4.Dengue Fever

Dengue Fever:

Dengue fever  also known as breakbone fever, is an infectious tropical disease caused by the dengue virus. Symptoms include fever, headache, muscle and joint pains, and a characteristic skin rash that is similar to measles. In a small proportion of cases the disease develops into the life-threatening dengue hemorrhagic fever, resulting in bleeding, low levels of blood platelets and blood plasma leakage, or into dengue shock syndrome, where dangerously low blood pressure occurs.

Dengue is transmitted by several species of mosquito within the genus Aedes, principally A. aegypti. The virus has four different types; infection with one type usually gives lifelong immunity to that type, but only short-term immunity to the others. Subsequent infection with a different type increases the risk of severe complications. As there is no commercially available vaccine, prevention is sought by reducing the habitat and the number of mosquitoes and limiting exposure to bites.

Treatment of acute dengue is supportive, using either oral or intravenous rehydration for mild or moderate disease, and intravenous fluids and blood transfusion for more severe cases. The incidence of dengue fever has increased dramatically since the 1960s, with around 50–100 million people infected yearly.

Sign & Symptoms:

Typically, people infected with dengue virus are asymptomatic (80%) or only have mild symptoms such as an uncomplicated fever. Others have more severe illness (5%), and in a small proportion it is life-threatening. The incubation period (time between exposure and onset of symptoms) ranges from 3–14 days, but most often it is 4–7 days. Therefore, travelers returning from endemic areas are unlikely to have dengue if fever or other symptoms start more than 14 days after arriving home. Children often experience symptoms similar to those of the common cold and gastroenteritis (vomiting and diarrhea) and have a greater risk of severe complications, though initial symptoms are generally mild but include high fever.

The characteristic symptoms of dengue are sudden-onset fever, headache (typically located behind the eyes), muscle and joint pains, and a rash. The alternative name for dengue, “breakbone fever”, comes from the associated muscle and joint pains. The course of infection is divided into three phases: febrile, critical, and recovery.

The febrile phase involves high fever, potentially over 40 °C (104 °F), and is associated with generalized pain and a headache; this usually lasts two to seven days. Vomiting may also occur. A rash occurs in 50–80% of those with symptoms in the first or second day of symptoms as flushed skin, or later in the course of illness (days 4–7), as a measles-like rash. Some petechiae (small red spots that do not disappear when the skin is pressed, which are caused by broken capillaries) can appear at this point, as may some mild bleeding from the mucous membranes of the mouth and nose. The fever itself is classically biphasic in nature, breaking and then returning for one or two days, although there is wide variation in how often this pattern actually happens.

In some people, the disease proceeds to a critical phase around the time fever resolves and typically lasts one to two days. During this phase there may be significant fluid accumulation in the chest and abdominal cavity due to increased capillary permeability and leakage. This leads to depletion of fluid from the circulation and decreased blood supply to vital organs. During this phase, organ dysfunction and severe bleeding, typically from the gastrointestinal tract, may occur. Shock (dengue shock syndrome) and hemorrhage (dengue hemorrhagic fever) occur in less than 5% of all cases of dengue, however those who have previously been infected with other serotypes of dengue virus (“secondary infection”) are at an increased risk. This critical phase, while rare, occurs relatively more commonly in children and young adults.

Associated problems

Dengue can occasionally affect several other body systems, either in isolation or along with the classic dengue symptoms. A decreased level of consciousness occurs in 0.5–6% of severe cases, which is attributable either to infection of the brain by the virus or indirectly as a result of impairment of vital organs, for example, the liver.

Other neurological disorders have been reported in the context of dengue, such as transverse myelitis and Guillain-Barré syndrome. Infection of the heart and acute liver failure are among the rarer complicated.

Causes:

Virology:

Dengue fever virus (DENV) is an RNA virus of the family Flaviviridae; genus Flavivirus. Other members of the same genus include yellow fever virus, West Nile virus, St. Louis encephalitis virus, Japanese encephalitis virus, tick-borne encephalitis virus, Kyasanur forest disease virus, and Omsk hemorrhagic fever virus.^[12] Most are transmitted by arthropods (mosquitoes or ticks), and are therefore also referred to as arboviruses (arthropod-borne viruses).

The dengue virus genome (genetic material) contains about 11,000 nucleotide bases, which code for the three different types of protein molecules (C, prM and E) that form the virus particle and seven other types of protein molecules (NS1, NS2a, NS2b, NS3, NS4a, NS4b, NS5) that are only found in infected host cells and are required for replication of the virus.^[13][14] There are four strains of the virus, which are called serotypes, and these are referred to as DENV-1, DENV-2, DENV-3 and DENV-4. The distinctions between the serotypes is based on the their antigenicity.

Transmission:

Dengue virus is primarily transmitted by Aedes mosquitoes, particularly A. aegypti.^[2] These mosquitoes usually live between the latitudes of 35° North and 35° South below an elevation of 1,000 metres (3,300 ft). They typically bite during the day, particularly in the early morning and in the evening, but they are able to bite and thus spread infection at any time of day all during the year. Other Aedes species that transmit the disease include A. albopictus, A. polynesiensis and A. scutellaris. Humans are the primary host of the virus, but it also circulates in nonhuman primates. An infection can be acquired via a single bite. A female mosquito that takes a blood meal from a person infected with dengue fever, during the initial 2–10 day febrile period, becomes itself infected with the virus in the cells lining its gut. About 8–10 days later, the virus spreads to other tissues including the mosquito’s salivary glands and is subsequently released into its saliva. The virus seems to have no detrimental effect on the mosquito, which remains infected for life. Aedes aegypti prefers to lay its eggs in artificial water containers, to live in close proximity to humans, and to feed on people rather than other vertebrates.

