Introduction of Dengue Fever
Dengue fever, a very old disease, has reemerged in the past 20 years with an expanded geographic distribution of both the viruses and the mosquito vectors, increased epidemic activity, the development of hyperendemicity (the co circulation of multiple serotypes), and the emergence of dengue hemorrhagic fever in new geographic regions. In 1998 this mosquito-borne disease is the most important tropical infectious disease after malaria, with an estimated 100 million cases of dengue fever, 500,000 cases of dengue hemorrhagic fever, and 25,000 deaths annually. The reasons for this resurgence and emergence of dengue hemorrhagic fever in the waning years of the 20th century are complex and not fully understood, but demographic, societal, and public health infrastructure changes in the past 30 years have contributed greatly. This paper reviews the changing epidemiology of dengue and dengue hemorrhagic fever by geographic region, the natural history and transmission cycles, clinical diagnosis of both dengue fever and dengue hemorrhagic fever, serologic and virologic laboratory diagnoses, pathogenesis, surveillance, prevention, and control. A major challenge for public health officials in all tropical areas of the world is to develop and implement sustainable prevention and control programs that will reverse the trend of emergent dengue hemorrhagic fever.
Dengue Virus and the Mosquito Vector
The dengue virus is a single-stranded RNA virus belonging to the Flaviviridae family. The viral genome is approximately 11 kb in length and is surrounded by an icosahedral nucleocapsid covered by a lipid envelope. The mature virion has three structural (core, membrane-associated and envelope) and seven non-structural (NS1, NS2a, NS2b, NS3, NS4a, NS4b and NS5) proteins.
Figure : mosquito vector
The envelope protein is involved in the main biological functions and is responsible for binding and transport into host cells. It is also associated with the induction of neutralizing antibodies and development of protective immune response in the host. The non-structural proteins are expressed as both membrane-associated and secreted forms and have been implicated in the pathogenesis of severe disease. There are four serotypes classified according to their immunological properties – DEN-1, DEN-2, DEN-3 and DEN-4. Infection with one dengue serotype confers lifelong immunity against that serotype but only transient protection against infection by other serotypes. All four serotypes have been associated with outbreaks, having seen DEN-2 as the predominant serotype of primary infection during the outbreak in 2005. Recent data have also demonstrated that the various genotypes within each serotype possess varying epidemic potential. The primary vector for the dengue virus is the A. aegypti mosquito, although the virus may be transmitted by the Aedes albopictus and Aedes polynesiensis as well. Infected humans are the main carriers and amplification host of the dengue virus.
Female mosquitoes acquire the virus by biting infected humans in the viraemic phase and become infective after an extrinsic incubation period of 7–14 days. Subsequently, the mosquito may transmit the virus during every feeding. The length of the extrinsic incubation period is dependent on the ambient temperature and the virus involved, both of which affect the replication rate of the virus in the vector. Aedes aegypti is a highly domesticated mosquito that breeds in artificial containers such as water storage tanks, subterranean pits, flowerpot trays and other ornamental containers. The vector is known to prefer to rest indoor, although studies have shown that they may seek oviposition outdoors. Peak biting activity is at dawn and dusk. The multiple feeding behavior of A. aegypti and its preference for human hosts are believed to contribute to the explosive spread of dengue virus, even in the presence of a low A. aegypti population.
Symptoms of Dengue Fever
Figure : symptoms of dengue fever
Laboratory Diagnosis of Dengue
Laboratory diagnosis of dengue can be performed by viral isolation, serological tests, dengue antigen tests and molecular detection. Virus isolation for dengue is performed by inoculation of the sample into live mice, live mosquitoes or cell cultures. Successful detection of virus may be affected by the presence of interfering antibodies and the heat-labile nature of the virus. It is normally used as a confirmatory test, being impractical for diagnosis or screening on a large scale. Dengue-specific immunoglobulin M (IgM) and immunoglobulin G (IgG) enzyme-linked immunosorbent assay (ELISA) is widely used in diagnosis as it is relatively inexpensive, has good sensitivity and is quick and easy to perform. IgM is detectable at 3–5 days after infection, peaks at about 2 weeks and declines to undetectable levels over 2–3 months. IgG becomes elevated after 9–10 days and persists at detectable levels for life. During secondary infection, IgG increases rapidly too much higher levels within 1–2 days after infection. Because the virus shares antigenic epitopes with other flaviviruses, the presence of cross-reactive antibodies may interfere with serological diagnosis.
The dengue NS1 antigen-capture ELISA is useful for detection of dengue early in the disease. The test sensitivity has been demonstrated to be significantly higher in primary dengue infection (97·3%) than in secondary dengue infection (70·0%), with a positive predictive value of 100% and negative predictive value of 97·3%. Although it is useful in the first week of disease and provides evidence of presence of the virus, its effectiveness in screening blood donors has not been established yet. Like the NS1 test, the dengue RNA test detects viral material that is typically present in the first 5 days of disease. The advantages of the test are good sensitivity and specificity, and the ability to rapidly detect minute quantities of dengue virus material in serum. The disadvantages are the relatively high cost and expertise needed particularly proper quality control to avoid false positives.
