The History of Dengue
The origins of dengue and its pathway to the present day are the subject of much debate. While debate does exist, agreement is made that both the virus and its primary vector, the Aedes aegypti mosquito had their origins in either Africa or Asia.
The Aedes aegypti mosquito is often referred to as a “New World” mosquito. This species is thought to have made its way out of Africa on slave ships during the 17th, 18th and 19th centuries. By 1800 it was well established in many large tropical cities, especially those with very active shipping ports. The mosquito population remained stable in these areas for many years before experiencing a growth explosion during and after World War II.
The name ‘dengue’ is thought to have origins in the Swahili language. The Swahili name “Ki-Dinga pepo” was used to describe a dengue-like illness reported in Africa during the 19th century.
The dengue virus had its origins in the jungles, evolving from a mosquito virus to one capable of causing disease in lower primates and humans. Development of the environment by humans through the establishment of settlements and deforestation helped to move the dengue virus out of the jungle to the rural environment. Commerce and economic development then moved people from rural areas to towns and cities, thus introducing the virus to another new environment. Transmission cycles in Asia were kept alive by a native mosquito species, the Aedes albopictus. When the virus was introduced to areas that had become infested with the Ae.aegypti mosquito, epidemics occurred.
The name ‘dengue’ is thought to have origins in the Swahili language. The Swahili name “Ki-Dinga pepo” was used to describe a dengue-like illness reported in Africa during the 19th century. This name gave birth to the terms denga and dinga which, along with the Ae.aegypti mosquito traveled with the slave trade to the New World. From these terms, the modern day nomenclature ‘dengue’ evolved. During the 19th century the disease also went under the fanciful name ‘The Dandy’ or ‘Dandy fever’.
The World War II Phenomenon
World War II had a major effect not only on the spread of the disease but also on scientific understanding. The war caused massive demographic changes and ecologic disturbances in the Asia region. While these changes were disruptive for the human population, they provided ideal conditions for mosquito breeding and virus transmission. Key factors include the disruption to water supplies, an increase in the number of suitable breeding sites for mosquitoes (for example abandoned weaponry and equipment) and the increased mobility of people throughout the region. Following the war the region saw massive urbanization projects as people moved towards cities seeking work, food and shelter. With little time to plan for this massive influx of people, cities grew haphazardly with inadequate water supply and waste disposal systems, creating ideal breeding grounds for mosquitoes and the transmission of viruses.
Dengue was a cause of severe morbidity for troops deployed in the Asia region. This motivated scientific research by both the American and Japanese military. Both of these countries established commissions that were successful in isolating the virus, with the first strain (from Hawaii) labeled as Dengue 1. An antigenically distinct strain (from New Guinea) was also isolated and labeled as Dengue 2. Over a decade later, during an epidemic in the Philippines in 1956, the Dengue 3 and Dengue 4 serotypes were isolated, completing the serotype family. Thousands of dengue viruses have been isolated since then with all isolates fitting into one of the four serotypes.
Gubler DJ (1997). Dengue and Dengue Hemhorrhagic Fever: It's history and resurgence as a global public health problem, p1-22. In (ed.) Gubler DJ and Kuno G Dengue and Dengue Hemhorragic Fever. (AB International, Wallingford, United Kingdom)
“By decade, the annual average number of cases of dengue fever or severe dengue reported to the World Health Organisation (WHO) continues to grow exponentially” (Nathan & Dayal-Drager, 20061)
Dengue the record breaker
Dengue has spread throughout the world at a rapid pace. In 2001, a record was set when 69 countries within the WHO South East Asia, Western Pacific and Americas regions reported dengue1. Just seven years later, dengue is now reported in over 100 countries within these regions. In 2002, the Americas region reported 1 million cases for the first time. While this figure has not been repeated, 2007 saw over 900,000 reported cases and large outbreaks have occurred in Brazil in both 2007 (559,954 cases reported2) and 2008 (472,997 cases reported2). While most cases occur and are reported from South East Asia, the Western Pacific and the Americas regions, major outbreaks are suspected to occur in Africa and the Middle East. True measurement of these outbreaks is hampered by poor reporting and surveillance efforts in these regions. Current disease trends do indicate that this is a disease that is not slowing down.
