Dengue fever is a disease that is triggered by a virus (DENV) and there are different serotypes related viruses (DENV-1, DENV-2, DENV-3, DENV-4) (Byron et al., 2009; Whitehorn et al., 2011). However they have 60-80% homology The virus belongs to the flaviviridae family genus and the flavivirus which is an aborvirus that is arthropod borne (Roach, 2002; Byron et al., 2009). Severity of dengue fever can progress to Dengue Haemorrhagic Fever (DHF) or Dengue Shock Syndrome (DSS) (Byron et al., 2009). It is an icosahedral virus that has an enveloped single stranded, positive sense genome (Byron et al., 2009; Whitethorn et al., 2011).
Figure 1. Dengue virus evoluntary tree (Hesse, 2007)
Transmission of Dengue virus
The virus is transmitted through a biological vector to human bloodstream from mosquito bites. The arthropod vector is Aedes mosquito mainly Aedes aegypti that is common in tropic or subtropics regions (Byron et al., 2009). Aedes albopictu is another mosquito vector. The mosquito that has acquired the virus can transmit it to uninfected human for the rest of its life (). Human being are the reservoir for the virus, mosquito bite an infected human to obtain the virus which it will transmit to another human being who will now become a carrier () Another reservoir is monkey in the DENV virus sylvatic cycle. The virus is found in the mosquitoes salivary gland and can also be transmitted from adult mosquito to its egg making it preserving the virus from season to season (Rolland, 1995)
Figure 1. Transmission cycles of dengue virus (Byron et al., 2009)
Symptoms and Clinical features of dengue fever
Infection by DENV maybe asymptomatic or show a wide range of clinical symptoms (Byron et al., 2009). Symptom are more severe in children below 15 years than in adults (Byron et al., 2009; Carlos et al., 2005). Dengue fever initiate with a high fever whereby the body temperature increases up to (104-105) Fahrenheit within 4-5 day from infection (Guzman et al., 2002). After 2-5 days of fever a red rash might appear followed by a second severe rash again that looks like measles accompanied by increase skin sensitivity and discomfort (Harris et al., 2000). Other symptoms are fatigue, muscle ache, joint ache, vomiting, Nausea, swollen lymph nodes, headache especially on the area behind the eyes, nasal stiffness, sore throat, coughing, retro-orbital pain, arthralgia, myalgia and gastrointestinal pain ( Byron et al., 2009; Guilarde et al., 2008). Leukopenia is common while thrombocytopenia is occasional, likely in patients with haemorrhagic signs like petechiae, gingival bleeding and epistaxis (Guilarde et al., 2008; Kittigul et al., 2008)
Pathogenesis of the Dengue virus (DENV)
Lack of animal models results to lack of knowledge of the actual pathogenesis of the virus but it anticipated it is multifactorial (Bryon, 2009).Dengue fever virus have four serotypes (homology of surface antigen) which make it hard for the immune system to combat and this is the basis of it virulence(Ross, 2010; Limon et al., 2005). Host genetics and background, viral genetics and host immune status determines the pathogenesis and how the immune system reacts (Sierra et al., 2007; Quinlivan, 2007; Tanaka and Mizokami, 2007; Byron et al., 2009). Once the virus access the body system through the skin epidermis Langerhans and keratinocytes cells are initially infected. However the immune system responds by producing antibodies that stick structural protein while inactivating the virus and hindering macrophage infection by the virus. At this point primary infection occurs which is the dengue fever. However antibody adherence does not inactivate the virus, viral replication occurs by attaching to the cell surface entry inside the cell cytoplasm and translation of viral proteins (Rothman, 2010; Byron et al., 2009). Subsequently the virus enters the blood stream and results ( primary viremia) where it will attach various tissue macrophages in various organs likely macrophages within the spleen (Bracken, 2005; Byron et al., 2009). As the virus replication expands to macrophages, monocytes, liver cells, bone marrow, the viral load of DENV increases (Chang et al., 2002; Burke and Kliks, 2006). Viral replication efficiency determines the viral load which can be measure in blood to determine the severity of the infection (Hesse, 2000; Halstead, 2003; Green and Rothman, 2006; Byron, 2009). Infected cells die through apoptosis and to some extend by necrosis (Byron et al., 2009; Chakravarti et al., 2006). Necrosis causes release of toxins which triggers coagulation and fibrinolytic systems. Based on bone marrow stromal severity of infection, IL-6, IL-8, IL-10, and IL-18 levels hemopiosis is inhibited reducing blood thrombogenicity (Byron et al., 2009; Chao et al., 2009). Viral load and viral tropism will increase resulting to severe thrombocytopenia and platelet dysfunction which cause capillary fragility, easy bruising and also gastrointestinal mucosal bleeding which are features of DHF while the infection triggers development of specific antibody and cellular immune response against DENV (Nachman, 2008; Chang et al., 2002). Ig antibodies bind to the virus during secondary infection thereby eliciting the infection by increasing the viral load (Nachman, 2008; Byron et al., 2009) If another different serotype invades the body, the immune system combats it the same way as it did previously due to minor difference present within various serotypes (Bryon, 2009; Huerre et al., 2001). Moreso, the dengue viruses have M proteins that assist in apoptosis of their target cell. Furthermore upon macrophage invasion, DENV, it triggers the pro-inflammatory cytokines release as well as other mediators by antigen presenting cells, cross reactive T-cells of low and high avidity, HLA and endothelial cells of the immune system which compromise abnormal homeostasis and tissue permeability (Byron et al., 2009; Carlos et al., 2005). This slows down virus elimination and can cause a more severe secondary infection, such as DHF or DSS (Byron et al., 2009).