Figure : laboratory diagnosis of dengue
Real-time reverse transcription–polymerase chain reaction (RT-PCR), using either a universal dengue oligonucleotide primer pair or a combination of the four serotype-specific oligonucleotide primers, is widely used for clinical diagnosis and public health surveillance. It has established detection limits of 0·1 plaque-forming units (PFU) mL−1 for DEN-1 and DEN-2, 1 PFU mL−1 for DEN-3 and 0·01 PFU mL−1 for DEN-4 and 88% correlation with virus isolation. Group-specific one-step PCR using universal dengue oligonucleotide primer pairs and SYBR green I is widely used for population surveillance as it is fast and cost-effective for mass screening, with a detection limit of 10–4·1 PFU mL−1. A prototype dengue RNA transcription-mediated amplification (TMA) assay (Gen-Probe, Inc., San Diego, CA, USA) was developed for use in large-scale screening of blood donor samples and uses target genomic sequences that are highly conserved across all four serotypes. The analytical sensitivity of the assay has been established at a detection of 14·9 copies mL−1 at 95% detection limit and 3·5 copies mL−1at 50% detection limit for DEN-1, with comparable sensitivity for all four serotypes, and with a specificity of 99·91%.
Dengue infection can produce a spectrum of clinical illness – undifferentiated fever, dengue fever (DF), DHF and dengue shock syndrome (DSS). In infants and children younger than 15 years, the patient is usually either asymptomatic or has a mild undifferentiated febrile illness with maculopapular rash.
Figure : transmission of virus
DF is characterized by the sudden onset of high fever, severe headache (especially in the retro-orbital area), arthralgia, myalgia, nausea, vomiting and rash. Infants and younger children tend to present with an undifferentiated febrile disease, often with rash. The acute febrile illness lasts approximately 2–7 days. DHF is clinically defined by high fever, hemorrhagic manifestations, thrombocytopenia and evidence of plasma leakage (Table 1). Four grades of severity have been defined (Table 2), where grades III and IV are considered to be DSS. The presence of thrombocytopenia with concurrent haemoconcentration differentiates grades I and II DHF from DF. Clinical deterioration usually occurs towards the end of the febrile phase when the patient progresses to the phase of plasma leakage. Table1. World Health Organization case definition for DHF and DSS
Case definition for DHF
The following must be present:
Fever or history of acute fever lasting 2–7 days, occasionally biphasic Hemorrhagic tendencies, evidenced by at least one of the following: A positive tourniquet test
Petechiae, ecchymosed or purport
Bleeding from the mucosa, gastrointestinal tract, injection sites or other locations Haematemesis or melaena
Thrombocytopenia (100 000 cells mm−3 or less)
Evidence of plasma leakage because of increased vascular permeability, manifested by at least one of the following: A rise in the haematocrit equal to or greater than 20% above average for age, sex and population A drop in the haematocrit following volume replacement treatment equal to or greater than 20% of baseline Signs of plasma leakage such as pleural effusion, ascites and hypoproteinaemia Case definition for DSS
Symptoms range from mild to severe. Severe symptoms include dengue shock syndrome (DSS) and dengue hemorrhagic fever (DHF). These usually require hospitalization.
There are currently no vaccines. The best method of prevention is to avoid mosquito bites. Treatment is possible if diagnosis occurs before the patient develops DSS or DHF.
The Centers for Disease Control and Prevention (CDC) estimate that 400 million people are infected each year.
Dengue fever is rare in the United States (U.S.), but around 100 cases are reported each year, mostly among people traveling from outside the country. Outbreaks have occurred in Texas, Florida, and Hawaii.
Here are some key points about dengue fever. More detail is in the main article.
- Dengue is transmitted by the mosquitoes Aedes aegypti and Aedes albopictus, which are found throughout the world.
- Around 2.5 billion people, or 40 percent of the world's population, live in areas where there is a risk of dengue transmission.
- Dengue is endemic in at least 100 countries in Asia, the Pacific, the Americas, Africa, and the Caribbean.
- Symptoms usually begin 4 to 7 days after the mosquito bite and typically last 3 to 10 days.
- Effective treatment is possible if a clinical diagnosis is made early.
Signs and symptoms
Mosquitoes spread dengue fever.
Symptoms vary depending on the severity of the disease.
Mild dengue fever
Symptoms can appear up to 7 days after being bitten by the mosquito that carries the virus.
- aching muscles and joints
- body rash that can disappear and then reappear
- high fever
- intense headache
- pain behind the eyes
- vomiting and feeling nauseous
Symptoms usually disappear after a week, and mild dengue rarely involves serious or fatal complications.
Dengue hemorrhagic fever
At first, symptoms of DHF may be mild, but they gradually worsen within a few days. As well as mild dengue symptoms, there may be signs of internal bleeding.
