Critical Analysis of Viral Hemorrhagic Febrile Diseases: Dengue and Ebola

Veronica Hart

Tulane University School of Public Health and Tropical Medicine

Spring 2016

In an analysis of dengue and Ebola, this paper will discuss the epidemiology, natural history, public health implications,

the evolution of treatment, prevention and control, the remaining challenges and the priorities moving forward for both

diseases. Ebola is a subset of viruses within the genus Ebolaviruses of the family Filoviridae1. There have been four

ebolaviruses described to cause disease in humans: Bundibugyo, Tai Forest, Sudan, Zaire1, 2. Dengue is a Flaviridae

family member, and is divided into four serotypes labeled one through four1. The dengue serotypes vary in amino acid

sequence up to 40 percent which is what results in each serotype having their own individual lifelong immunity and a

temporary immunity for the other three serotypes3, 4.

The dengue virus is viable in humans, mosquitos (Aedes aegypti, Aedes albopictus, Aedes polynesiensis and Aedes

scutellaris) and African and Malaysian monkeys1. Aedes aegypti is the prominent mosquito involved in dengue

transmission5. The four mosquitos act as the dengue vector1. As of 2015, the reservoir of Ebola is believed to be forest-

dwelling fruit bats2. Although monkeys were first suspected of being the reservoir, they were narrowed out due to primate

outbreaks that had a high mortality rate2, 4. Swine have also been identified as an intermediate host2. A dissimilarity

between Ebola and dengue is disease transmission. Dengue is categorized as a vector-borne disease meaning it is

transmitted from host to vector to host; Ebola is transmitted through zoonosis and human-to-human transmission3, 4.

Research is still ongoing as to how Ebola is transmitted from bats to humans, but one hypothesis is that the virus is

transmitted during interaction with dead infected mammals2. Once the initial human is infected, others can be infected

through direct contact with bodily fluids including blood, semen, emesis and excrement as well as contact with organs2.

The highest rates of transmission occur during funerals with poorly prepared bodies and at the latest stages of the disease

through hemorrhaging, vomiting and diarrhea2. Those who contract Ebola as a hospital-acquired infection have very high

mortality rates2.

The incubation period for Ebola is five to 12 days and is followed by the sudden clinical symptomology of arthralgia,

conjunctivitis, diarrhea, fever, hemorrhaging, liver failure, maculopapular rash, myalgia, sore throat and/or vomiting1.

Those with Ebola are not infectious until the first symptoms appear2. The first symptom is usually a fever2. Severe

hemorrhagic symptoms are usually manifested between day five and seven from multiple sites including the

gastrointestinal tract, lungs and the gums1. The length of time between onset of symptomology and death varies greatly,

occurring between days seven and sixteen1. Ebola has a case fatality between 50 and 90 percent1. The incubation period

for dengue is shorter than Ebola’s at five to eight days1. One of the main similarities between the Ebola and dengue is they

both can result in the clinical symptom of viral hemorrhagic fever (VHF)6. VHF is described as a syndrome with viral

etiology, vasotropism, a tendency towards bleeding, fever and occasional capillaropathy6. All cases of VHF should be

reported to health authorities2. A geographical focal point is another key part of VHF6. This means that the region

contributes to the virus maintaining its circulation in that region, thus leading to the exacerbation of symptomology6.

Dengue has three clinical presentations; classic dengue, dengue hemorrhagic fever (DHF) and dengue shock syndrome

(DSS)3. Those who have experienced dengue will consistently state that dengue was the worst illness that they ever

experienced when asked5. Classic dengue fever has varying symptomology depending on the age of the infected person3.

