Research Article

Dengue Fever: Causes, Prevention and Recent Advances  

Anum Jaweria1 , Fatima Naeem1 , Momna Malik1 , Faqeeha Javaid1 , Qurban Ali1 , Shahbaz  Ahmad2 , Muhammad Fahad Khan1 , Idrees Ahmad Nasir1
1 Centre of Excellence in Molecular Biology, University of the Punjab, Lahore Pakistan
2 Institute of Agricultural Sciences, University of the Punjab, Lahore, 54590 Pakistan
Author    Correspondence author
Journal of Mosquito Research, 2016, Vol. 6, No. 29   doi: 10.5376/jmr.2016.06.0029
Received: 11 Aug., 2016    Accepted: 17 Aug., 2016    Published: 17 Nov., 2016
© 2016 BioPublisher Publishing Platform
This is an open access article published under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Preferred citation for this article:

Jaweria A., Naeem F., Malik M., Javaid F., Ali Q., Ahmad S., Khan M.F., and Nasir I.A., 2016, Dengue Fever: causes, prevention and recent advances, Journal of Mosquito Research, 6(29): 1-9 (doi: 10.5376/jmr.2016.06.0029)


Dengue virus (DENV) is the most prevailing arthropod borne pathogen. Its four serotypes are present in tropical regions. It affects about 50 to 100 million population annually. Infection proceeds into Dengue shock syndrome and Dengue hemophilic fever which are more dangerous than dengue fever. Diagnosis and treatment is needed to be done on time to lessen the harmful effects. In this review we will discuss viral structure, life cycle of Dengue virus, its diagnosis, and its prevention and about the recent advances on Dengue research.

Dengue virus; Hemophilic fever; Diagnosis; Syndrome; Viral structure; Recent advances

1 Introduction

Dengue virus (DENV) causes a deadly disease Dengue fever which is transmitted by a vector mosquito. Sig and symptoms well-suited to dengue were published before centuries by Chin Dynasty (265-420AD). First time it was reported by Graham that vector for dengue is an arthropod Culex quinquefasciatus (Rigau-Perez et al., 1998). It was supported by few researchers as Ashburg but Australian researchers contrarily proposed that A. aegypti is the major vector (Ashburn et al., 2004; Ahmed et al., 2013). Before World War II a lot of studies were conducted to comprehend the basics of dengue virus such as mode of transmission and pathogenesis etc. Disease was obviously expanded because of socioeconomic burden being imposed by WW11. As troops traveled and utilized modern facilities for transportation inland and within different countries epidemic became distant reaching. Overcrowding of population lead to increased transmission rate and emergence of multiple severely pathogenic serotypes (Gubler, 2011). First case recorded as probable dengue fever was found in medical information bank of china, in 992 AD termed as ʻʻwater poison” thought to be transmitted by flying insects (Gubler, 2006; Yaqoob et al., 2015; Tahir et al., 2016). Disease was named and acknowledged in 19th century. First Dengue epidemic was reported in 1970S that appeared side by side in Asia, Africa and America. Up to our knowledge first incorrigible case was reported in 1789 and the term “break bone fever” was coined by Benjamin Rush regarding to its symptoms such as severe bone pain and skin rash. Later in 20th century it was recognized that it is a viral disease and transmitted by mosquito (Jayaratne et al., 2012; Nazir et al., 2014; Rasheed et al., 2014; Javed et al., 2015). It is reported that Origin of prime mosquito vector A. aegypti, was from Africa or Asia.


2 Materials and Methods

2.1 Causes

Dengue fever is caused by one of four closely associated dengue viruses (DENV1-DENV4) all of these belong to flavivirdae family and Flavivirus genus. These viruses’ possess close similarity to West Nile infection virus and yellow fever virus.


2.2 Transmission

Infected mosquito usually Aedes aegypti and A. Albopictus varieties with virus in its blood will bite man leading to dengue fever and other serious manifestations of the disease (Skinner, 2013). A. Albopictus feed upon multiple hosts however it is still a vector for transmission of dengue (Abdallah et al., 2012) These mosquitoes are found in the stagnant water pools nearby the populated area where they breed and bite in day time, early hours in the morning and in the evening before sunset (Brady et al., 2012) Most cases seen are usually the people residing  tropical or subtropical regions and along the shores such as Texas-Mexico border (Guzman and Kouri, 2002). By now about 50% of population is living in dengue endemic areas. It has been reported that dengue is now became endemic in 125 countries (Murray et al., 2013). Transfer of dengue virus from human to mosquito takes place when mosquito bites a person suffering from virus (DENV). It attaches and enters the gut epithelium where it replicates. New progeny of virus shed in hemocoel, infection spread to other parts such as salivary gland. From here it is transmitted to another host upon feeding or probing. There are certain factors affecting for this rapid spread of the dengue virus such as increased travel of individuals from endemic areas to those free from dengue (La Ruche et al., 2010), overcrowding, temperature; a direct relationship is found between environmental temperature and number of mosquitos infected (Watts et al., 1987), titer of DENV2 in the blood meal; there is also an evidence of direct relationship between titer and number of Aedes aegypti with infected midgut (Nguyet et al., 2013), competence of dengue strains; Aedes Albopictus more sensitive being infected as compared to Aedes aegypti but the later disseminate the virus readily to all organs so possess a high potential regarding to spread in nature (Scott and Morrison, 2010), human infectiousness; human are infectious to the mosquito about one and half day before onset of symptoms and 5 days after the appearance of sign and symptoms (Cleland and Bradley, 1918).


