Dengue Fever

Dengue fever and dengue hemorrhagic fever (DHF) are acute febrile diseases which occur in the tropics, can be life-threatening, and are caused by four closely related virus serotypes of the genus Flavivirus, family Flaviviridae. It is also known as breakbone fever. It occurs widely in the tropics, including northern Argentina, northern Australia, the entirety of Bangladesh, Barbados, Bolivia, Brazil, Cambodia, Costa Rica, Dominican Republic, Guatemala, Guyana, Honduras, India, Indonesia, Jamaica, Laos, Malaysia, Mexico, Pakistan, Panama, Paraguay, Philippines, Puerto Rico, Samoa, Singapore, Sri Lanka, Suriname, Taiwan, Thailand, Trinidad, Venezuela and Vietnam, and increasingly in southern China. Unlike malaria, dengue is just as prevalent in the urban districts of its range as in rural areas. Each serotype is sufficiently different that there is no cross-protection and epidemics caused by multiple serotypes (hyperendemicity) can occur. Dengue is transmitted to humans by the Aedes aegypti or more rarely the Aedes albopictus mosquito, which feed during the day.

The WHO says some 2.5 billion people, two fifths of the world's population, are now at risk from dengue and estimates that there may be 50 million cases of dengue infection worldwide every year. The disease is now endemic in more than 100 countries.

Signs and symptoms

The disease manifests as a sudden onset of severe headache, muscle and joint pains (myalgias and arthralgias—severe pain that gives it the nickname break-bone fever or bonecrusher disease), fever, and rash. The dengue rash is characteristically bright red petechiae and usually appears first on the lower limbs and the chest; in some patients, it spreads to cover most of the body. There may also be gastritis with some combination of associated abdominal pain, nausea, vomiting, or diarrhea.

Some cases develop much milder symptoms which can be misdiagnosed as influenza or other viral infection when no rash is present. Thus travelers from tropical areas may pass on dengue inadvertently, having not been properly diagnosed at the height of their illness. Patients with dengue can pass on the infection only through mosquitoes or blood products and only while they are still febrile. The classic dengue fever lasts about two to seven days, with a smaller peak of fever at the trailing end of the disease (the so-called "biphasic pattern"). Clinically, the platelet count will drop until the patient's temperature is normal. Cases of DHF also show higher fever, variable hemorrhagic phenomena, thrombocytopenia, and hemoconcentration. A small proportion of cases lead to dengue shock syndrome (DSS) which has a high mortality rate. DHF combined with a cirrhotic liver has been suspected in rapid development of hepatocellular carcinoma (HCC). Given that the dengue virus (DEN) is related to the Hepatitis C virus, this is an avenue for further research as HCC is among the top five cancerous causes of death outside Europe and North America. Normally HCC does not occur in a cirrhotic liver for ten or more years after the cessation of the poisoning agent. DHF patients can develop HCC within one year of cessation of poisoning agent.

Diagnosis

The diagnosis of dengue is usually made clinically. The classic picture is high fever with no localising source of infection, a petechial rash with thrombocytopenia and relative leukopenia – low platelet and white blood cell count. Care has to be taken as diagnosis of DHF can mask end stage liver disease and vice versa.

1. Fever, bladder problem, constant headaches, eye pain, severe dizziness and loss of appetite.
2. Hemorrhagic tendency (positive tourniquet test, spontaneous bruising, bleeding from mucosa, gingiva, injection sites, etc.; vomiting blood, or bloody diarrhea)
3. Thrombocytopenia (<100,000 platelets per mm³ or estimated as less than 3 platelets per high power field)
4. Evidence of plasma leakage (hematocrit more than 20% higher than expected, or drop in hematocrit of 20% or more from baseline following IV fluid, pleural effusion, ascites, hypoproteinemia)
5. Encephalitic occurrences.

Dengue shock syndrome is defined as dengue hemorrhagic fever plus:

• Weak rapid pulse,
• Narrow pulse pressure (less than 20 mm Hg)
• Cold, clammy skin and restlessness.
• Dependable, immediate diagnosis of dengue can be performed in rural areas by the use of Rapid Diagnostic Test kits, which also differentiate between primary and secondary dengue infections. Serology and polymerase chain reaction (PCR) studies are available to confirm the diagnosis of dengue if clinically indicated. Dengue can be a life threatening fever.

Cause

Dengue fever is caused by Dengue virus (DENV), a mosquito-borne flavivirus. DENV is an ssRNA positive-strand virus of the family Flaviviridae; genus Flavivirus. There are four serotypes of DENV. The virus has a genome of about 11000 bases that codes for three structural proteins, C, prM, E; seven nonstructural proteins, NS1, NS2a, NS2b, NS3, NS4a, NS4b, NS5; and short non-coding regions on both the 5' and 3' ends.

Prevention

Vaccine development

There is no tested and approved vaccine for the dengue flavivirus. There are many ongoing vaccine development programs. Among them is the Pediatric Dengue Vaccine Initiative set up in 2003 with the aim of accelerating the development and introduction of dengue vaccine(s) that are affordable and accessible to poor children in endemic countries. Thai researchers are testing a dengue fever vaccine on 3,000–5,000 human volunteers after having successfully conducted tests on animals and a small group of human volunteers. A number of other vaccine candidates are entering phase I or II testing.