Approximately 75 percent of first time dengue infections present asymptomatically2. Infants and young children, whom

experience symptoms, most often have an undifferentiated fever that is accompanied by a maculopapular rash3. On the

other hand, older children and adults experience mild fever or a combination of a high fever, severe headache, a rash and

eye, muscle and joint pain when symptomatic3. The case fatality for classic dengue fever is very low (as one percent)3. In

areas of epidemics, bleeding complications may present in some, but it is very important to distinguish this from cases of

DHF and DSS3. The most common hypothesis for the causation of DHF and DSS is exposure to a second serotype of

dengue, this is known as antibody-dependent enhancement (ADE)4. DHF and DSS can also be caused by dual dengue

infections, but this has only been documented in rare occasions4. Genetics may also play a role in the development of

DHF and DSS4. The main difference between classic dengue and the two more severe cases is the presence of plasma

leakage that results in an increased hemoconcentration3. The four main clinical manifestations of DHF is high fever

accompanied by hemorrhagic fever, hepatomegaly and circulatory failure3. DHF can be distinguished from classic dengue

due to the presence of petechiae during the initial fever stage3. Symptomology usually disappears with the fever, although

sometimes fluid or electrolyte therapy is needed to aid in recovery3. DSS adds the component of shock to DHF3. Patients

CRITICAL ANALYSIS OF VHF DISEASES HART 2

with DSS experience deterioration (caused by circulatory failure and circumoral cyanosis) a three to seven days into the

fever3. Those with DSS also experience a weak and rapid pulse along with acute abdominal pain3. DSS requires

immediate treatment in order to prevent death3. Those that receive efficient appropriate volume replacement therapy

recover quickly3. If volume replacement therapy is not provided, patients experience intracranial hemorrhaging and

convulsions3. Consciousness is soon lost and death occurs shortly after3. The terminal stage usually occurs 12 to 24 hours

after the onset of shock3. DHF and DSS is experienced by more half a million people yearly4.

Diagnosis for both Ebola and dengue is made using IgM and IgG antibody ELISA testing and PCR testing1, 2. Another

similarity that they share is that the only treatment for dengue and Ebola is treatment of symptoms1. While dengue is not

considered a potential bioterror weapon7, Ebola is on the list of potential bioterrorism weapons1. Since the 2014 Ebola

outbreak, concern about Ebola’s use in a potential terror attack has grown8. Ebola cases should observe strict patient

isolation in order to prevent further transmission, whereas dengue cases should be prevented from contact with

mosquitoes in order to prevent further vector development1.

There is evidence of dengue epidemics that date back to the year 992 and has been present in the Americas for more than

200 years3, 5. There are many hypotheses about where dengue originated, the most prominent one is that dengue originated

in the lower primates and mosquitoes of Southeast Asia5. DHF and DSS has been present since 1780, but had long

intervals separating rare occurrences5. With the increase in DHF and DSS incidence during the last half of the 1900’s, due

to the increase in global travel and urbanization coupled with a decrease in urban planning, more research has been done

about DHF and DSS5. As the number of epidemics increases and the time between them decreases, the serotypes are at an

increased chance of movement between regions5. The circulation of more than one serotype puts the region at a high risk

of developing epidemic levels of DHF and DSS3. Global wars have also played a role in the increase in classic dengue,

DHF and DSS5. The average attack rate during a dengue epidemic is 40 to 50 percent but can reach up to 90 percent in

some areas5. Dengue is most commonly seen in the American continents tropics, but dengue is also seen in the Asian

tropics3. Very little is known about dengue on the African continent3.

Evidence of Ebola dates back to 1976, which was an outbreak of 284 cases with a mortality rate of 53 percent1. This

outbreak was followed shortly by an outbreak in the DRC (former Zaire) that resulted in 318 cases and 88 percent

mortality1. Since an unusual 15-year period without confirmed Ebola cases in the eighties and nineties, there have been

over 20 outbreaks1, 9. In 2014, West Africa experienced the worst outbreak of Ebola in known history10. The three

countries most affected were Guinea, Liberia and Sierra Leone10. The original case of this outbreak occurred in late

December of 2013 in a southeastern village of Guinea11. Unlike the previous outbreaks, the 2014 Ebola outbreak involved

a complex chain of infections concentrated in Guinea, Liberia and Sierra Leone. All previous outbreaks were able to be

contained due to the rural location2. This was not the case for the 2014 outbreak2. Although the first confirmed case was

identified in March of 2014, the World Health Organization (WHO) did not classify the outbreak as such till August

eighth of 201411. Naturally occurring cases of Ebola have only been identified on the African continent9.