Figure 2 Proposed pathogenicity of dengue virus (Byron et al., 2009).
Diagnosis of dengue fever
Dengue fever is diagnosed based on the clinical symptoms. Test and examination to identify the DENV can be done through antibody titre of the DENV (Jesse et al., 2004; Hesse, 2007). Another method is by doing a white blood cell count which is very low in infected patient (Jesse et al., 2004; Hesse, 2007; Ross 2010).Blood test to detect DENV via serology and ELISA to identify IGM antibodies (Hesse, 2007; Byron et al., 2009; Whitehorn et al., 2011). Carrying out a liver function test (ALT and AST) which is elevated in infected individuals (Byron et al., 2009).
Further laboratory tests like polymerase chain reaction can be done for the virus types, specifically RT-PCR which identify viral RNA in patient samples (blood,liver,CFS) and can be modified to quantitative RT-PRC or using a Taqman probe when dealing with small quantities Of RNA (Hesse, 2007; Ross, 2010). Immunohistochemistry using antidengue monoclonal antibodies to identify viral RNA (Jesse et al., 2004)
Can be done by shielding away from the Aedes mosquitoe and also reducing the mosquito population by covering the body through clothing to reduce chances of mosquito bites. Mosquitoe nets can be used (Argawal et al., 1998; Byron et al., 2009). Moreso travelling in times or to areas where mosquitoes are absent (An et al., 2004).Usage of mosquitoe repellents is also essential. In high risk areas, hose opening should be closed (windows, doors etc.) (Byron et al., 2004). Eliminating water stagnant by covering them as well as putting insecticides can kill the mosquitoe (Argawal et al., 1998; Byron et al., 2009). Moreso still water collecting containers like drums, flowerpots buckets should be eliminated (Byron et al., 2009) furthermore the World Health Organisation have made efforts to enforce correct disposal of these items via chemical methods and environmental management (World Health Organisation Media Centre, 2002; Argawal et al., 1998; Byron et al., 2009). Improving community dengue virus vector control programs and moreso monitoring and surveillance should be done in order to determine the control measures effectiveness (World Health Organisation Media Centre, 2002)
Currently there is no vaccine against the dengue fever virus but there is ongoing research to develop vaccine against the virus (Byron et al., 2009). One promising vaccine been worked on is a live attenuated virus vaccine named West Nile virus, which is measles based virus to eradicate dengue (World Health Organisation Media Centre, 2002). This vaccine have been used in Thailand although there is no evidence that it can combat all four serotypes of dengue in order to avoid complications of dengue fever (DHF and DSS) (Argawal et al., 1998; Byron et al., 2009; World Health Organisation Media Centre, 2002).
Treatment for dengue virus is not specific, to care for symptoms like dehydration, the patient must rest and consume copious amount of fluids, intravenous electrolytes is given to compensate the dehydration (Jesse et al., 2004; Hesse, 2007). For high fever, joint pain and headache antipyretic drugs like Acetaminophen (Tylenol) and codeine should be administered (Jesse et al., 2004; Hesse, 2007; Byron et al., 2009). Moreso drugs such as corticosteroids or carbazochrome sodium sulfonate are administered in order to inhibit the increase capillary permeability as well as stopping plasma leakage (Byron et al., 2009). Asprin and non-steroidal should be administered under doctor supervision for anti- inflammatory purposes (Byron et al., 2009). Treatment can reduce the mortality rate from 20% to 1% (Jesse et al., 2004; Hesse, 2007; Byron et al., 2009).
Dengue fever has re-emerged since 20 years ago accompanied by an expansion in geographic distribution thereby increasing the epidemic, moreso with the upcome of hyperendemicity (Debarati and Schimmer, 2005). An estimation by the World Health Organisation of about 2.5 billion people are affected by the dengue virus each year. World Health Organisation estimated, that yearly there are 50-100 million cases per year with more than 500 000 cases of hospital admission with 15,00 deaths (World Health Organisation, 2002; Debarati and Schimmer, 2005 ). Dengue fever endemic has increase from 9 countries in 1970 to 100 countries currently (Debarati and Schimmer, 2005; World Health Organisation, 2002 ). The first dengue fever epidemics occurred in 1779-1780 in continents like Africa, Asia and South America (). Recently in 1998, there was a pandemic in United States resulting to less than 1% fatality rate. The mortality rate ranges from 1-10 % (Debarati and Schimmer, 2005; Byron et al., 2009). Increasing expansion of the disease all over the world is due to increase in population as well as lack of vector control programs (Gubler et al., 2004; Hesse, 2000). However due to control and preventive measures the number of cases is increasing from travellers who are carrying the virus from high risk areas such as sub-tropical and tropical region (Byron et al., 2009).
Figure 3. Global epidemiology of Dengue virus (LaRive, 2008).
Global cases and outbreaks of dengue fever
In Venezuela, 2007 there was an outbreak of 80,000 dengue fever cases in which 6,000 persisted to DHF. In the same year above 890,000 cases were reported in America of which 26,000 persisted to DHF the route of transmission being endemic and from travellers ( Byron et al., 2009; World Health Organisation Media Centre, 2002). Most recent outbreak occurred in 2005 in Brownsville Texas with 25 reported cases and 16 DHF (Whitethorn et al., 2011) The virus was also transmitted to neighbouring state Tamaulipas where there was 1251 case reported in which 223 had DHF (Bebarati and Schimmer, 2005; Whitehorn et al., 2011).