Dengue fever

Dengue fever (UK /ˈdɛŋɡeɪ/ or 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 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. 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 global problem since the Second World War and is endemic in more than 110 countries. Apart from eliminating the mosquitoes, work is ongoing on a vaccine, as well as medication targeted directly at the virus.

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).^[12]

 

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.^[2] The distinctions between the serotypes is based on the their antigenicity

 

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 typically bite during the day, particularly in the early morning and in the evening,^[16][17] but they are able to bite and thus spread infection at any time of day all during the year.^[18] Other Aedes species that transmit the disease include A. albopictus, A. polynesiensis and A. scutellaris.^[2] Humans are the primary host of the virus,^[2][12] but it also circulates in nonhuman primates.^[19] An infection can be acquired via a single bite.^[20] 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.^[21] 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.^[22]

 

Dengue can also be transmitted via infected blood products and through organ donation.^[23][24] In countries such as Singapore, where dengue is endemic, the risk is estimated to be between 1.6 and 6 per 10,000 transfusions.^[25] Vertical transmission (from mother to child) during pregnancy or at birth has been reported.^[26] Other person-to-person modes of transmission have also been reported, but are very unusual.^[9] 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.^[7]

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.^[5] Other risk factors for severe disease include female sex, high body mass index,^[7] and viral load.^[27] While each serotype can cause the full spectrum of disease,^[13] virus strain is a risk factor.^[7] Infection with one serotype is thought to produce lifelong immunity to that type, but only short term protection against the other three.^[2][9] 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.^[14] Dengue can be life-threatening in people with chronic diseases such as diabetes and asthma.^[14]

 

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,^[1] CTLA4, TGFβ,^[13] DC-SIGN, PLCE1, and particular forms of human leukocyte antigen from gene variations of HLA-B.^[7][14] A common genetic abnormality in Africans, known as glucose-6-phosphate dehydrogenase deficiency, appears to increase the risk.^[27] Polymorphisms in the genes for the vitamin D receptor and FcγR seem to offer protection against severe disease in secondary dengue infection.^[14]

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 cytokines and interferons, 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. Fluid from the bloodstream leaks through the wall of small blood vessels into body cavities due to capillary permeability. 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 due to infection of the stromal cells 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.^[27]

Viral replication

Once inside the skin, dengue virus binds to Langerhans cells (a population of dendritic cells in the skin that identifies pathogens).^[27] 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.^[13] DC-SIGN, a non-specific receptor for foreign material on dendritic cells, seems to be the main point of entry.^[14] 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 exocytosis. They are then able to enter other white blood cells, such as monocytes and macrophages.^[13]

 

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.^[13] 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.^[13]

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.^[13][14] 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.^[27]

 

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.^[6][7] These changes appear associated with a disordered state of the endothelial glycocalyx, which acts as a molecular filter of blood components.^[7] 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.^[27]

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.^[5] 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.^[28] Warning signs typically occur before the onset of severe dengue.^[8] 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).^[8][29][30]

The diagnosis should be considered in anyone who develops a fever within two weeks of being in the tropics or subtropics.^[7] 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.^[9] 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.^[5][31]

 

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.^[7] In severe disease, plasma leakage results in hemoconcentration (as indicated by a rising hematocrit) and hypoalbuminemia.^[5] Pleural effusions or ascites can be detected by physical examination when large,^[5] but the demonstration of fluid on ultrasound may assist in the early identification of dengue shock syndrome.^[1][5] The use of ultrasound is limited by lack of availability in many settings.^[1] Dengue shock syndrome is present if pulse pressure drops to ≤ 20 mm Hg along with peripheral vascular collapse.^[7] Peripheral vascular collapse is determined in children via delayed capillary refill, rapid heart rate, or cold extremities.^[8]

Classification

The World Health Organization's 2009 classification divides dengue fever into two groups: uncomplicated and severe.^[1][28] This replaces the 1997 WHO classification, which needed to be simplified as it had been found to be too restrictive, though the older classification is still widely used^[28] including by the World Health Organization's Regional Office for South-East Asia as of 2011.^[32] Severe dengue is defined as that associated with severe bleeding, severe organ dysfunction, or severe plasma leakage while all other cases are uncomplicated.^[28] The 1997 classification divided dengue into undifferentiated fever, dengue fever, and dengue hemorrhagic fever.^[5][33] 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.^[33] Grades III and IV are referred to as "dengue shock syndrome".^[28][33]

There are 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.^[16][37] The World Health Organization recommends an Integrated Vector Control program consisting of five elements:^[16]

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.^[16] This is done by emptying containers of water or by adding insecticides or biological control agents to these areas,^[16] 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.^[16] 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).^[20]

Management

There are no specific antiviral drugs for dengue, however maintaining proper fluid balance is important.^[7] 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.^[38] 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.^[5]

 

Intravenous hydration is usually only needed for one or two days.^[38] 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.^[5] Invasive medical procedures such as nasogastric intubation, intramuscular injections and arterial punctures are avoided, in view of the bleeding risk.^[5] Paracetamol (acetaminophen) is used for fever and discomfort while NSAIDs such as ibuprofen and aspirin are avoided as they might aggravate the risk of bleeding.^[38] 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.^[39] Packed red blood cells or whole blood are recommended, while platelets and fresh frozen plasma are usually not.^[39]

 

During the recovery phase intravenous fluids are discontinued to prevent a state of fluid overload.^[5] If fluid overload occurs and vital signs are stable, stopping further fluid may be all that is needed.^[39] 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.^[39].^[15]