2.3 Replication of Dengue virus

Dengue virus (DENV) belongs to Flaviviridae family of positive strand enveloped RNA virus. Three structural proteins are present in mature virion:

(1) Capsid protein C. (2) Membrane protein M. (3) Envelope protein E


C protein forms viral nucleocapsid. Lipid bilayer is present around the nucleocapsid, in which E and M proteins are anchored (180 copies). DENV is icosahedral and having spherical nucleocapsid. E is present in the form of homodimers, arranged as three parallel head to tail configuration. Monomers of E play important role in infectious stages of dengue virus (Mukhopadhyay et al., 2005).


2.4 Replication and assembly of dengue virus particles

When virus enters into the cell uncoating of nucleocapsid starts, the RNA is translated as single polyprotein (Clyde et al., 2006). Then signal transfer sequences of polyprotein starts it’s back & forth translocation across the (ER) membrane. Polyprotein processed translationally by viral and cellular proteases into protein (C, E and prM) and other non-structural proteins like (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NSS). Glycosylation of E protein occur at Asn153 and Asn67 residue for proper protein folding (Bryant et al., 2007). After protein folding and translation, non-structural proteins start viral replication. RNA is newly synthesized packed by C protein and form nucleocapsid. Then heterodimers are formed by prM and E, which convert into trimer, these interactions induce a surface lattice, which is responsible for virion budding (Kuhn et al., 2002). 180 prM/E present in virion in heterodimer form which projects outward in the form of trimeric 60 spikes. Immature particles when move through secretory pathway in ER becomes mature. Acidic pH of Golgi network dissociates heterodimer of prM/E which then form dimer. This enables endoprotease Furin to destroy prM. Cleavage by Furin causes generation of ‘Pr’ and ‘M’ peptide (Zybert et al., 2008). Pr and M peptide act as chaperons that stabilize E protein when transit by secretory pathway and prevent it from premature fusion. Pr peptide dissociation enables mature virion formation which has capacity to infect cells.


2.5 Interaction with receptors & viral entry

When natural infection occurs, monocytes, dendritic cells and macrophages are the primary targets of Dengue virus infection (Jessie et al., 2004). Dengue virus infects the midgut initially from where it replicates and spread to other body organs and compartments.


Many studies showed that Dengue virus uses multiple receptors to enter the cell. Dengue virus uses Clathrin endocytosis method to enter the cell.


For internalization, Dengue virus uses different approaches e.g. single particle approach and alternative approach which is independent of lipid rafts, caveolae and clathrin (Acosta et al., 2009).


2.6 Membrane fusion of Dengue virus

Acidic pH of endosomes stimulates the dissociation of homodimers of E which causes the exposure of hydrophobic peptide and the projection of domain II outwardly with target membrane (Stiasny et al., 2002). Then fusion loop insert its hydrophobic residues into the target membrane which trigger E trimers assembly. Then domain III shift and folded back to fusion peptide and forms hair like conformation. This mechanism forces the viral and target membrane to move or bend toward each other to fuse and release nucleocapsid in the cell cytosol.


2.7 Requirement of glycolysis for optimal replication of DENV

Virus depends upon cellular metabolism of host for biosynthetic building blocks and to provide energy which is necessary for their replication. Glutamine and glucose are the main two carbon sources. Glutamine is used in viral replication to maintain TCA cycle (Fontaine et al., 2014). But metabolic profiling showed that carbon metabolism (glycolysis) is continuously altered during life cycle of virus. Consumption of glucose increases dengue virus infection period. Expression of hexokinase 2 and glucose transporter I up regulated in cells infected by dengue virus. By inhibit the glycolytic pathway, reduce the infectious virion production and RNA synthesis of virus shows that there is a need of glycolysis for Dengue virus infection.


3 Results

3.1 Sign and symptoms of Dengue fever

Dengue fever is also called break bone fever. In this situation high fever lasts for 3 to 14 days. Other symptoms of dengue fever are (Health and Services, 1996): Retro-orbital pain, Frontal headache, Myalgias, Rash, Low WBC, Hemorrhage, and Dehydration.


In most cases dengue infection shows no symptoms, mostly in those patients having no previous history and in children.


If patients did not get treated on time then dengue hemorrhagic fever appears which most severe and fatal. Warning signs starts to appear in this condition which includes (Hyattsville, 2004): Persistent vomiting, Severe abdominal pain, Change in temperature condition (mild to severe), and Irritability.


Dengue hemorrhagic fever convert into dengue shock syndrome (DSS) in these more pathetic symptoms appears: cold clammy skin, restlessness, rapid, narrow and weak pulse rate.