There are many risk factors that have been identified to have an association with developing dengue, but all humans are at

risk of contracting dengue3. Those most at risk for contracting dengue are found between 35ᵒN and 35ᵒS, are typically at

lower elevations (due to increased likelihood for vector survival and reproduction) and live in urban areas with moderate

to high human and housing densities3. Those who live in houses with little to no screening, do not remove items that

collect water from their property and spend long periods of time being inactive or spend significant periods of time in

their homes are also at higher risk3. Due to the higher risk of developing dengue by spending time around homes, women

and small children have a higher risk of contracting dengue3. Everyone is at risk of contracting Ebola, but health care

workers (especially those handling secretions and excretions), those working in environments with bats and those

handling Ebola burials2.

Of the vector-based viral diseases, dengue is the most prevalent in humans4. Most countries in the tropics and subtropics

are have endemic levels of dengue2. Endemic regions will then experience an epidemic on average every two to five

years2. There are 100 million cases a year and approximately two billion people are at risk at any given time4. Addressing

dengue as a matter of public health importance is an effective way to address the astronomical costs (more than 200

million dollars, with inflation) that are associated with the hospitalization, care and emergency vector control that are

linked to dengue3. Fear of dengue also reduces tourism rates, which alters the economy, therefore affecting the ability of

an area to address dengue4. Domestic sanitation is the main method of controlling this disease, therefore improving the

CRITICAL ANALYSIS OF VHF DISEASES HART 3

personal beliefs and knowledge about dengue, causation, prevention and control will ultimately result in reduction in the

transmission of disease3. The use of domestic sanitation as a way to control dengue removes the need for chemical use and

very little energy is required3. There is also rising concern about the spread of dengue to more temperate regions of the

globe, thus increasing the amount of people at risk for contracting dengue4. With the rising prevalence of dengue,

prevention and control of Aedes egypti and dengue are one of the most important public health issues4. Controlling Aedes

aegypti not only reduces the number of dengue infections, but it also addresses yellow fever, chikungunya and zika

transmission 4. This makes Aedes aegypti a multi-functional public health target.

In the 2014 Ebola outbreak, Mali, Nigeria, Senegal and the DRC all experienced cases10. Due to early intervention these

countries were able to reduce transmission, therefore reducing the number of cases10. This indicates that, like dengue,

Ebola is a preventable disease when cases are managed properly10. An example of the negative consequences of poor case

management is the U.S. cases of Ebola in late September of 201411. Due to the delay in patient diagnosis the patient was

isolated inefficiently, resulting in two nurses being subsequently infected11. The delayed reaction also resulted in the

patient’s death12. The 2014 Ebola epidemic also is a prime example of what happens when public health systems fail due

to national governments and organizations not placing enough weight on the importance of public health13. The

monumental cost of the 2014 Ebola outbreak is a depressing outcome of insufficient political interest in maintaining

prevention methods13.

There are four main factors that play a role in the ability of a country to prevent or contain a disease outbreak10. Countries

should have a supportive political environment, a supportive economic environment, a supportive sociocultural

environment and an effective health system10.

Still today, the main method of prevention in regards to dengue is mosquito repellant2. In the 1950’s and 1960’s a major

effort was undertaken as an effort to remove the dengue vector from the population3. The main method of reduction was

the use of DDT four times a year5. Aedes aegypti was eradicated from more than 22 countries by 19623, 5. Due to low

socioeconomic status of some of the countries participating in this effort and the banning of DDT, Aedes aegypti

eradication policies went lax3. This resulted in the reemergence of Aedes aegypti in the majority of Latin America3. DHF

and DSS epidemics quickly followed in the 1980’s3. After DDT was no longer being used, organophosphorous larvicides

and adulticidal aerosols as ultra-low volume concentrates were used as mosquito control5. The goal for Aedes aegypti

eradication was terminated in the early 1970’s5. The program was supported again by the Pan America Health

Organization in 1985, but they switched their main elimination method to integrating community-based Aedes aegypti

control5. This new plan was developed because officials knew that without a vaccine, control methods would need to be

affordable as they would need to be maintained indefinitely5. Yet another hindrance towards progress was the lack of a

comprehensive document that providing an outline about dengue prevention, control and clinical symptomology which

was not available until December 19913.