The Spread of Dengue and its vector in Americas and Asia Pacific2
Spread of Dengue 1950-70
Epidemic DHF in Asia
Spread of Dengue 1970-80
Epidemic DHF in Asia
Spread os Dengue 1980-96
Epidemic DHF in Asia
Reinfestation of Aedes aegypti in the Americas2
Infestation of Aedes aegypti 1930's
Aedes aegypti distribution
Infestation of Aedes aegypti 1970
Aedes aegypti distribution
Infestation of Aedes aegypti 2002
Aedes aegypti distribution
Dengue Epidemics in the Americas
Dengue Epidemics in the Americas 2000, 9 Countries
2000, 9 Countries
Dengue Epidemics in the Americas 2001, 11 Countries
2001, 11 Countries
Dengue is a significantly under-reported disease, making it difficult to ascertain the number of dengue fever (DF) cases caused by the virus each year. Current estimates place this number at anywhere between 50-100 million4. Of these dengue fever cases, anywhere between 200,000 – 500,000 cases will develop into dengue haemorrhagic fever (DHF) each year4.
The reasons behind the reemergence of dengue as a major global health problem are many and varied. Changes in human activity over the last few decades have created a set of conditions that both the virus and the vector have been able to capitalize on. Demographic changes such as uncontrolled population growth have resulted in unplanned and haphazard urbanization. Large populations of people are living closely together in housing devoid of proper water storage and waste disposal. Humans are also inadvertently providing a plethora of mosquito breeding sites through the increased use of non-biodegradable materials such as plastic packaging and rubber tyres. Mosquito populations are rapidly increasing and many of the countries affected do not have effective mosquito control programs to adequately respond to this problem.
The increased mobility of humans through affordable and fast transportation has allowed the virus to enter susceptible populations and establish itself in new regions. This has resulted in large epidemics which further enhances the virus’ ability to move to new, susceptible populations. The deterioration of health care services has also created favourable conditions for the spread of the virus.
Nathan M B and Dayal-Drager R. (2006). Recent epidemiological trends, the global strategy and public health advances in dengue. Report of the Scientific Working Group on Dengue, 2006
PAHO Dengue website (cited August 2008) [http://www.paho.org/english/ad/dpc/cd/Dengue.htm]
Gubler DJ. (1997). Dengue & Dengue Hemhorrhagic Fever : It's history & resurgence as a global public health problem, p 122. In (ed.) Gubler DJ, Kuno G, Dengue & Dengue Hemhorrhagic fever. AB International, Wallingford, UK.
WHO Dengue Factsheet (cited 2002), [http://www.who.int/mediacentre/factsheets/fs117/en/].
Experience a new Diagnosing dengue
The diagnosis of dengue infection involves similar diagnostic issues to other acute viral infections, such as influenza. Clinical diagnosis is of some benefit, but is not definitive. Laboratory findings should ideally be obtained to confirm the diagnosis.
When laboratory testing is impractical, evidence, such as recent, laboratory-confirmed, dengue cases in the local area are very instructive when presented with a patient exhibiting characteristic signs and symptoms.
Detection of virus or antibodies
In the laboratory, dengue fever is diagnosed by identifying either the:
Dengue virus (virus culture or PCR)
Antibodies to the virus (serology testing).
RT-PCR (reverse-transcriptase polymerase chain reaction) – a rapid test that detects viral DNA in serum up to 10 days following symptom onset. Its use is limited by concerns over standardisation issues, but if managed properly it is a highly sensitive detection method.1
Serologic testing is the most practical and widely utilised test today. All serology laboratory tests require that a sample of blood is collected from the subject. Tests currently available include:
HI (haemagglutination inhibition) – the gold standard diagnostic for dengue because of its high sensitivity for detecting dengue antibodies and its ease of use.
MAC-ELISA (IgM antibody-capture enzyme-linked immunosorbent assay) – widely utilised, but is limited by an inability to differentiate between dengue virus serotypes. 1
PRNT (plaque reduction neutralisation test) relatively expensive, but the most sensitive and specific serological test for dengue virus. Has the advantage of being able to differentiate serotypes in primary infections.
