{Footnote 26 Footnote 28}. These messages are also being spread by television and radio ^{Footnote 33}.

Investigational therapies are under development

Several experimental pre- and post-exposure treatments are currently under development to provide cross protection across Ebola species and work after a single dose ^{Footnote 2 Footnote 34}. Two infected Americans received the experimental drug, which contains three monoclonal human-mouse chimeric antibodies manufactured in the plant Nicotiana benthamiana ^{Footnote 35}. These antibodies demonstrated 100% protection against EBOV in infected cynomolgus macaques, and upon re-infection of these nonhuman primates at 10 and 13 weeks following the initial EBOV challenge, 100% and 66% of the animals were shown to be protected, respectively ^{Footnote 36}.

Another investigational treatment uses small interfering RNAs specific to certain EBOV genes to inhibit virus replication. A study demonstrated 66% and 100% protection from EBOV in macaques after four and seven post-exposure treatments, respectively ^{Footnote 37}.

Several experimental vaccines have also shown promise against EBOV in nonhuman primates, including an adenovirus-based and a vesicular stomatitis virus (VSV)-based vaccine. For example, the VSV-based vaccine has demonstrated high protective efficacy against EBOV disease, with an absence of noticeable adverse events in non-human primates ^{Footnote 38 Footnote 39 Footnote 40}. Discussions are ongoing about fast tracking both the adenovirus and the VSV based Ebola vaccines for Phase 1 clinical trials.

The use of experimental antibody-based treatments on two Americans infected with EBOV has led to a WHO-hosted discussion on the ethical considerations of including such treatments in the response efforts ^{Footnote 1 Footnote 41}.

Conclusion

There are a number of factors that make the Ebola virus outbreak in West Africa a challenge to control. The EBOV has efficient ways to paralyze host defence mechanisms and attack vital organs. It resides in a poorly understood wildlife reservoir and has emerged in countries that have challenges in both health care capacity and risk communication. All these factors have occurred in the context of increasing global travel.

Canada has been an integral part of the global response through financial contributions, laboratory support, seminal work in developing vaccines and post exposure treatment and international collaborations. The Public Health Agency is coordinating the national response to enable the optimal detection, investigation, management and reporting of any potential cases of EBOV within our borders.

The WHO has identified the Ebola outbreak as a public health emergency of international concern. This will continue to require national and international collaboration and the ongoing vigilance of front line health care and public health professionals to end the outbreak in West Africa and prevent its global spread.

Acknowledgements

Dr. Huston is the Scientific Editor of the Canada Communicable Disease Report and recused herself from the editorial decisions involved in this manuscript. Many thanks to Dr. Tom Wong for taking on the Editor role for this Rapid Communication. Thank you to Mike Drebot and Tim Booth for their support in developing this manuscript and the reviewers who offered timely and useful feedback while participating in response efforts.