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DENGUE FEVER also known as  breakbone fever , is a  mosquito-borne  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 plateletsand blood plasma leakage, or into  dengue shock syndrome . .

Signs and symptoms:

Signs and 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  commoncold  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. he 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 .  Nausea and 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- likerash.A rash described as "islands of white in a sea of red" has also been described. [


Cause 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 encephalitie virus,  Japaneseencephalitisvirus , tick-borne encephalitis virus ,  Kyasanur forest disease virus, and Omsk hemorrhagic fever virus .  Most are transmitted by arthropods (mosquitoes or ticks), and are therefore also referred to as  arboviruses ( ar thropod- bo rne 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 .  There are five [1]  strains of the virus, called serotypes, of which the first four are referred to as DENV-1, DENV-2, DENV-3 and DENV-4 . []  The fifth type was announced in 2013.The distinctions between the serotypes is based on the their  antigenicity . ]


TRANSMISSION Dengue virus is primarily transmitted by  Aedes  mosquitoes, particularly  A. aegypti These mosquitoes usually live between the  latitude  of 35° North and 35° South below an  elevatio  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. polynesiesis  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 , is particularly involved, as it 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 . [  Other person-to-person modes of transmission have also been reported, but are very unusual.The genetic variation in dengue viruses is region specific, suggestive that establishment into new territories is relatively infrequent, despite dengue emerging in new regions in recent decades. [


PREDISPOSITION Severe disease is more common in babies and young children, and in contrast to many other infections it is more common in children that are relativelY well nourished . [ Other  risk factorfor severe disease include female sex, high body mass index,and  viral load [29  While each serotype can cause the full spectrum of disease , [ virus strain is a risk factor. [ 9 Infection with one serotype is thought to produce lifelong immunity to that type, but only short term protection against the other three . [  The risk of severe disease from secondary infection increases if someone previously exposed to serotype DENV-1 contracts serotype DENV-2 or DENV-3, or if someone previously exposed to DENV-3 acquires DENV-2 . [ Dengue can be life-threatening in people with chronic diseases such as diabetes and  asthma Polymorphisms (normal variations) in particular genes have been linked with an increased risk of severe dengue complications. Examples include the genes coding for the proteins known asTNF α, mannan-binding lectinCTLA   TGFβ   DC-SIGN   PLCE, and particular forms of human leukocyte antigen from gene variations of  HLAB.  A common genetic abnormality, especially in Africans, known as glucose-6-phosphate dehydrogenase deficiency, appears to increase the risk . ]  Polymorphisms in the genes for the vitamin D receptOrand   FcγR  seem to offer protection against severe disease in secondary dengue infection


VIRAL REPLICATION Once inside the skin, dengue virus binds to Langerhans cells (a population of dendritic cell  in the skin that identifies pathogens ).The virus enters the cells through binding between viral proteins and membrane proteins on the Langerhans cell, specifically the C-type lectins  called DC-SIGN, mannose receptor and CLEC5A .  DC-SIGN, a non-specific receptor for foreign material on dendritic cells, seems to be the main point of entry . [  The dendritic cell moves to the nearest lymph noDe . Meanwhile, the virus genome is translated in membrane-bound vesicles on the cell's endoplasmic reticulum where the cell's protein synthesis apparatus produces new viral proteins that replicate the viral RNA and begin to form viral particles. Immature virus particles are transported to the Golgi apparatUs , the part of the cell where some of the proteins receive necessary sugar chains (glycoproteins). The now mature new viruses bud on the surface of the infected cell and are released by  exocytosisThey are then able to enter other white blood cells, such as  monocytesand  macrophages . [ The initial reaction of infected cells is to produce interferon, a cytokine that raises a number of defenses against viral infection through the innate immune system by augmenting the production of a large group of proteins mediated by the JAK-STAT pathway. Some serotypes of dengue virus appear to have mechanisms to slow down this process. Interferon also activates the adaptive immune system, which leads to the generation of  antibodiesagainst the virus as well as T cells that directly attack any cell infected with the virus .  Various antibodies are generated; some bind closely to the viral proteins and target them for phagocytosis (ingestion by specialized cellsand destruction), but some bind the virus less well and appear instead to deliver the virus into a part of the phagocytes where it is not destroyed but is able to replicate further


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 . [  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 . .