Unfortunately, the traditional programs that are historically used have been largely ineffective3. These programs have

consisted of paternalistic, centralized and vertical programs that are neither affordable nor manageable due to the

emphasis in the use of ultra-low volume insecticides as a measure of control against adult mosquitoes3, 5. Another key

factor contributing to the burden of dengue is the inability of dengue surveillance to recognize and react at a speed which

allows course of epidemics to be effected3. Surveillance should be structurally simple, representative of the population,

flexible, have adequate specificity and sensitivity and provide functional data with which to move forward with3. As

mentioned previously, the speed of urbanization in the last half of the 1950’s resulted in a lack of urban planning5. This

results in poor housing quality, inadequate water supplies, and sewer and waste management systems that could not and

cannot support the growing population5. With urbanization, also came the increase in non-biodegradable packaging, thus

providing mosquito larvae with suitable habitats5. Dengue outbreaks have 200 plus years of treatment and containment

precedent to work with3. The 2014 Ebola outbreak had no previous framework from which to utilize11. This was due to

previous Ebola outbreaks being contained in one geographic location2.

As Ebola prevention programs are improved upon on for future outbreaks, interventions should aim reduce the likelihood

of an outbreak so that the likelihood of a natural, accidental or intentional outbreak has been greatly reduced as well as

have efficient surveillance programs in place14. Efficient surveillance programs should be able to detect threats early and

then allow a rapid and efficient response through the use of effective communication and cooperation between invested

groups and involved countries14. Using a proof-of-concept policy analysis tool (a measure of comparing the pros and cons

CRITICAL ANALYSIS OF VHF DISEASES HART 4

of policy goals in order to determine the most effective policies for a particular outbreak), the RAND Corporation has

identified interventions that should be effective in future outbreaks14. These interventions include training all health care

providers to utilize personal protective equipment, utilizing vaccination as U.S. trials progress, introduce rapid training of

health care volunteers and implement Ebola treatment centers within hospitals14. They also determined that the

implementation of regional curfews during outbreaks could be effective as a way to prevent the spread of disease14.

Traditional public health measures when supported and funded properly by governments and organizations are an

effective measure in which to stop the spread of disease13. These techniques were very effective during the 2003 SARS

epidemic13. These measures include efficient patient isolation and case reporting, tracking transmission routes, use of

quarantine and public education programs13.

Moving forward, the effectiveness of Mali, Nigeria, Senegal and the DRC’s response to Ebola cases should be used as a

model for government officials, international organizations and aid agencies reacting to further cases10. In order to

accomplish this, officials are working on identifying potential Ebola hot zones, as well as working on risk reduction

policies to prevent further outbreaks10. There are 34 total countries at risk for Ebola with ten identified as high risk for an

Ebola outbreak, including the three countries that experienced the 2014 Ebola outbreak10. These countries are distributed

throughout Sub-Saharan Africa, the Middle East and southern parts of Asia10. Pakistan has been identified as the most

dangerous potential outbreak destination if Ebola were to spread beyond the African borders due to the combination of a

failed political state with a highly urbanized society10. Another useful tool that could be used to address future Ebola

outbreaks is the Intra-Action Report (IAR) developed by the RAND Organization11. The IAR provides a framework for

capturing and organizing the information about an outbreak during said outbreak11. It also provides the opportunity to

improve upon the problems that have occurred and utilize opportunities to improve actionable items of concern within the

outbreak11.

The main challenge moving forward with dengue is the promotion of responsibilities to the individuals and communities

in dengue susceptible regions, as well as providing them with adequate motivation and instruction in order to address

dengue at a grassroots level3.

Both dengue and Ebola have vaccines that are in the works15, 16. Dengvaxia, a live recombinant tetravalent vaccine and the

first dengue vaccine, is in the final stages of clinical trials15. This vaccine is given in a series of 3 shots over a year in

people aged nine to 4515. The WHO will be making recommendations on the vaccine in April of 201615. There are five

other vaccines of multiple different types in various stages of clinical trials15. There are more than ten Ebola vaccines in

various clinical trial stages16. The WHO had hoped that there would be an effective vaccine by the end of 2015 but that

goal was not met16. Since there are no therapeutics for either disease, vaccine availability would be a major advancement

for both dengue and Ebola15.