CF (complement fixation) – reasonably difficult to perform, this test is not routinely used for dengue diagnosis.1
Primary infection - diagnosis by antibody detection
The detection of IgM antibodies is indicative of an active primary infection. IgM antibodies are usually detected in infected patients by Day 5 following the onset of symptoms. Some patients will produce IgM antibodies as early as Day 3.
The most commonly employed commercial methods for the detection of antibodies are ELISA (enzyme-linked immunosorbent assay) or rapid immunochromatographic diagnostic tests.
Secondary infection - diagnosis by antibody detection
A secondary infection elicits a distinct immune response, an anamnestic response, that is distinguished by elevated levels of IgG antibodies. IgM antibodies may also be produced, but these are usually at lower levels than those found in a primary infection. Some patients may not produce any IgM antibodies.
Secondary infections can therefore be identified through detection of these elevated IgG antibodies.
Routine blood test findings
Reduced white blood cell count (leukopenia) is a common finding associated with dengue fever, but is less commonly found in dengue haemorrhagic fever cases. Reduced counts of the blood cells that cause normal blood clotting (thrombocytopenia) whilst not often present in dengue fever cases, is a very common finding in dengue haemorrhagic fever sufferers.
DE PAULA, Sérgio OliveiraFONSECA Benedito Antônio Lopes da. 2004. Dengue: a review of the laboratory tests a clinician must know to achieve a correct diagnosis. Braz J Infect Dis [online] 8, (62008-10-12): 390-398.
An established array of signs and symptoms alert clinicians’ suspicion to the possibility of dengue infection, especially if laboratory tests have proven recent cases in a nearby area.
Common clinical signs and symptoms of dengue infection in adults include:
Mild to high fever
Bone and/or joint pain
Painful eye sockets
Raised (maculopapular) rash on the skin – often present in infected children and infants
Dengue haemorrhagic fever
A complicated, potentially deadly manifestation of dengue fever, dengue haemorrhagic fever, occurs in a minority of those infected. Some evidence suggests it more commonly develops in individuals who have been infected on more than one occasion.1 1-20% of dengue haemorrhagic fever cases usually result in fatality, although this rate has been known to be higher during outbreaks in areas with poor or no medical facilities. High quality medical care is known to minimise this mortality.2
Key clinical and laboratory findings in dengue haemorrhagic fever are:
Internal bleeding (haemorrhagic phenomena)
Thrombocytopenia with haemoconcentration.
Dengue shock syndrome
It is estimated that nearly 30% of patients suffering DHF will progress to dengue shock syndrome3.
Acute abdominal pain is often experienced prior to its development and the patient’s condition rapidly deteriorates soon after an apparent recovery from fever i.e. after body temperature appears to normalise three to seven days after the onset of fever.
Dengue shock syndrome is usually either reversed with 24 hours of onset following corrective fluid replacement therapy or, in some cases, death occurs within 12-24 hours if treatment is not administered or the patient does not respond. It is therefore very important that medical assistance is sought and treatment is instigated without delay.
(Adapted from Chapters 2 and 4 of Dengue haemorrhagic fever – Diagnosis, treatment, prevention and control. Second Edition, WHO, Geneva, 1997, except where otherwise indicated)
WHO Dengue Factsheet (cited 2002), [http://www.who.int/mediacentre/factsheets/fs117/en/].
Gubler PJ and Meltzer M (1999) Impact of Dengue Hemorrhagic fever on the developing world Adv.Virus Res. 53; 35-70
IMIA Internal Market Research Report (2008)
Enter in a muskeeto world
Signs and Symptoms
Infection with the dengue virus causes a spectrum of illness and may present as: 1
Classic Dengue Fever
Classic Dengue Fever is a non-fatal febrile illness, typically seen in older children and adults. Symptoms include1,2:
- Arthralgia - The majority of adults will suffer severe muscle pain and arthralgia localized in the limbs, back and loin. Patients may be so incapacitated that they are unable to walk
- 10-30% DF cases show hepatomegaly
- Some patients may experience depression during convalescence
Symptoms will typically last for 5 - 7days and usually precede fever by 6 – 12 hours. The onset of headache and fever is abrupt. Fever does not usually exceed 40.5°C and may last as long as ten days. It may subside only to return, reaching its peak on the last day of the febrile phase.