M anagement There are no specific antiviral drugs for dengue, however maintaining proper fluid balance is important. [ 9  Treatment depends on the symptoms. [ 38  Those who are able to drink, are passing urine, have no "warning signs" and are otherwise healthy can be managed at home with daily follow up and oral rehydration therapyThose who have other health problems, have "warning signs" or who cannot manage regular follow up should be cared for in hospital. [7 ]  In those with severe dengue care should be provided in an area where there is access to an intensive care unit . Intravenous hydration, if required, is typically only needed for one or two days .  The rate of fluid administration is titrated to a urinary output of 0.5–1 mL/kg/h, stable vital sigNs  and normalization of hematocrit . []  The smallest amount of fluid required to achieve this is recommended . [  Invasive medical procedures such as nasogastric intubation  intramuscular arterial punctures are avoided, in view of the bleeding risk . [   Paracetamol (acetaminophen ) is used for fever and discomfort while  NSAID  such as  ibuprofenand  aspirin are avoided as they might aggravate the risk of bleeding . []  Blood transfusionis initiated early in people presenting with unstable vital signs in the face of a  decreasing hematocrit , rather than waiting for the hemoglobin concentration to decrease to some predetermined "transfusion trigger" level . ]  Packed red blood cells or whole blood are recommended, while platelets and fresh frozen plasmaare usually not .  Corticosteroids do not appear to affect outcomes and may cause harm, thus are not recommended


DIAGNOSIS The diagnosis of dengue is typically made clinically, on the basis of reported symptoms and physical examination this applies especially in endemic areas .  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 ceLlcouNt , 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 cuffat 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 1 inch 2  (6.25 cm 2 ). The diagnosis should be considered in anyone who develops a fever within two weeks of being in the tropics or subtropics. [ 9 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,  virl hemorrhagicfevertyphoidfeve  meningococcal disease, measles, and influenza. [


CLASSIFICATION The World Health Organization's 2009 classification divides dengue fever into two groups: uncomplicated and severe . [ This replaces the 1997 WHO classification, which needed to be simplified as it had been found to be to restrictive, though the older classification is still widely used [30  including by the World Health ORganization's Regional Office for South-East Asia as of 2011 .  Severe dengue is defined as that associated with severe bleeding, severe organ dysfunction, or severe plasma leakage while all other cases are uncomplicated .  The 1997 classification divided dengue into undifferentiated fever, dengue fever, and dengue hemorrhagic fever . [  Dengue hemorrhagic fever was subdivided further into grades I–IV. Grade I is the presence only of easy bruising or a positive tourniquet test in someone with fever, grade II is the presence of spontaneous bleeding into the skin and elsewhere, grade III is the clinical evidence of shock, and grade IV is shock so severe that blood pressure and pulse cannot be detected .  Grades III and IV are referred to as "dengue shock syndrome.

Laboratory test:

Laboratory test 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% sensitive however is only 60–80% in subsequent infections.All tests may be negative in the early stages of the diseasePCR 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 .


P revention There 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 : Advocacy, social mobilization and legislation to ensure that public health bodies and communities are strengthened; Collaboration between the health and other sectors (public and private); An integrated approach to disease control to maximize use of resources; Evidence-based decision making to ensure any interventions are targeted appropriately; and 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 getting rid of open sources of water, or if this is not possible , by adding insecticides or biological control agents  to these areas. [ 19  Generalized spraying with  organophosphateor   pyrethroid  insecticides, while sometimes done, is not thought to be effective.Reducing open collections of water through environmental modification is the preferred method of control, given the concerns of negative health effects from insecticides and greater logistical difficulties with control agents.



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