Cholera


Cholera is an infection of the small intestine that is caused by the bacterium Vibrio cholerae. The main symptoms are profuse watery diarrhea and vomiting. Transmission is primarily through consuming contaminated drinking water or food. The severity of the diarrhea and vomiting can lead to rapid dehydration and electrolyte imbalance. Primary treatment is with oral rehydration solution and if these are not tolerated, intravenous fluids. Antibiotics are beneficial in those with severe disease. Worldwide it affects 3-5 million people and causes 100,000-130,000 deaths a year as of 2010. Cholera was one of the earliest infections to be studied by epidemiologicalmethods.[citation needed]

Contents

[edit]Signs and symptoms

A person with severe dehydration due to cholera. Note the sunken eyes and decreased skin turgor which produces wrinkled hands
The primary symptoms of cholera are profuse painless diarrhea and vomiting of clear fluid.[1] These symptoms usually start suddenly, one to five days after ingestion of the bacteria.[1] The diarrhea is frequently described as "rice water" in nature and may have a fishy odor.[1] An untreated person with cholera may produce 10-20 liters of diarrhea a day[1] with fatal results. For every symptomatic person there are 3 to 100 people who get the infection but remain asymptomatic.[2]
If the severe diarrhea and vomiting are not aggressively treated it can, within hours, result in life-threatening dehydration and electrolyte imbalances.[1] The typical symptoms of dehydration include low blood pressure, poor skin turgor (wrinkled hands), sunken eyes, and a rapid pulse.[1]

[edit]Cause

Main article: Vibrio cholerae
Drawing of Death bringing the cholera, inLe Petit Journal
Transmission is primarily due to the fecal contamination of food and water due to poorsanitation.[3] This bacterium can, however, live naturally in any environment.[4]

[edit]Susceptibility

About one hundred million bacteria must typically be ingested to cause cholera in a normal healthy adult.[1] This dose, however, is less in those with lower gastric acidity (for instance those using proton pump inhibitors).[1] Children are also more susceptible with two to four year olds having the highest rates of infection.[1] Individuals' susceptibility to cholera is also affected by theirblood type, with those with type O blood being the most susceptible.[1][5]
It has been said that cystic fibrosis genetic mutation in humans has maintained a selective advantage: heterozygous carriers of the mutation (who are thus not affected by cystic fibrosis) are more resistant to V. cholerae infections.[6] In this model, the genetic deficiency in the cystic fibrosis transmembrane conductance regulator channel proteins interferes with bacteria binding to the gastrointestinal epithelium, thus reducing the effects of an infection.

[edit]Transmission

Cholera is typically transmitted by either contaminated food or water. In the developed world, seafood is the usual cause, while in the developing world it is more often water.[1] Cholera has been found in only two other animal populations: shellfish and plankton.[1]
People infected with cholera often have diarrhea, and if this highly liquid stool, colloquially referred to as "rice-water," contaminates water used by others, disease transmission may occur.[7] The source of the contamination is typically other cholera sufferers when their untreated diarrheal discharge is allowed to get into waterways or into groundwater or drinking water supplies. Drinking any infected water and eating any foods washed in the water, as well as shellfish living in the affected waterway, can cause a person to contract an infection. Cholera is rarely spread directly from person to person. Both toxic and nontoxic strains exist. Nontoxic strains can acquire toxicity through a temperate bacteriophage.[8] Coastal cholera outbreaks typically followzooplankton blooms, thus making cholera a zoonotic disease.

[edit]Mechanism

Most bacteria, when consumed, do not survive the acidic conditions of the human stomach.[9] The few bacteria that do survive conserve theirenergy and stored nutrients during the passage through the stomach by shutting down much protein production. When the surviving bacteria exit the stomach and reach the small intestine, they need to propel themselves through the thick mucus that lines the small intestine to get to the intestinal walls, where they can thrive. V. cholerae bacteria start up production of the hollow cylindrical protein flagellin to make flagella, the cork-screw helical fibers they rotate to propel themselves through the mucus of the small intestine.
Once the cholera bacteria reach the intestinal wall, they no longer need the flagella propellers to move. The bacteria stop producing the protein flagellin, thus again conserving energy and nutrients by changing the mix of proteins which they manufacture in response to the changed chemical surroundings. On reaching the intestinal wall, V. cholerae start producing the toxic proteins that give the infected person a watery diarrhea. This carries the multiplying new generations of V. cholerae bacteria out into the drinking water of the next host if proper sanitation measures are not in place.
The cholera toxin (CTX or CT) is an oligomeric complex made up of six protein subunits: a single copy of the A subunit (part A), and five copies of the B subunit (part B), connected by a disulfide bond. The five B subunits form a five-membered ring that binds to GM1 gangliosideson the surface of the intestinal epithelium cells. The A1 portion of the A subunit is an enzyme that ADP-ribosylates G proteins, while the A2 chain fits into the central pore of the B subunit ring. Upon binding, the complex is taken into the cell via receptor-mediated endocytosis. Once inside the cell, the disulfide bond is reduced, and the A1 subunit is freed to bind with a human partner protein called ADP-ribosylation factor 6(Arf6).[10] Binding exposes its active site, allowing it to permanently ribosylate the Gs alpha subunit of the heterotrimeric G protein. This results in constitutive cAMP production, which in turn leads to secretion of H2O, Na+, K+, Cl−, and HCO3− into the lumen of the small intestine and rapid dehydration. The gene encoding the cholera toxin is introduced into V. cholerae by horizontal gene transfer. Virulent strains of V. cholerae carry a variant of temperate bacteriophage called CTXf or CTXφ.
Microbiologists have studied the genetic mechanisms by which the V. cholerae bacteria turn off the production of some proteins and turn on the production of other proteins as they respond to the series of chemical environments they encounter, passing through the stomach, through the mucous layer of the small intestine, and on to the intestinal wall.[11] Of particular interest have been the genetic mechanisms by which cholera bacteria turn on the protein production of the toxins that interact with host cell mechanisms to pump chloride ions into the small intestine, creating an ionic pressure which prevents sodium ions from entering the cell. The chloride and sodium ions create a salt-water environment in the small intestines, which through osmosis can pull up to six liters of water per day through the intestinal cells, creating the massive amounts of diarrhea. The host can become rapidly dehydrated if an appropriate mixture of dilute salt water and sugar is not taken to replace the blood's water and salts lost in the diarrhea.
By inserting separate, successive sections of V. cholerae DNA into the DNA of other bacteria, such as E. coli that would not naturally produce the protein toxins, researchers have investigated the mechanisms by which V. cholerae responds to the changing chemical environments of the stomach, mucous layers, and intestinal wall. Researchers have discovered there is a complex cascade of regulatory proteins that control expression of V. cholerae virulence determinants. In responding to the chemical environment at the intestinal wall, the V. cholerae bacteria produce the TcpP/TcpH proteins, which, together with the ToxR/ToxS proteins, activate the expression of the ToxT regulatory protein. ToxT then directly activates expression of virulence genes that produce the toxins, causing diarrhea in the infected person and allowing the bacteria to colonize the intestine.[11] Current research aims at discovering "the signal that makes the cholera bacteria stop swimming and start to colonize (that is, adhere to the cells of) the small intestine."[11]