Laboratory findings include:
Dengue Haemorrhagic Fever
Dengue Haemorrhagic Fever (DHF) is a severe form of dengue infection. Children under the age of 16 living in dengue-endemic areas are at the highest risk of developing DHF. Infants born to dengue-immune mothers are also at risk of developing severe dengue.
The WHO Case definition:
- High continuous fever for 2 – 7 days
- Haemorrhagic tendencies
- Thrombocytopenia (≤ 100,000 mm-3)
- Plasma leakage
DHF is distinguished from DF (dengue fever) by:
- Plasma leakage (caused by an increase in vascular permeability)
- impaired platelet function
- disseminated intravascular coagulation (DIC)
The disease is graded according to the severity of illness. There are four grades:
|Non-shock DHF||DHF with shock|
Grade III (DSS)
Grade IV (DSS)
Clinical course of infection
Incubation period 7-10 days:
- Abrupt onset high fever (up to 41°C)
- Facial flushing
- Skin erythema
Other symptoms that may be observed:
- Injected pharynx
- Abdominal pain
Towards the end of the febrile phase of the illness, circulatory disturbances are often observed.
|Mild DHF||Severe DHF|
Approximately 30% of DHF patients will progress to Dengue Shock Syndrome.
Dengue Shock Syndrome1,2
Dengue Shock Syndrome (DSS) can develop in patients with severe DHF. It will develop rapidly and its onset is acute, occurring at defervescence. DSS is a dangerous condition. If patients do not receive proper treatment, they will die within 12 – 24 hours. Patients often remain conscious until the terminal stages.
Patients will exhibit:
- Cold extremities
- Acute abdominal pain
- Subnormal temperature
- Blotchy, cold and clammy skin
- Rapid and weak pulse
- George R, et al (1997). Clinical spectrum of dengue infection p89 - 113. In Gubler DJ and Duno G, Dengue and Dengue Hemorrhagic Fever. CAB International, NY, USA
- WHO Dengue Factsheet (cited 2002), [http://www.who.int/mediacentre/factsheets/fs117/en/].
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Treatment of dengue fever
It is important to avoid ingestion of aspirin and brufen as they increase bleeding complications.
The World Health Organisation states that although there are no therapeutic treatments for dengue fever, early effective treatment (including adequate hydration) and informed observation can relieve symptoms and prevent severe complications including death.
If any early signs of dengue haemorrhagic fever or shock (see below) are observed then medical attention should be sought urgently.
Treatment of dengue haemorrhagic fever
Treatment for both dengue haemorrhagic fever and dengue shock syndrome focuses on the rapid replenishment of fluids that have been lost as a result of fever, reduced appetite and vomiting. Plasma loss can easily be corrected either through oral hydration or intravenous fluid therapy. Hospitalisation may be necessary for intravenous (IV) therapy where significant dehydration (> 10% of body weight) has occurred, but early treatment results in a favourable outcome in most cases.
Patients need to be closely observed for early signs of deterioration such as restlessness, acute abdominal pain, cold extremities and skin congestion, especially from the third day of fever onwards.
Monitoring dengue haemorrhagic fever
Constant monitoring of plasma volume helps prevent and reduce the incidence of dengue shock syndrome. Haemoglobin levels, heart rate, blood pressure and urine output are useful indicators to monitor plasma loss.
If plasma loss is not detected and treated early enough the onset of dengue shock syndrome can lead to further complications that could be fatal.
Treatment of dengue shock syndrome
Although a medical emergency, dengue shock syndrome is usually rapidly reversible with timely and adequate fluid replacement. Administration of IV fluids as well as oxygen therapy is necessary.
If vital signs remain critical and there is persistent shock (40-50% reduction in blood pressure), fresh whole blood transfusion may be necessary.
As plasma loss continues for 24 – 48 hours, fluids need to be replenished over this period and should only be discontinued when haematocrit level drops to approximately 40%, vital signs stabilised, urine output indicates adequate hydration and strong pulse and normal blood pressure can be measured.
Monitoring dengue shock syndrome
Routine measurements are important in evaluating the success of treatment. Importantly, qualified nursing staff can measure and monitor:
- Frequency and volume of urine output
- Vital signs - pulse, blood pressure and breathing (respiration)
- Red blood cell characteristics (haemoglobin levels)
- Type, volume and rate of fluid/s administered.