A person with Dengue hemorrhagic fever may experience:
- bleeding from the mouth, gums, or nose
- clammy skin
- damage to lymph and blood vessels
- internal bleeding, which can lead to black vomit and feces, or stools
- a lower number of platelets in the blood
- sensitive stomach
- small blood spots under the skin
- weak pulse
Without prompt treatment, DHF can be fatal.
Dengue shock syndrome
DSS is a severe form of dengue. It can be fatal.
Apart from symptoms of mild dengue fever, the person may experience:
- intense stomach pain
- sudden hypotension, or a fast drop in blood pressure
- heavy bleeding
- regular vomiting
- blood vessels leaking fluid
Without treatment, this can result in death.
Dengue is a virus, so there is no specific treatment or cure. However, intervention can help, depending on how severe the disease is.
For milder forms, treatment includes:
Preventing dehydration: A high fever and vomiting can dehydrate the body. The person should drink clean water, ideally bottled rather than tap water. Rehydration salts can also help replace fluids and minerals.
Painkillers, such as Tylenol or paracetamol: These can help lower fever and ease pain.
Non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin or ibuprofen, are not advised, as they can increase the risk of internal bleeding.
More severe forms of dengue fever may need:
- intravenous (IV) fluid supplementation, or drip, if the person cannot take fluids by mouth
- blood transfusion, for patients with severe dehydration
Hospitalization will allow the individual to be properly monitored, in case symptoms get worse.
There are four dengue viruses (DENV) that cause dengue fever. They are all spread by a species of mosquito known as Aedes aegypti, and more rarely by the Aedes albopictus mosquito.
The viruses jumped from monkeys to humans between 100 and 800 years ago, according to the CDC, but dengue remained a minor problem until the middle of the twentieth century.
Aedes aegypti originated in Africa, but nowadays it is found in tropical areas around the world, especially in and around areas of human population.
The virus is transmitted from an infected mosquito to a human. A mosquito bites a person who is infected with the dengue virus, and the virus is passed on when the mosquito bites someone else.
It it possible to have dengue fever more than once. A second infection carries a higher risk of developing a harsher form.
Dengue fever is most common in subtropical and tropical areas, such as Central and South America, parts of Africa, parts of Asia, the Caribbean, and the Pacific.
Most cases of dengue among U.S. citizens occur in Puerto Rico, the U.S. Virgin Islands, Samoa, and Guam, where the virus is endemic.
High-risk regions are:
- Central and South America
- the Caribbean
- tropical Asia, including Bangladesh, Indonesia, and parts of China
- Northern Australia
Unlike malaria, dengue can happen in both urban areas and rural areas, but research published in 2011 suggested that it is more common in rural areas.
The signs and symptoms of dengue fever are similar to some other diseases, such as typhoid fever and malaria. This can sometimes delay an accurate diagnosis.
The doctor will assess the symptoms and the person's medical and travel history, and they may order some blood tests to confirm the diagnosis.
No vaccine can protect against dengue fever. Only avoiding mosquito bites can prevent it.
Anyone who lives in or travels to an at-risk area can use a number of ways to avoid being bitten.
If you are spending time in a tropical region, use mosquito nets that are treated with insecticide.
Clothing: Reduce the amount of skin exposed by wearing long pants, long-sleeved shirts, and socks, tucking pant legs into shoes or socks, and wearing a hat.
Mosquito repellents: Use a repellent with at least 10 percent concentration of diethyltoluamide (DEET), or a higher concentration for longer lengths of exposure. Avoid using DEET on young children.
Mosquito traps and nets: Nets treated with insecticide are more effective, otherwise the mosquito can bite through the net if the person is standing next to it. The insecticide will kill mosquitoes and other insects, and it will repel insects from entering the room.
Door and window screens: Structural barriers, such as screens or netting, can keep mosquitos out.
Avoid scents: Heavily scented soaps and perfumes may attract mosquitos.
Camping gear: Treat clothes, shoes, and camping gear with permethrin, or purchase clothes that have been pretreated.
Timing: Try to avoid being outside at dawn, dusk, and early evening.
Stagnant water: The Aedes mosquito breeds in clean, stagnant water. Checking for and removing stagnant water can help reduce the risk.
To reduce the risk of mosquitoes breeding in stagnant water:
- turn buckets and watering cans over and store them under shelter so that water cannot accumulate
- remove excess water from plant pot plates
- scrub containers to remove mosquito eggs
- loosen soil from potted plants, to prevent puddles forming on the surface
- make sure scupper drains are not blocked and do not place potted plants and other objects over them
- use non-perforated gully traps, install anti-mosquito valves, and cover any traps that are rarely used
- do not place receptacles under an air-conditioning unit
- change the water in flower vases every second day and scrub and rinse the inside of the vase
- prevent leaves from blocking anything that may result in the accumulation of puddles or stagnant water
When camping or picnicking, choose an area that is away from still water.