[edit]Genetic structure

Amplified fragment length polymorphism (AFLP) fingerprinting of the pandemic isolates of Vibrio cholerae has revealed variation in the genetic structure. Two clusters have been identified: Cluster I and Cluster II. For the most part, Cluster I consists of strains from the 1960s and 1970s, while Cluster II largely contains strains from the 1980s and 1990s, based on the change in the clone structure. This grouping of strains is best seen in the strains from the African continent.[12]

[edit]Diagnosis

A rapid dip-stick test is available to determine the presence of V. cholerae.[4] In those that test positive, further testing should be done to determine antibiotic resistance.[4] In epidemic situations, a clinical diagnosis may be made by taking a history and doing a brief examination. Treatment is usually started without or before confirmation by laboratory analysis.
Stool and swab samples collected in the acute stage of the disease, before antibiotics have been administered, are the most useful specimens for laboratory diagnosis. If an epidemic of cholera is suspected, the most common causative agent is Vibrio cholerae O1. If V. cholerae serogroup O1 is not isolated, the laboratory should test for V. cholerae O139. However, if neither of these organisms is isolated, it is necessary to send stool specimens to a reference laboratory. Infection with V. cholerae O139 should be reported and handled in the same manner as that caused by V. cholerae O1. The associated diarrheal illness should be referred to as cholera and must be reported in the United States.[13]
A number of special media have been employed for the cultivation for cholera vibrios. They are classified as follows:

[edit]Enrichment media

  1. Alkaline peptone water at pH 8.6
  2. Monsur's taurocholate tellurite peptone water at pH 9.2

[edit]Plating media

  1. Alkaline bile salt agar (BSA): The colonies are very similar to those on nutrient agar.
  2. Monsur's gelatin Tauro cholate trypticase tellurite agar (GTTA) medium: Cholera vibrios produce small translucent colonies with a greyish black center.
  3. TCBS medium: This the mostly widely used medium; it contains thiosulphate, citrate, bile salts and sucrose. Cholera vibrios produce flat 2–3 mm in diameter, yellow nucleated colonies.
Direct microscopy of stool is not recommended, as it is unreliable. Microscopy is preferred only after enrichment, as this process reveals the characteristic motility of Vibrio and its inhibition by appropriate antisera. Diagnosis can be confirmed, as well, as serotyping done byagglutination with specific sera.

[edit]Prevention

Cholera hospital in Dhaka, showing typical cholera beds.
Although cholera may be life-threatening, prevention of the disease is normally straightforward if proper sanitation practices are followed. In developed countries, due to nearly universal advancedwater treatment and sanitation practices, cholera is no longer a major health threat. The last major outbreak of cholera in the United States occurred in 1910-1911.[14][15] Effective sanitation practices, if instituted and adhered to in time, are usually sufficient to stop an epidemic. There are several points along the cholera transmission path at which its spread may be halted:
  • Sterilization: Proper disposal and treatment of infected fecal waste water produced by cholera victims and all contaminated materials (e.g. clothing, bedding, etc.) is essential. All materials that come in contact with cholera patients should be sterilized by washing in hot water, usingchlorine bleach if possible. Hands that touch cholera patients or their clothing, bedding, etc., should be thoroughly cleaned and disinfected with chlorinated water or other effective antimicrobial agents.
  • Sewage: antibacterial treatment of general sewage by chlorine, ozone, ultraviolet light or other effective treatment before it enters the waterways or underground water supplies helps prevent undiagnosed patients from inadvertently spreading the disease.
  • Sources: Warnings about possible cholera contamination should be posted around contaminated water sources with directions on how to decontaminate the water (boiling, chlorination etc.) for possible use.
  • Water purification: All water used for drinking, washing, or cooking should be sterilized by either boiling, chlorination, ozone water treatment, ultraviolet light sterilization (e.g. by solar water disinfection), or antimicrobial filtration in any area where cholera may be present. Chlorination and boiling are often the least expensive and most effective means of halting transmission. Cloth filters, though very basic, have significantly reduced the occurrence of cholera when used in poor villages inBangladesh that rely on untreated surface water. Better antimicrobial filters, like those present in advanced individual water treatment hiking kits, are most effective. Public health education and adherence to appropriate sanitation practices are of primary importance to help prevent and control transmission of cholera and other diseases.