Criteria for Recovery
The following criteria should be met before discharge:
- Absence of fever for at least 24 hours
- Appetite is back to normal
- Significant clinical improvement
- Good urine output
- Stable blood pressure
- >2 days after recovery from shock
- No respiratory problems
- Platelet count of >50 000 per mm
- WHO (1997) Chapter 3 Treatment. In Dengue haemorrhagic fever – Diagnosis, treatment, prevention and control. Second Edition, WHO, UK.
Comfort & Ease
Prevention and control
The main means (vector) by which humans become infected with dengue virus is the bite of the Aedes mosquito (Aedes aegypti) when it is carrying the virus. Any prevention programme for dengue must focus on surveying and controlling the prevalence of this insect.
Preventive surveillance against infestations is accepted as being a less costly control method than eradication after infestation.
Surveillance determines changes in the geographical distribution and density of the mosquitoes in question, which can be used to plan and evaluate control programmes over time. Surveillance measures can include monitoring the Aedes mosquito population and its susceptibility to insecticides, as well as focusing on high-risk areas during specific environmental conditions.
Once vector surveillance has been conducted, a vector prevention or control plan can be established.
Four main methods of controlling mosquito populations are:
- Environmental management (most effective)
- Chemical control
- Biological control
- Integrated control.
Environmental management is the most effective means of vector control. It is done with the objective of preventing or reducing the breeding of Aedes mosquitoes and human-vector contact (i.e. reducing the number of times humans are bitten by infected mosquitoes).
Environmental management strategies focus on the destruction, modification, disposal or recycling of containers and natural larval habitats that produce most adult Aedes mosquitoes in each community.
These programmes are best conducted concurrently with health education programmes and campaigns that encourage the community to participate actively in the execution of container management programmes (e.g. regular household sanitation or clean-up campaigns).
Methods for environmental management
Three environmental management methods prevent, control and reduce human-vector contact:
- Improvement of water supply and storage
- Solid waste management
- Modification of man-made larval habitats.
To control urban Aedes mosquitoes, the supply of water must be reliable and regular to reduce or eliminate the need for water storage containers. If water storage containers must be used, they should be well covered. Screen covers allow collection of rainwater but prevent adult mosquitoes from escaping.
Reducing, reusing and recycling plastic containers and tyres otherwise left to lay dormant and collect water reduces potential larval habitats.
Any man-made objects (bamboo fences, tyres, containers, buckets, roof gutters and outdoor sinks etc.) that retain water should always be covered or inverted.
Chemicals or insecticides are widely used to control Aedes mosquitoes. DDT was used from the 1940s till early 1960s when resistance to DDT emerged. Currently, there are three methods of applying chemical control:
Larvicide application - used to treat household containers holding drinking water. These larvicides have extremely low toxicity and are safe for human consumption.
Perifocal treatment - uses sprayers to apply insecticides to larval habitats and surrounding areas. This not only destroys larval infestations but also kills adult mosquitoes. However, it should only be used around non-drinking water.
Space spraying - usually used in dengue outbreak emergencies. Microscopic vapours of insecticides are sprayed into to air to kill adult mosquitoes. This insecticide mist can be applied using portable machines, vehicle mounted generators or even helicopters and aircraft. An aerial spraying from an aircraft is mostly used to treat a large area fast and may be the most cost effective despite the high initial cost.
The indiscriminate use of insecticides should be discouraged. During low Aedes season, routine environmental management methods should be employed together with larvicide application.
Insecticides are toxic and safety precautions need to be observed. Reading instructions on pesticide labels, using safety gloves and masks, thorough washing of body and work clothes should all be performed.
Aedes have developed resistance to some insecticides, as chemicals have been widely used to control mosquitoes over the past 40 years. Baseline data on insecticide susceptibility should be obtained before control programmes are started and to continue monitoring susceptibility levels regularly.
Bed nets or curtains are effective against night-feeding mosquitoes. They are also useful for bedridden individuals and infants. Insect repellents and clothing impregnated with permethrin are also useful protection measures
Fish that eat mosquito lava and the biocide, H-14 (BTI), are frequently utilised for the biological control of Aedes mosquito populations. Their advantages are that they are chemical free and specifically target mosquitoes. BTI is to be environmentally safe when used near drinking water.