Dengue can also be transmitted via infected blood products and through organ donation. In countries such as Singapore, where dengue is endemic, the risk is estimated to be between 1.6 and 6 per 10,000 transfusions. Vertical transmission (from mother to child) during pregnancy or at birth has been reported.

Severe disease

It is not entirely clear why secondary infection with a different strain of dengue virus places people at risk of dengue hemorrhagic fever and dengue shock syndrome. The most widely accepted hypothesis is that of antibody-dependent enhancement (ADE). The exact mechanism behind ADE is unclear. It may be caused by poor binding of non-neutralizing antibodies and delivery into the wrong compartment of white blood cells that have ingested the virus for destruction. There is a suspicion that ADE is not the only mechanism underlying severe dengue-related complications, and various lines of research have implied a role for T cells and soluble factors such as cytokines and the complement system.

Severe disease is marked by the problems of capillary permeability (an allowance of fluid and protein normally contained within blood to pass) and disordered blood clotting. These changes appear associated with a disordered state of the endothelial glycocalyx, which acts as a molecular filter of blood components. Leaky capillaries (and the critical phase) are thought to be caused by an immune system response.^[7] Other processes of interest include infected cells that become necrotic—which affect both coagulation and fibrinolysis (the opposing systems of blood clotting and clot degradation)—and low platelets in the blood, also a factor in normal clotting.

Diagnosis:

The diagnosis of dengue is typically made clinically, on the basis of reported symptoms and physical examination; this applies especially in endemic areas.^[1] However, early disease can be difficult to differentiate from other viral infections. A probable diagnosis is based on the findings of fever plus two of the following: nausea and vomiting, rash, generalized pains, low white blood cell count, positive tourniquet test, or any warning sign (see table) in someone who lives in an endemic area. Warning signs typically occur before the onset of severe dengue. The tourniquet test, which is particularly useful in settings where no laboratory investigations are readily available, involves the application of a blood pressure cuff at between the diastolic and systolic pressure for five minutes, followed by the counting of any petechial hemorrhages; a higher number makes a diagnosis of dengue more likely with the cut off being more than 10 to 20 per 2.5 cm² (1 inch²).

The diagnosis should be considered in anyone who develops a fever within two weeks of being in the tropics or subtropics. It can be difficult to distinguish dengue fever and chikungunya, a similar viral infection that shares many symptoms and occurs in similar parts of the world to dengue. Often, investigations are performed to exclude other conditions that cause similar symptoms, such as malaria, leptospirosis, viral hemorrhagic fever, typhoid fever, meningococcal disease, measles, and influenza.

The earliest change detectable on laboratory investigations is a low white blood cell count, which may then be followed by low platelets and metabolic acidosis.^[5] A moderately elevated level of aminotransferase (AST and ALT) from the liver is commonly associated with low platelets and white blood cells. In severe disease, plasma leakage results in hemoconcentration (as indicated by a rising hematocrit) and hypoalbuminemia. Pleural effusions or ascites can be detected by physical examination when large, but the demonstration of fluid on ultrasound may assist in the early identification of dengue shock syndrome.

Laboratory Tests:

The diagnosis of dengue fever may be confirmed by microbiological laboratory testing. This can be done by virus isolation in cell cultures, nucleic acid detection by PCR, viral antigen detection (such as for NS1) or specific antibodies (serology). Virus isolation and nucleic acid detection are more accurate than antigen detection, but these tests are not widely available due to their greater cost. Detection of NS1 during the febrile phase of a primary infection may be greater than 90% however is only 60–80% in subsequent infections. All tests may be negative in the early stages of the disease. PCR and viral antigen detection are more accurate in the first seven days. In 2012 a PCR test was introduced that can run on equipment used to diagnose influenza; this is likely to improve access to PCR-based diagnosis.

These laboratory tests are only of diagnostic value during the acute phase of the illness with the exception of serology. Tests for dengue virus-specific antibodies, types IgG and IgM, can be useful in confirming a diagnosis in the later stages of the infection. Both IgG and IgM are produced after 5–7 days. The highest levels (titres) of IgM are detected following a primary infection, but IgM is also produced in reinfection. IgM becomes undetectable 30–90 days after a primary infection, but earlier following re-infections. IgG, by contrast, remains detectable for over 60 years and, in the absence of symptoms, is a useful indicator of past infection. After a primary infection IgG reaches peak levels in the blood after 14–21 days. In subsequent re-infections, levels peak earlier and the titres are usually higher. Both IgG and IgM provide protective immunity to the infecting serotype of the virus. The laboratory test for IgG and IgM antibodies can cross-react with other flaviviruses and may result in a false positive after recent infections or vaccinations with yellow fever virus or Japanese encephalitis.

Prevention:

here are no approved vaccines for the dengue virus. Prevention thus depends on control of and protection from the bites of the mosquito that transmits it. The World Health Organization recommends an Integrated Vector Control program consisting of five elements: (1) Advocacy, social mobilization and legislation to ensure that public health bodies and communities are strengthened, (2) collaboration between the health and other sectors (public and private), (3) an integrated approach to disease control to maximize use of resources, (4) evidence-based decision making to ensure any interventions are targeted appropriately and (5) capacity-building to ensure an adequate response to the local situation. The primary method of controlling A. aegypti is by eliminating its habitats. This is done by emptying containers of water or by adding insecticides or biological control agents to these areas, although spraying with organophosphate or pyrethroid insecticides is not thought to be effective.^[3] Reducing open collections of water through environmental modification is the preferred method of control, given the concerns of negative health effect from insecticides and greater logistical difficulties with control agents. People can prevent mosquito bites by wearing clothing that fully covers the skin, using mosquito netting while resting, and/or the application of insect repellent (DEET being the most effective).