[edit]Surveillance

Surveillance and prompt reporting allow for containing cholera epidemics rapidly. Cholera exists as a seasonal disease in many endemic countries, occurring annually mostly during rainy seasons. Surveillance systems can provide early alerts to outbreaks, therefore leading to coordinated response and assist in preparation of preparedness plans. Efficient surveillance systems can also improve the risk assessment for potential cholera outbreaks. Understanding the seasonality and location of outbreaks provide guidance for improving cholera control activities for the most vulnerable.[16] For prevention to be effective it is important that cases are reported to national health authorities.[1]

[edit]Vaccine

A number of safe and effective oral vaccines for cholera are available.[3][17] Dukoral, an orally administered, inactivated whole cell vaccine, has an efficacy of 85%, with minimal side effects.[18] It is available in over 60 countries. However, it is not currently recommended by the Centers for Disease Control and Prevention (CDC) for most people traveling from the United States to the third world.[19] One injectable vaccine was found to be effective for two to three years. It must be noted that the protective efficacy was 28% lower in children less than 5 years old.[17]However, as of 2010, it has limited availability.[3] Work is under way to investigate the role of mass vaccination.[20] The World Health Organization (WHO) recommends immunization of high risk groups, such as children and people with HIV, in countries where this disease isendemic.[3] If people are immunized broadly, herd immunity results, with a decrease in the amount of contamination in the environment.[4]

[edit]Treatment

Cholera patient being treated by medical staff in 1992.

[edit]Fluids

In most cases, cholera can be successfully treated with oral rehydration therapy (ORT),which is highly effective, safe, and simple to administer.[4] Rice-based solutions are preferred to glucose-based ones due to greater efficiency.[4] In severe cases with significant dehydration, intravenousrehydration may be necessary. Ringer's lactate is the preferred solution.[1] Large volumes and continued replacement until diarrhea has subsided may be needed.[1] Ten percent of a person's body weight in fluid may need to be given in the first two to four hours.[1] This method was first tried on a mass scale during a war in Pakistan, and was found to have much success.[21]
If commercially produced oral rehydration solutions are too expensive or difficult to obtain, solutions can be made. One such recipe calls for 1 liter of boiled water, 1 teaspoon of salt, 8 teaspoons of sugar, and added mashed banana for potassium and to improve taste.[22]

[edit]Electrolytes

As there frequently is initially acidosis, the potassium level may be normal, even though large losses have occurred.[1] As the dehydration is corrected, potassium levels may decrease rapidly, and thus need to be replaced.[1]

[edit]Antibiotics

Antibiotic treatments for one to three days shorten the course of the disease and reduce the severity of the symptoms.[1] People will recover without them, however, if sufficient hydration is maintained.[4] Doxycycline is typically used first line, although some strains of V. choleraehave shown resistance.[1] Testing for resistance during an outbreak can help determine appropriate future choices.[1] Other antibiotics that have been proven effective include cotrimoxazole, erythromycin, tetracycline, chloramphenicol, and furazolidone.[23] Fluoroquinolones, such as norfloxacin, also may be used, but resistance has been reported.[24]
In many areas of the world, antibiotic resistance is increasing. In Bangladesh, for example, most cases are resistant to tetracycline,trimethoprim-sulfamethoxazole, and erythromycin.[4] Rapid diagnostic assay methods are available for the identification of multiple drug-resistant cases.[25] New generation antimicrobials have been discovered which are effective against in in vitro studies.[26]

[edit]Prognosis

If people with cholera are treated quickly and properly, the mortality rate is less than 1%; however, with untreated cholera, the mortality rate rises to 50–60%.[1][27] For certain genetic strains of cholera, such as the one present during the 2010 epidemic in Haiti and the 2004 outbreak in India, death can occur within two hours of the first sign of symptoms.[28]

[edit]Epidemiology

See also: Cholera outbreaks and pandemics
Hand bill from the New York City Board of Health, 1832. The outdated public health advice demonstrates the lack of understanding of the disease and its actual causative factors.
It is estimated that cholera affects 3-5 million people worldwide, and causes 100,000-130,000 deaths a year as of 2010.[3] This occurs mainly in the developing world.[29] In the early 1980s, death rates are believed to have been greater than 3 million a year.[1] It is difficult to calculate exact numbers of cases, as many go unreported due to concerns that an outbreak may have a negative impact on the tourism of a country.[4] Cholera remains both epidemic and endemic in many areas of the world.[1]
Although much is known about the mechanisms behind the spread of cholera, this has not led to a full understanding of what makes cholera outbreaks happen some places and not others. Lack of treatment of human feces and lack of treatment of drinking water greatly facilitate its spread, but bodies of water can serve as a reservoir, and seafood shipped long distances can spread the disease. Cholera was not known in the Americas for most of the 20th century, but it reappeared towards the end of that century and seems likely to persist.[30]

[edit]History

The word cholera is from Greek: χολέρα kholera from χολή kholē "bile". Cholera likely has its origins in the Indian subcontinent; it has been prevalent in the Ganges delta since ancient times.[1] The disease first spread by trade routes (land and sea) to Russia in 1817, then toWestern Europe, and from Europe to