Integrated control combines all the above methods into an effective and economical prevention and control programme against the Aedes mosquitoes.
- WHO (1997) Chapter 5 Vector surveillance and control . In Dengue haemorrhagic fever – Diagnosis, treatment, prevention and control. Second Edition, WHO, UK.
Fitting The immune response to dengue virus infection
It must be considered in the context of primary versus secondary dengue infections.
A primary infection essentially describes the first dengue virus infection experienced by an individual.
A secondary infection is a sequential infection with a dengue serotype that a person has not been previously exposed to. Such an infection will elicit a secondary immune response. However, such a response may also be triggered if a person has previously been exposed to a flavivirus (either through infection or vaccination) that is not dengue.
NS1 antigen is produced from Day 1 after onset of fever and up to Day 9
Detectable levels of IgM antibody will be produced by Day 5 of infection, sometimes as early as Day 3
IgM levels peak in 2 weeks, followed by a 2 week rapid decay
Undetectable 2 to 3 months after infection
Low levels of IgG are detected in the early convalescent phase, not during the acute phase
NS1 antigen is produced from Day 1 after onset of fever and up to Day 9
IgM response is more varied
Usually preceded by IgG and appears quite late during the febrile phase
Minority of patients will show no detectable levels of IgM
May not be produced until 20 days after onset of infection
May be produced at low or undetectable levels
High levels of IgG are detectable during the acute phase
Reach levels above those found in primary or past infection
IgG may be detectable by Day 3 of symptoms, but generally detectable Day 5-6
Persist for 30-40 days then decline to levels found in primary or past infection
Innis BL (1997). Antibody Response to Virus Infection. In Gubler DJ and Kuno G, Dengue and Dengue Hemorrhagic Fever, CAB International, NY, USA
Vornham V and Juno G (1997) Laboratory diagnosis of dengue virus infections. In Gubler DJ and Kuno G, Dengue and Dengue Hemorrhagic Fever, CAB International, NY, USA
Multiple private, not-for-profit and public organisations direct their efforts towards creation of dengue vaccines. The Paediatric Dengue Vaccine Initiative (PDVI) works across public and private sectors to encourage the eventual safe marketing of any effective, affordable vaccination against dengue where it is most needed.
It is hoped that once a safe and effective vaccine is widely available, it will have an exponentially greater impact on reducing the worldwide incidence of dengue fever than any environmental or social preventative measure can currently hope to achieve.
The production methods by which effective vaccines may become commercially produced are varied and encompass vaccines containing1:
- Weakened, non-harmful forms of dengue viruses (live attenuated vaccines)
- Cloned copies of dengue viruses grown under controlled conditions in laboratories (infectious clone technology)
- Small sections of dengue virus DNA intended to be taken in by the bodies cells once injected (DNA vaccines)
- Specific proteins extracted from the dengue virus (subunit vaccines)
- Dead dengue viruses (inactivated vaccines)
- Genes from dengue virus that have been injected into another, less harmful virus that then carries the genes around the body (recombinant vaccinia virus vectors).
Whilst much research is focusing on arriving at a safe, effective vaccination, many other organizations are directing their attention toward identifying potential therapeutic treatments to aid those already infected with the dengue virus.
DENFRAME’s treatment research programme focuses on identifying potential small molecule therapeutic agents by utilising and maintaining two candidate libraries - one in Europe and one in Asia that are screened for potential therapeutic value. The Asian library includes many compounds derived from traditional Chinese medicine.2
Meanwhile, research ongoing within Novartis also focuses on identifying small molecules to interfere with dengue virus replication and testing them on other flaviviruses, such as Japanese Encephalitis and Yellow Fever in the hope that some may prove useful at combating a range of related viruses.3
- Initiative for Vaccine Research (cited Aug 2008) [http://www.who.int/vaccine_research/diseases/vector/en/index.html]
- Denframe: Consortium for the Study of Dengue Disease (cited Aug 2008) [http://www.denframe.org/index.html]
- Novartis Institute for Tropical Diseases (cited Aug 2008) [http://www.nitd.novartis.com/research/dengue_unit.shtml]