Treating the Patient With Severe Dengue virus Infection

Dengue has been called the most important mosquito-transmitted viral disease in terms of morbidity and mortality. Dengue fever is a benign, acute febrile syndrome occurring in tropical regions. In a small proportion of cases, the virus causes increased vascular permeability that leads to a bleeding diathesis or disseminated intravascular coagulation (DIC) known as e

 hemorrhagic fever (DHF). Secondary infection by a different dengue virus serotype has been confirmed as an important risk factor for the development of DHF.

In 20-30% of DHF cases, the patient develops shock, known as the dengue shock syndrome (DSS).

Worldwide, children younger than 15 years make up 90% of DHF cases

 In the Americas, however, DHF occurs in adults and children.

Dengue fever is not contagious through person-to-person contact.

Complications

 

• Brain damage from prolonged shock or intracranial hemorrhage
• Myocarditis
• Encephalopathy
• Liver failure

Go to Dengue Infection, Pediatric Dengue, and Dermatologic Manifestations of Dengue for complete information on these topics.

Dengue medicines to be imported from India for dengue patients

 A special team of the Punjab Health Department is set to leave for India within the next few days to finalise matters with the neighbouring country’s authorities for importing medicines and chemicals to counter the dengue virus, 

On the instructions of Punjab Chief Minister Shahbaz Sharif, the health secretary contacted the Indian high commissioner and worked out a plan to go to India to ensure that the medicines are in accordance with the standards of the World Health Organization.

Machines which separate platelets from blood are also being imported from Germany, an official told The Express Tribune.

However, a member of the Special Emergency Committee, set up for eradication of dengue, said that there were no specific medicines for treating dengue virus, adding that anti-mosquito sprays and chemicals were being imported from India.

“Mosquitoes that carry the virus have become resistant to certain sprays. A spray of specific composition is effective against them which we are importing from India,” the member, who is also a doctor, said on condition of anonymity.

Additionally, an 11-member team of Sri Lankan experts, comprising epidemiologists and public health experts, will reach Lahore today to provide technical assistance to the Punjab government.

CM Shahbaz Sharif, while presiding over a meeting to review measures against dengue on Tuesday, said that a special committee comprising assembly members should negotiate for providing diagnostic facilities to dengue patients in private laboratories at reasonable charges. Sharif added that stern action will be taken against those involved in taking advantage of the outbreak through price hikes of mosquito repellants.

This Week in PLoS Medicine: Ghostwriting; Dengue & population density; Neonatal mortality

Six new articles published this week in PLoS Medicine, including the monthly editorial which coincides with the launch of the new Ghostwriting Collection.

The PLoS Medicine editors discuss new perspectives on ghostwriting and reflect on the suggested remedies put forth this month in the journal.

Wolf-Peter Schmidt and colleagues, studying 75,000 geo-referenced households in Vietnam during two dengue epidemics, report that human population densities typical of villages are most prone to dengue outbreaks; rural areas may contribute as much to dissemination of dengue fever as do cities.

Mikkel Oestergaard and colleagues develop annual estimates of neonatal mortality rates and neonatal deaths for 193 countries for 1990 to 2009, and provide forecasts into the future.

Linus Bengtsson and colleagues examine the use of mobile phone positioning data to monitor population movements during disasters and outbreaks, finding that reports on population movements can be generated within twelve hours of receiving data.

Peter Gething and Andrew Tatem discuss the potential impact of mobile phone positioning data on disaster response and highlight challenges that must be addressed if use of this technology is to develop.

In the final article in a 3-part series addressing the current challenges and opportunities for the development of Health Policy and Systems Research (HPSR),Sara Bennett and colleagues lay out an agenda for action moving forward.

Remember you can comment on, annotate and rate any PLoS Medicine article andsee the views, citations and other indications of impact of an article on that articles metrics tab.

Virology

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 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.^] 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. All four serotypes can cause the full spectrum of disease.^] Infection with one serotype is believed to produce lifelong immunity to that serotype but only short term protection against the others.\

The severe complications on secondary infection occurs 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.

Transmission

Dengue virus is primarily transmitted by Aedes mosquitoes, particularly A. aegypti.These mosquitoes usually live between the latitudes of 35° North and 35° South below an elevationof 1,000 metres (3,300 ft). They bite primarily during the day.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 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 aegyptiprefers to lay its eggs in artificial water containers, to live in close proximity to humans, and to feed off 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 10,000transfusions.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.

[edit]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

 Women are more at risk than men.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 as TNFα, mannan-binding lectin, CTLA4, TGFβ

 DC-SIGN, and particular forms of human leukocyte antigen. A common genetic abnormality in Africans, known as glucose-6-phosphate dehydrogenase deficiency, appears to increase the risk

 Polymorphisms in the genes for the vitamin D receptor and FcγR seem to offer protection against severe disease in secondary dengue infection.

[edit]Mechanism

When a mosquito carrying dengue virus 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 signaling proteins, such as interferon, which 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 fever

[edit]Viral reproduction

Once inside the skin, dengue virus binds to Langerhans cells (a population of dendritic cells 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 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 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 to enter other white blood cells, such as monocytes and 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 antibodies against 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 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.

Dengue virus is primarily transmitted by Aedes mosquitoes, particularly A. aegypti. These mosquitoes usually live between the latitudes of 35° North and 35° South below an elevationof 1,000 metres (3,300 ft). They bite primarily during the day. 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 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 aegyptiprefers to lay its eggs in artificial water containers, to live in close proximity to humans, and to feed off people rather than other vertebrates^]transfusion

Severe disease

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
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.

[edit]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.
Women are more at risk than men.
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 as TNFα, mannan-binding lectin,CTLA4, TGFβ,DC-SIGN, and particular forms of human leukocyte antigen
 A common genetic abnormality in Africans, known as glucose-6-phosphate dehydrogenase deficiency, appears to increase the risk.
Polymorphisms in the genes for the vitamin D receptor and FcγR seem to offer protection against severe disease in secondary dengue infection.

[edit]Mechanism

When a mosquito carrying dengue virus 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 signaling proteins, such as interferon, which 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 fever.

[edit]Viral reproduction

Once inside the skin, dengue virus binds to Langerhans cells (a population of dendritic cells 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 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 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 to enter other white blood cells, such as monocytes and 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 antibodies against 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 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.

 

[edit]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 two problems: dysfunction of endothelium (the cells that line blood vessels) and disordered blood clotting.
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 viral load 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.^[

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 two problems: dysfunction of endothelium (the cells that line blood vessels) and disordered blood clotting. 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 viral load 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.^[