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From Wikipedia, the free encyclopedia Jump to: navigation, search For other uses, see Dengue fever (disambiguation). Dengue fever Classification and external resources The typical rash seen in dengue fever ICD-10 A90. ICD-9 061 DiseasesDB 3564 MedlinePlus 001374 eMedicine med/528 MeSH C02.782.417.214 Dengue fever (UK: /ˈdɛŋɡeɪ/, US: /ˈdɛŋɡiː/), 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 morbilliform skin rash. In a small proportion of cases the disease develops to the life-threatening dengue hemorrhagic fever (bleeding, low levels of blood platelets and blood plasma leakage) and dengue shock syndrome (circulatory failure). Dengue is transmitted by several species of mosquito within the Aedes genus, 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 is believed to increase the risk of severe complications. As there is no 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 over the last 50 years, with around 50–100 million people infected yearly. Dengue is currently endemic in more than 110 countries. Early descriptions of the condition date from 1779, and its viral cause and the transmission were elucidated in the early 20th century. Dengue has become a worldwide problem since the Second World War. Contents [hide] 1 Signs and symptoms 1.1 Clinical course 1.2 Associated problems 2 Cause 2.1 Virology 2.2 Transmission 2.3 Predisposition 3 Mechanism 3.1 Viral reproduction 3.2 Severe disease 4 Diagnosis 4.1 General 4.2 Classification 4.3 Virology and serology 5 Prevention 6 Management 7 Epidemiology 8 History 8.1 Etymology 8.2 Discovery 9 Research 10 Notes 11 References 12 External links Signs and symptoms Schematic depiction of the symptoms of dengue fever People infected with dengue virus are commonly asymptomatic or only have mild symptoms such as an uncomplicated fever.[1][2] Others have more severe illness, and in a small proportion it is life-threatening.[1] The incubation period (time between exposure and onset of symptoms) ranges from 3–14 days, but most often it is 4–7 days.[3] This means that travellers returning from endemic areas are unlikely to have dengue if fever or other symptoms start more than 14 days after arriving home.[4] Children often experience symptoms similar to those of the common cold and gastroenteritis (vomiting and diarrhea),[5] but are more susceptible to the severe complications.[4] Clinical course The characteristic symptoms of dengue are: a sudden-onset fever, headache (typically behind the eyes), muscle and joint pains, and a rash. The alternative name for dengue, "break-bone fever", comes from the associated muscle and joints pains.[1][6] The course of infection is divided into three phases: febrile, critical, and recovery.[7] The febrile phase involves high fevers, frequently over 40 °C (104 °F) and is associated with generalized pain and a headache; this usually lasts two to seven days.[6][7] Flushed skin and some small red spots called petechiae, which are caused by broken capillaries, may occur at this point,[7] as may some mild bleeding from mucous membranes of the mouth and nose.[4][6] The critical phase, if it occurs, follows the resolution of the high fever and typically lasts one to two days.[7] 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.[7] During this phase, organ dysfunction and severe bleeding (typically from the gastrointestinal tract) may occur.[4][7] Shock and hemorrhage occur in less than 5% of all cases of dengue,[4] however those who have previously been infected with other serotypes of dengue virus ("secondary infection") have an increased risk.[4][8] The recovery phase occurs next, with resorption of the leaked fluid into the bloodstream.[7] This usually lasts two to three days.[4] The improvement is often striking, but there may be severe itching and a slow heart rate.[4][7] It is during this stage that a fluid overload state may occur, which if it affects the brain may reduce the level of consciousness or cause seizures.[4] Associated problems Dengue may occasionally affect several other body systems.[7] This may be either in isolation or along with the classic dengue symptoms.[5] A decreased level of consciousness occurs in 0.5–6% of severe cases. This may be caused by infection of the brain by the virus or indirectly due to impairment of vital organs, for example, the liver.[5][9] Other neurological disorders have been reported in the context of dengue, such as transverse myelitis and Guillain-Barré syndrome.[5] Infection of the heart and acute liver failure are among the rarer complications of dengue.[4][7] Cause Virology Main article: Dengue virus A TEM micrograph showing dengue virus virions (the cluster of dark dots near the center) Dengue fever virus (DENV) is an RNA virus of the family Flaviviridae; genus Flavivirus. Other members of the same family 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.[9] Most are transmitted by arthropods (mosquitoes or ticks), and are therefore also referred to as arboviruses (arthropod-borne viruses).[9] The dengue virus genome (genetic material) contains about 11,000 nucleotide bases, which code for the three different types of protein molecules that form the virus particle (C, prM and E) 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.[8][10] 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.[2] All four serotypes can cause the full spectrum of disease.[8] Infection with one serotype is believed to produce lifelong immunity to that serotype but only short term protection against the others.[2][6] The severe complications on secondary infection seem to occur particularly if someone previously exposed to serotype DENV-1 then contracts serotype DENV-2 or serotype DENV-3, or if someone previously exposed to type DENV-3 then acquires DENV-2.[10] Transmission The mosquito Aedes aegypti feeding off a human host 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).[2] They bite primarily during the day.[11] Other mosquito species—Aedes albopictus, A. polynesiensis and several A. scutellaris—may also transmit the disease.[2] Humans are the primary host of the virus,[2][9] but it may also circulate in nonhuman primates.