Mosquito control
 
Primary prevention of dengue mainly resides in mosquito control. There are two primary methods: larval control and adult mosquito control. In urban areas, Aedes mosquitos breed on water collections in artificial containers such as plastic cups, used tires, broken bottles, flower pots, etc. Periodic draining or removal of containers is the most effective way of reducing the breeding grounds for mosquitos.[citation needed] Larvicide treatment is another effective way to control the vector larvae, but the larvicide chosen should be long-lasting and preferably have World Health Organization clearance for use in drinking water. There are some very effective insect growth regulators (IGRs) available which are both safe and long-lasting (e.g., pyriproxyfen). For reducing the adult mosquito load, fogging with insecticide is somewhat effective.

Prevention of mosquito bites is another way of preventing disease. This can be achieved by using insect repellent, mosquito traps or mosquito nets.

• Mesocyclops

In 1998, scientists from the Queensland Institute of Medical Research (QIMR) in Australia and Vietnam's Ministry of Health introduced a scheme that encouraged children to place a water bug, the crustacean Mesocyclops, in water tanks and discarded containers where the Aedes aegypti mosquito was known to thrive. This method is viewed as being more cost-effective and more environmentally friendly than pesticides, though not as effective, and requires the continuing participation of the community.

Even though this method of mosquito control was successful in rural provinces, not much is known about how effective it could be if applied to cities and urban areas. The Mesocyclops can survive and breed in large water containers but would not be able to do so in small containers that most urban dwellers have in their homes. Also, Mesocyclops are hosts for the guinea worm, a pathogen that causes a parasite infection, and so this method of mosquito control cannot be used in countries that are still susceptible to the guinea worm. The biggest dilemma with Mesocyclops is that its success depends on the participation of the community. This idea of a possible parasite-bearing creature in household water containers dissuades people from continuing the process of inoculation and, without the support and work of everyone living in the city, this method will not be successful.

• Wolbachia

In 2009, scientists from the School of Integrative Biology at The University of Queensland revealed that by infecting Aedes mosquitos with the bacterium Wolbachia, the adult lifespan was reduced by half. In the study, super-fine needles were used to inject 10,000 mosquito embryos with the bacterium. Once an insect was infected, the bacterium would spread via its eggs to the next generation. A pilot release of infected mosquitoes could begin in Vietnam within three years. If no problems are discovered, a full-scale biological attack against the insects could be launched within five years.

• Mosquito mapping

In 2004, scientists from the Federal University of Minas Gerais, Brazil, discovered a fast way to find and count mosquito population inside urban areas. The technology, named Intelligent Monitoring of Dengue (in Portuguese), uses traps with kairomones that capture Aedes gravid females, and upload insect counts with a combination of cell phone, GPS and internet technology. The result is a complete map of the mosquitoes in urban areas, updated in real time and accessible remotely, that can inform control methodologies. The technology was recognized with a Tech Museum Award in 2006.

Potential antiviral approaches

Dengue virus belongs to the family Flaviviridae, which includes the hepatitis C virus, West Nile and Yellow fever viruses among others. Possible laboratory modification of the yellow fever vaccine YF-17D to target the dengue virus via chimeric replacement has been discussed extensively in scientific literature, but as of 2009 no full scale studies have been conducted.

In 2006 a group of Argentine scientists discovered the molecular replication mechanism of the virus, which could be specifically attacked by disrupting the viral RNA polymerase. In cell culture and murine experiments morpholino antisense oligomers have shown specific activity against Dengue virus.

In 2007 virus replication was attenuated in the laboratory by interfering with activity of the dengue viral protease, and a project to identify drug leads with broad spectrum activity against the related dengue, hepatitis C, West Nile, and yellow fever viruses was launched.

Treatment

The mainstay of treatment is timely supportive therapy to tackle shock due to hemoconcentration and bleeding. Close monitoring of vital signs in critical period (between day 2 to day 7 of fever) is critical. Increased oral fluid intake is recommended to prevent dehydration. Supplementation with intravenous fluids may be necessary to prevent dehydration and significant concentration of the blood if the patient is unable to maintain oral intake. A platelet transfusion is indicated in rare cases if the platelet level drops significantly (below 20,000) or if there is significant bleeding. The presence of melena may indicate internal gastrointestinal bleeding requiring platelet and/or red blood cell transfusion.

Aspirin and non-steroidal anti-inflammatory drugs should be avoided as these drugs may worsen the bleeding tendency associated with some of these infections. Patients may receive paracetamol preparations to deal with these symptoms if dengue is suspected.

Research

Emerging evidence suggests that mycophenolic acid and ribavirin inhibit dengue replication. Initial experiments showed a fivefold increase in defective viral RNA production by cells treated with each drug. In vivo studies, however, have not yet been done. Unlike HIV therapy, lack of adequate global interest and funding greatly hampers the development of a treatment regime.

Alternative medicine

In Brazilian traditional medicine, cat's claw herb is used to treat patients with dengue. In Philippines, the tawa-tawa herb is used to treat patients with dengue.