Over the next ten years, I think that international organizations should work with national and local governments to

encourage grass roots prevention and control methods. There are multiple ways in which this should be addressed in order

for the incidence of dengue and Ebola to decrease. The most important is community education programs. As Dr. Eva

Harris has stated, there has been great success in teaching communities in the tropics about the life cycle to school aged

children17. The interactive classroom environment has invigorated the children to be passionate about dengue prevention.

The children then take this excitement home to their households teaching their parents and following through with

prevention methods. There is no reason that this cannot be effective with Ebola prevention. Another vital piece to this is

educating governments that programs such as these are effective, as well as showing them that just because a disease is

not a problem now, does not mean that it cannot be. More research should also be done on disease physiology, virology

and distribution so that decisions are based on updated, accurate information. Lastly, I think that vaccine development for

both Ebola and dengue should be continued in the next decade so that there can be long term solutions to these diseases.

CRITICAL ANALYSIS OF VHF DISEASES HART 5

REFERENCES

1. Berger S, Calisher C, Keystone J Exotic viral diseases: a global guide. Hamilton, Ont.: B.C. Decker; 2003.

2. Heymann DL, ed. Control of Communicable Diseases Manual. 20 ed. Washington, D.C.: APHA Press; 2015.

3. Pan American Health Organization. Dengue and Dengue Hemorrhagic Fever in the Americas: Guidelines for Prevention and

Control. Washington D.C.: PAHO Library Cataloguing in Publication Data; 1994.

4. Krause RM. Emerging Infections. New York: Academic Press; 1998.

5. Gubler DJ, Kuno G. Dengue and Dengue Hemorrhagic Fever. Cambridge, UK: University Press; 1997.

6. Kuhn JH. Filoviruses: A Compendium for 40 Years of Epidemiological, Clinical, and Laboratory Studies. New York:

Springer Wien; 2008.

7. CDC. Bioterrorism Agents/Diseases. Emergency Preparedness and Response. Available at:

http://emergency.cdc.gov/agent/agentlist.asp. Accessed March 27, 2016.

8. Doward J. Top-secret military warning on Ebola biological weapon terror threat. The Guardian. February 2015.

9. CDC. Outbreaks Chronology: Ebola Virus Disease. Ebola (Ebola Virus Disease). March 24, 2016. Available at:

http://www.cdc.gov/vhf/ebola/outbreaks/history/chronology.html#modalIdString_outbreaks. Accessed March 26, 2016.

10. Gelfeld B, Efron S, Moore M, Blank J. Mitigating the Impact of Ebola in Potential ot Zones: A Prook-of-Concept Approach

to Help Decisionmakers Prepare for High-Risk Senarios Outside Guinea, Liberia, and Sierra Leone. Santa Monica,

California: RAND Corporation; 2015.

11. Chamberlin M, Okunogbe A, Moore M, Abir M. Intra-Action Report--A Dynamic Tool for Emergency managers and

Policymakers: A Proof of Concept and Illustrative Application to the 2014-2015 Ebola Crisis. Santa Monica, California:

RAND Corporation; 2015.

12. McCarthy M. Liberian man being treated for Ebola in Texas dies. BMJ. October 2014;349.

13. Hughes JM. The Ebola epidemic: A costly and preventable global health security and humanitarian crisis. Infectious Disease

News. November 2014.

14. Chamberlin M, Efron S, Moore M. A Simple Approach to Assessing Potential health Emergency Interventions: A Proof-of-

Concept and Illustrative Application to the 2014-2015 Ebola Crisis. Santa Monica, California: RAND Corporation; 2015.

15. World Health Organization. Dengue Vaccine Research. Immunization, Vaccines and Biologicals. December 14, 2015.

Available at: http://www.who.int/immunization/research/development/dengue_vaccines/en/. Accessed March 30, 2016.

16. World Health Organization. Ebola vaccines, therapies, and diagnostics. Essential medicines and health products. November

21, 2015. Available at: http://www.who.int/medicines/emp_ebola_q_as/en/. Accessed March 30, 2016.

17. Viral Outbreak: The Science of Emerging Diseases [DVD]. Howard Hughes Medical Institute, 2010.