[12] An infection may be acquired via a single bite.[13] A mosquito that takes a blood meal from a person infected with dengue fever 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 and tends to live in close proximity to humans, and prefers to feed off people rather than other vertebrates.[14] Dengue may also be transmitted via infected blood products and through organ donation.[15][16] In countries such as Singapore, where dengue is endemic, the risk is estimated to be between 1.6 and 6 per 10,000 transfusions.[17] Vertical transmission (from mother to child) during pregnancy or at birth has been observed.[13] Other person-to-person modes of transmission have been reported, but are very unusual.[6] 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.[4] Women are more at risk than men.[10] Dengue may be life-threatening in people with chronic diseases such as diabetes and asthma.[10] It is thought that polymorphisms (normal variations) in particular genes may increase the risk of severe dengue complications. Examples include the genes coding for the proteins known as TNFα, mannan-binding lectin,[1] CTLA4, TGFβ,[8] DC-SIGN, and particular forms of human leukocyte antigen.[10] A common genetic abnormality in Africans, known as glucose-6-phosphate dehydrogenase deficiency, appears to increase the risk.[18] Polymorphisms in the genes for the vitamin D receptor and FcγR seem to offer protection.[10] Mechanism When a mosquito carrying DENV bites a person, the virus enters the skin together with the mosquito's saliva. It binds to and enters white blood cells, and reproduces inside the cells while they move throughout the body. The white blood cells respond by producing a number of signalling proteins (such as interferon) that are responsible for many of the symptoms, such as the fever, the flu-like symptoms and the severe pains. In severe infection, the virus production inside the body is greatly increased, and many more organs (such as the liver and the bone marrow) can be affected, and fluid from the bloodstream leaks through the wall of small blood vessels into body cavities. As a result, less blood circulates in the blood vessels, and the blood pressure becomes so low that it cannot supply sufficient blood to vital organs. Furthermore, dysfunction of the bone marrow leads to reduced numbers of platelets, which are necessary for effective blood clotting; this increases the risk of bleeding, the other major complication of dengue.[18] Viral reproduction After entering the skin, DENV binds to Langerhans cells (a population of dendritic cells in the skin that identifies pathogens).[18] 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.[8] DC-SIGN, a non-specific receptor for foreign material on dendritic cells, seems to be the main one.[10] The dendritic cell moves to the nearest lymph node. Meanwhile, the virus genome is replicated in membrane-bound vesicles on the cell's endoplasmic reticulum, where the cell's protein synthesis apparatus produces new viral proteins, and the viral RNA is copied. Immature virus particles are transported to the Golgi apparatus, the part of the cell where the 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 exocytosis. They are then able enter other white blood cells (such as monocytes and macrophages).[8] The initial reaction of infected cells is to produce the 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 DENV appear to have mechanisms to slow down this process. Interferon also activates the adaptive immune system, which leads to the generation of antibodies against the virus as well as T cells that directly attack any cell infected with the virus.[8] Various antibodies are generated; some bind closely to the viral proteins and target them for phagocytosis (ingestion by specialized cells) and 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.[8] Severe disease Further information: Antibody-dependent enhancement It is not entirely clear why secondary infection with a different strain of DENV 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.[8][10] There is a suspicion that ADE is not the only mechanism underlying severe dengue-related complications,[1] and various lines of research have implied a role for T cells and soluble factors (such as cytokines and the complement system).[18] Severe disease is marked by two problems: dysfunction of endothelium (the cells that line blood vessels) and disordered blood clotting.[5] Endothelial dysfunction leads to the leakage of fluid from the blood vessels into the chest and abdominal cavities, while coagulation disorder is responsible for the bleeding complications. Higher levels of virus in the blood and involvement of other organs (such as the bone marrow and the liver) are associated with more severe disease. Cells in the affected organs die, leading to the release of cytokines and activation of both coagulation and fibrinolysis (the opposing systems of blood clotting and clot degradation). These alterations together lead to both endothelial dysfunction and coagulation disorder.[18] Diagnosis General Warning signs[19] Abdominal pain Ongoing vomiting Liver enlargement Mucosal bleeding High hematocrit with low platelets Lethargy The diagnosis of dengue is typically made clinically, on the basis of reported symptoms and physical examination; this applies especially in endemic areas.[1] Early disease can however be difficult to differentiate from other viral infections.[4] 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.[19] Warning signs typically occur before the onset of severe dengue.[7] The tourniquet test, which is particularly useful in settings where no laboratory investigations are readily available, involves the application of a blood pressure cuff for five minutes, followed by the counting of any petechial hemorrhages; a higher number makes a diagnosis of dengue more likely.[7] It may 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.[6] Often, investigations are performed to exclude other conditions that cause similar symptoms, such as malaria, leptospirosis, typhoid fever, and meningococcal disease.[4] 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.[4] In severe disease, plasma leakage may result in hemoconcentration (as indicated by a rising hematocrit) and hypoalbuminemia.[4] Pleural effusions or ascites may be detected by physical examination when large,[4] but the demonstration of fluid on ultrasound may assist in the early identification of dengue shock syndrome.[1][4] The use of ultrasound is limited by lack of availability in many settings.[1] Classification The World Health Organization's 2009 classification divides dengue fever into two groups: uncomplicated and severe.[1][19] This replaces the 1997 WHO classification, which needed to be simplified as it had been found to be too restrictive, but the older classification is still widely used.[19] The 1997 classification divided dengue into undifferentiated fever, dengue fever, and dengue hemorrhagic fever.[4][20] Dengue hemorrhagic fever was subdivided further into four grades (grade I–IV). Grade I is the presence only of easy bruising or a positive "tourniquet test" (see below) 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.[20] Grades III and IV are referred to as "dengue shock syndrome".[19][20] Virology and serology Dengue fever may also be diagnosed by microbiological laboratory testing.[19] This can be done by virus isolation in cell cultures, nucleic acid detection by PCR, viral antigen detection or specific antibodies (serology).[10][21] Virus isolation and nucleic acid detection are more accurate than antigen detection, but these tests are not widely available due to their greater cost.[21] All tests may be negative in the early stages of the disease.[4][10] Apart from serology, laboratory tests are only of diagnostic value during the acute phase of the illness. 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 secondary and tertiary infections. The 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 the 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. In the laboratory test the IgG and the IgM antibodies can cross-react with other flaviviruses, such as yellow fever virus, which can make the interpretation of the serology difficult.[6][10][22] The detection of IgG alone is not considered diagnostic unless blood samples are collected 14 days apart and a greater than fourfold increase in levels of specific IgG is detected. In a person with symptoms, the detection of IgM is considered diagnostic.[22] Prevention A 1920s photograph of efforts to disperse standing water and thus decrease mosquito populations There are currently no approved vaccines for the dengue virus.[1] Prevention thus depends on control of and protection from the bites of the mosquito that transmits it.[11][23] 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.[11] The primary method of controlling A. aegypti is by eliminating its habitats.[11] This may be done by emptying containers of water or by adding insecticides or biological control agents to these areas.[11] 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.[11] People may prevent mosquito bites by wearing clothing that fully covers the skin and/or the application of insect repellent (DEET being the most effective).[13] Management There are no specific treatments for the dengue fever virus.[1] Treatment depends on the symptoms, varying from oral rehydration therapy at home with close follow-up, to hospital admission with administration of intravenous fluids and/or blood transfusion.[24] A decision for hospital admission is typically based on the presence of the "warning signs" listed in the table above, especially in those with preexisting health conditions.[4] Intravenous hydration is usually only needed for one or two days.[24] The rate of fluid administration is titrated to a urinary output of 0.5–1 mL/kg/hr, stable vital signs and normalization of hematocrit.[4] Invasive medical procedures such as nasogastric intubation, intramuscular injections and arterial punctures are avoided, in view of the bleeding risk.[4] Acetaminophen may be used for fever and discomfort while NSAIDs such as ibuprofen and aspirin are avoided as they might aggravate the risk of bleeding.[24] Blood transfusion is initiated early in patients 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.[25] Packed red blood cells or whole blood are recommended, while platelets and fresh frozen plasma are usually not.[25] During the recovery phase intravenous fluids are discontinued to prevent a state of fluid overload.[4] If fluid overload occurs and vital signs are stable, stopping further fluid may be all that is needed.[25] If a person is outside of the critical phase, a loop diuretic such as furosemide may be used to eliminate excess fluid from the circulation.[25] Epidemiology See also: Dengue fever outbreaks Dengue distribution in 2006. Red: Epidemic dengue and Ae. aegypti Aqua: Just Ae. aegypti. Most people with dengue recover without any ongoing problems.[19] The mortality is 1–5% without treatment,[4] and less than 1% with adequate treatment.[19] Severe disease carries a mortality of 26%.[4] Dengue is believed to infect 50 to 100 million people worldwide a year with half a million life-threatening infections requiring hospitalization,[1] resulting in approximately 12,500–25,000 deaths.[5][26] The burden of disease from dengue is estimated to be similar to other childhood and tropical diseases, such as tuberculosis, at 1600 disability-adjusted life years per million population.[10] It is the most common viral disease transmitted by arthropods.[8] As a tropical disease it is deemed only second in importance to malaria.[4] It is endemic in more than 110 countries.[4] The World Health Organization counts dengue as one of sixteen neglected tropical diseases.[27] The incidence of dengue increased 30 fold between 1960 and 2010.[28] This increase is believed to be due to a combination of urbanization, population growth, increased international travel, and global warming.[1] The geographical distribution is around the equator with 70% of the total 2.5 billion people living in endemic areas from Asia and the Pacific.[28] In the United States, the rate of dengue infection among those who return from an endemic area with a fever is 2.9–8.0%,[13] and it is the second most common infection after malaria to be diagnosed in this group.[6] Until 2003, dengue was classified as a potential bioterrorism agent, but subsequent reports removed this classification as it was deemed too difficult to transfer and only caused hemorrhagic fever in a relatively small proportion of people.[29] History Etymology The origins of the word "dengue" are not clear, but one theory is that it is derived from the Swahili phrase Ka-dinga pepo, which describes the disease as being caused by an evil spirit.[30] The Swahili word dinga may possibly have its origin in the Spanish word dengue, meaning fastidious or careful, which would describe the gait of a person suffering the bone pain of dengue fever.[31] However, it is possible that the use of the Spanish word derived from the similar-sounding Swahili.[30] Slaves in the West Indies having contracted dengue were said to have the posture and gait of a dandy, and the disease was known as "dandy fever".[32][33] The term "break-bone fever" was first applied by physician and Founding Father Benjamin Rush, in a 1789 report of the 1780 epidemic in Philadelphia. In the report he uses primarily the more formal term "bilious remitting fever".[29][34] The term dengue fever came into general use only after 1828.[33] Other historical terms include "breakheart fever" and "la dengue".[33] Terms for severe disease include "infectious thrombocytopenic purpura" and "Philippine", "Thai", or "Singapore hemorrhagic fever".[33] Discovery The first record of a case of probable dengue fever is in a Chinese medical encyclopedia from the Jin Dynasty (265–420 AD) which referred to a "water poison" associated with flying insects.[30][35] There have been descriptions of epidemics in the 17th century, but the most plausible early reports of dengue epidemics are from 1779 and 1780, when an epidemic swept Asia, Africa and North America.[35] From that time until 1940, epidemics were infrequent.[35] In 1906, transmission by the Aedes mosquitoes was confirmed, and in 1907 dengue was the second disease (after yellow fever) that was shown to be caused by a virus.[36] Further investigations by John Burton Cleland and Joseph Franklin Siler completed the basic understanding of dengue transmission.[36] The marked rise of spread of dengue during and after the Second World War has been attributed to ecologic disruption. The same trends also led to the spread of different serotypes of the disease to different areas, and the emergence of dengue hemorrhagic fever, which was first reported in the Philippines in 1953. In the 1970s, it became a major cause of child mortality. Around the same time it emerged in the Pacific and the Americas.[35] Dengue hemorrhagic fever and dengue shock syndrome were first noted in Middle and Southern America in 1981, as DENV-2 was contracted by people who had previously been infected with DENV-1 several years earlier.[9] Research Current research efforts to prevent and treat dengue have included different means of vector control,[37] vaccine development, and antiviral drugs.[23] With regards to vector control, a number of novel methods have been used to reduce mosquito numbers with some success including the placement of the fish Poecilia reticulata or copepods in standing water to eat the mosquito larva.[37] There are ongoing programs working on a dengue vaccine to cover all four serotypes.[23] One of the concerns is that a vaccine may increase the risk of severe disease through antibody-dependent enhancement.[38] The ideal vaccine is safe, effective after one or two injections, covers all serotypes, does not contribute to ADE, is easily transported and stored, and is both affordable and cost-effective.[38] A number of vaccines are currently undergoing testing.[10][29][38] It is hoped that the first products will be commercially available by 2015.[23] Apart from attempts to control the spread of the Aedes mosquito and work to develop a vaccine against dengue, there are ongoing efforts to develop antiviral drugs that might be used to treat attacks of dengue fever and prevent severe complications.[39][40] Discovery of the structure of the viral proteins may aid the development of effective drugs.[40] There are several plausible targets. The first approach is inhibition of the viral RNA-dependent RNA polymerase (coded by NS5), which copies the viral genetic material, with nucleoside analogs. Secondly, it may be possible to develop specific inhibitors of the viral protease (coded by NS3), which splices viral proteins.[41] Finally, it may be possible to develop entry inhibitors, which stop the virus entering cells, or inhibitors of the 5' capping process, which is required for viral replication.[39] Notes ^ a b c d e f g h i j k l m Whitehorn J, Farrar J (2010). "Dengue". Br. Med. Bull. 95: 161–73. doi:10.1093/bmb/ldq019. PMID 20616106. ^ a b c d e f g WHO (2009), pp. 14–16 ^ Gubler (2010), p. 379 ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa Ranjit S, Kissoon N (July 2010). "Dengue hemorrhagic fever and shock syndromes". Pediatr. Crit. Care Med. 12 (1): 90–100. doi:10.1097/PCC.0b013e3181e911a7. PMID 20639791. ^ a b c d e f Varatharaj A (2010). "Encephalitis in the clinical spectrum of dengue infection". Neurol. India 58 (4): 585–91. doi:10.4103/0028-3886.68655. PMID 20739797. ^ a b c d e f g h Chen LH, Wilson ME (October 2010). "Dengue and chikungunya infections in travelers". Curr. Opin. Infect. Dis. 23 (5): 438–44. doi:10.1097/QCO.0b013e32833c1d16. PMID 20581669. ^ a b c d e f g h i j k l WHO (2009), pp. 25–27 ^ a b c d e f g h i j Rodenhuis-Zybert IA, Wilschut J, Smit JM (August 2010). "Dengue virus life cycle: viral and host factors modulating infectivity". Cell. Mol. Life Sci. 67 (16): 2773–86. doi:10.1007/s00018-010-0357-z. PMID 20372965. ^ a b c d e Gould EA, Solomon T (February 2008). "Pathogenic flaviviruses". The Lancet 371 (9611): 500–9. doi:10.1016/S0140-6736(08)60238-X. PMID 18262042. ^ a b c d e f g h i j k l m Guzman MG, Halstead SB, Artsob H, et al. (December 2010). "Dengue: a continuing global threat". Nat. Rev. Microbiol. 8 (12 Suppl): S7–S16. doi:10.1038/nrmicro2460. PMID 21079655. ^ a b c d e f WHO (2009), pp. 59–60 ^ "Vector-Borne Viral Infections". World Health Organization. Retrieved 17 January 2011. ^ a b c d Center for Disease Control and Prevention. "Chapter 5 – Dengue Fever (DF) and Dengue Hemorrhagic Fever (DHF)". 2010 Yellow Book. Retrieved 2010-12-23. ^ Gubler (2010), pp. 377–78 ^ Wilder-Smith A, Chen LH, Massad E, Wilson ME (January 2009). "Threat of dengue to blood safety in dengue-endemic countries". Emerg. Infect. Dis. 15 (1): 8–11. doi:10.3201/eid1501.071097. PMC 2660677. PMID 19116042. ^ Stramer SL, Hollinger FB, Katz LM, et al. (August 2009). "Emerging infectious disease agents and their potential threat to transfusion safety". Transfusion 49 Suppl 2: 1S–29S. doi:10.1111/j.1537-2995.2009.02279.x. PMID 19686562. ^ Teo D, Ng LC, Lam S (April 2009). "Is dengue a threat to the blood supply?". Transfus Med 19 (2): 66–77. doi:10.1111/j.1365-3148.2009.00916.x. PMC 2713854. PMID 19392949. ^ a b c d e Martina BE, Koraka P, Osterhaus AD (October 2009). "Dengue virus pathogenesis: an integrated view". Clin. Microbiol. Rev. 22 (4): 564–81. doi:10.1128/CMR.00035-09. PMC 2772360. PMID 19822889. ^ a b c d e f g h WHO (2009), pp. 10–11 ^ a b c WHO (1997). "Chapter 2: clinical diagnosis". Dengue haemorrhagic fever: diagnosis, treatment, prevention and control (2nd ed.). Geneva: World Health Organization.. pp. 12–23. ISBN 9241545003. ^ a b WHO (2009), pp. 90–95 ^ a b Gubler (2010), p. 380 ^ a b c d WHO (2009), p. 137 ^ a b c WHO (2009), pp. 32–37 ^ a b c d WHO (2009), pp. 40–43 ^ WHO media centre (March 2009). "Dengue and dengue haemorrhagic fever". World Health Organization. Retrieved 2010-12-27. ^ Neglected Tropical Diseases. "Diseases covered by NTD Department". World Health Organization. Retrieved 2010-12-27. ^ a b WHO (2009), p. 3 ^ a b c Barrett AD, Stanberry LR (2009). Vaccines for biodefense and emerging and neglected diseases. San Diego: Academic. pp. 287–323. ISBN 0-12-369408-6. ^ a b c Anonymous (2006). "Etymologia: dengue". Emerg. Infec. Dis. 12 (6): 893. ^ Harper D (2001). "Etymology: dengue". Online Etymology Dictionary. Retrieved 2008-10-05. ^ Anonymous (1998-06-15). "Definition of Dandy fever". MedicineNet.com. Retrieved 2010-12-25. ^ a b c d Halstead SB (2008). Dengue (Tropical Medicine: Science and Practice). River Edge, N.J: Imperial College Press. pp. 1–10. ISBN 1-84816-228-6. ^ Rush AB (1789). "An account of the bilious remitting fever, as it appeared in Philadelphia in the summer and autumn of the year 1780". Medical enquiries and observations. Philadelphia, Pa.: Prichard and Hall. pp. 104–117. ^ a b c d Gubler DJ (July 1998). "Dengue and dengue hemorrhagic fever". Clin. Microbiol. Rev. 11 (3): 480–96. PMC 88892. PMID 9665979. ^ a b Henchal EA, Putnak JR (October 1990). "The dengue viruses". Clin. Microbiol. Rev. 3 (4): 376–96. PMC 358169. PMID 2224837. ^ a b WHO (2009), p. 71 ^ a b c Webster DP, Farrar J, Rowland-Jones S (November 2009). "Progress towards a dengue vaccine". Lancet Infect Dis 9 (11): 678–87. doi:10.1016/S1473-3099(09)70254-3. PMID 19850226. ^ a b Sampath A, Padmanabhan R (January 2009). "Molecular targets for flavivirus drug discovery". Antiviral Res. 81 (1): 6–15. doi:10.1016/j.antiviral.2008.08.004. PMC 2647018. PMID 18796313. ^ a b Noble CG, Chen YL, Dong H, et al. (March 2010). "Strategies for development of Dengue virus inhibitors". Antiviral Res. 85 (3): 450–62. doi:10.1016/j.antiviral.2009.12.011. PMID 20060421. ^ Tomlinson SM, Malmstrom RD, Watowich SJ (June 2009). "New approaches to structure-based discovery of dengue protease inhibitors". Infectious Disorders Drug Targets 9 (3): 327–43. PMID 19519486. References Gubler DJ (2010). "Dengue viruses". In Mahy BWJ, Van Regenmortel MHV. Desk Encyclopedia of Human and Medical Virology. Boston: Academic Press. ISBN 0-12-375147-0. WHO (2009). Dengue Guidelines for Diagnosis, Treatment, Prevention and Control. World Health Organization. ISBN 9241547871. External links Find more about Dengue fever on Wikipedia's sister projects: Definitions from Wiktionary Images and media from Commons Learning resources from Wikiversity News stories from Wikinews Quotations from Wikiquote Source texts from Wikisource Textbooks from Wikibooks Dengue fever at the Open Directory Project "Dengue". WHO. Retrieved 2010-12-24. "Dengue". US Centers for Disease Control and Prevention. Retrieved 2010-12-24. "Dengue fever". UK Health Protection Agency. Retrieved 2010-12-24. [hide]v · d · eZoonotic viral diseases (A80–B34, 042–079) Arthropod/ (arbovirus) Mosquito Bunyaviridae Arbovirus encephalitis: La Crosse encephalitis (LCV) · California encephalitis (CEV) Viral hemorrhagic fever: Rift Valley fever (RVFV) Flaviviridae Arbovirus encephalitis: Japanese encephalitis (JEV) · Australian encephalitis (MVEV, KUNV) · St. Louis encephalitis (SLEV) · West Nile fever (WNV) Viral hemorrhagic fever: Dengue fever (DV) other: Yellow fever (YFV) · Zika fever Togaviridae Arbovirus encephalitis: Eastern equine encephalomyelitis (EEEV) · Western equine encephalomyelitis (WEEV) · Venezuelan equine encephalomyelitis (VEEV) other: Chikungunya (CV) · O'Nyong-nyong fever (OV) · Ross River fever (RRV) Tick Bunyaviridae Viral hemorrhagic fever: Crimean-Congo hemorrhagic fever (CCHFV) Flaviviridae Arbovirus encephalitis: Tick-borne encephalitis (TBEV) · Powassan encephalitis (PV) · Deer tick virus encephalitis (DTV) Viral hemorrhagic fever: Omsk hemorrhagic fever (OHFV) · Kyasanur forest disease (KFDV/Alkhurma virus)) · Langat virus (LGTV) Reoviridae Colorado tick fever (CTFV) Mammal Rodent (Robovirus) Arenaviridae Viral hemorrhagic fever: Lassa fever (LV) · Venezuelan hemorrhagic fever (Guanarito virus) · Argentine hemorrhagic fever (Junin virus) · Bolivian hemorrhagic fever (Machupo virus) · Lujo virus Bunyaviridae Puumala virus · Andes virus · Sin Nombre virus · Hantavirus (HV) Bat Filoviridae VHF: Ebola hemorrhagic fever · Marburg hemorrhagic fever Rhabdoviridae Australian bat lyssavirus · Mokola virus · Duvenhage virus · Lagos bat virus · Chandipura virus(sandfly) Bornaviridae Menangle · Henipavirus · Borna disease (Borna disease virus) Multiple Rhabdoviridae Rabies (RV) M: VIR virs(prot)/clss cutn/syst (hppv/hiva, infl/zost/zoon)/epon drugJ(dnaa, rnaa, rtva, vacc) Retrieved from "http://en.wikipedia.org/wiki/Dengue_fever"

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