DSS is 10% or higher rate of fatality. If it is early recognized it can be less than 1%. It can occur in adults and children both.


3.2 Laboratory diagnosis of dengue

For better, accurate and in time cure of dengue, the detection of infection, its severity and its further pathogenesis is most important. It not only helps to determine the stage of disease spread but also gives a new approach to further studies for outbreak control, vaccine development and their clinical trials.


Laboratory methods for confirming the dengue virus infection might involve the isolation of the virus, nucleic acid & antigens or antibodies, or a combined technique (Chen and Wilson, 2010). After disease onset, the viral presence can be checked in serum, in the bloods, in plasma and in other tissues within 4-5 days. In the start of disease, isolation is easy and effective. After a certain period, serology is the only technique left. The patient’s response to same antibodies differs depending on the immune system of patient. A person who has a previous exposure of flavi virus or has been immunized against this virus will develop antibodies quickly as compared to that person who has no previous exposure to this. So, their primary response to the infection will be slow because of the production of primary antibodies (Chawla et al., 2014).


The very first antibodies produced in the result of infection are IgM. Their production increases with the time and then decreases to a certain limit after two weeks of infection. At this time the amount of IgM decreases to this much level that it’s not detectable. The number of IgM at 3 to 5 days is 50%. It increases to 80% by the 5th day of infection (Lee et al., 2008). The amount is an increase of 99% by the 9th day. After this a decline in the IgM amount starts which is not detectable after two to three months. However the anti-dengue serum can still be detected after many months of disease too. However, in second exposure to dengue give a rapid increase in production of immunoglobulins. IgG is the found at higher levels in the blood of the victim and these can persist for longer duration i.e for many months to even throughout life (Waggoner et al., 2013). A wide range for disease tests are used which depend on the type of sample used and also the onset duration. Also the test type depends for which purpose testing is being done.


4 Discussions

4.1 Requirements for diagnosis

4.1.1 Clinical management

Symptoms of dengue vary, according to different strains involved in disease propagation, many of which are non-specific. So, only the clinical investigations based on the symptoms are not reliable. Moreover, the disease severity also varies in individuals and in some cases can become more lethal within few days. That is why a detailed investigation in the beginning of disease onset is required (Lee et al., 2008).


Before the 5th day of illness, the disease is diagnosed by isolation of viral RNA in a culture medium and its detection by nucleic acid amplification test or by doing ELISA. However this is a very lengthy procedure and can take 24 to 48 hours, as isolation from the culture medium requires more time and expertise. NS1 antigen kits are now available to test dengue infection in fewer hours with great accuracy. After 5th day, antigens disappear from the blood and the resultant antibodies reside there. NS1 antigen may be detected in some patients. Different serological tests are available depending upon the area (Wiwanitkit, 2009; Normile, 2013).


4.1.2 Differential diagnosis

Symptoms of dengue fever can easily be mixed with the symptoms of other fever. It depends on the origin of the patient which helps to rule out either its dengue fever or non-dengue fever.


4.2 Current diagnostic methods

4.2.1 Virus isolation

Disease causative should be collected in early phase of disease onset, max of 5 days. This phase is called viraemia. Virus isolation is possible from different sources like blood, plasma, serum and other tissues. These samples can be spoiled by heat as they are sensitive to heat. So, these should be stored at 4 to 8°C. But if sample required to be stored for more time than-70°C is an ideal temperature (Normile, 2013). Cell cultures are mostly used methods for virus isolation. The mosquito’s cell lines C6/36 or AP61 are the hosts mostly used. It has been observed that all of these cell lines are not pathogenic. So a specified technique of screening is used the immune assay and antibody-virus complex tests are used. It usually takes 4 to 5 weeks.


4.2.2 Nucleic acid detection

Following techniques are used for the detection of viral nucleic acid:


RT-PCR technology has helped to better investigate the disease in less time and with great accuracy. In situ RT-PCR, paraffin pleated tissues are used. Detection procedure involves these basic steps; 1. extraction and purification. 2. Amplification. 3. Detection and characterization by liquid phase separation method. However now a days, silica based kits are being used for this purpose. Initial reverse transcription is done by targeting the C/prM region of the dengue virus in a nested RT-PCR using a universal primer. After this another serological PCR is run. A combination of 4 primers is used in serotype PCR which gives fast and robustic results (Rico-Hesse, 1990). The PCR products are then separated on the electrophoresis gel and the bands are then visualized under UV light. Dengue serotypes are differentiated on the basis of band sizes.


Real time PCR

Real time PCR is an efficient single step procedure which uses four primers each specific for each serotype and gives the quantitative results on each step. Fluorescent probes make the detection easy. Although all of these probes are not effective for all kind of strains. These are specific for only few strains (Rico-Hesse, 1990; Ranjit and Kissoon, 2011).


RT-PCR tests can be of two types. Either “singleplex” or it can be “multiplex”. Multiplex assays can test all possible types of the virus in one reaction. Bt chances of contamination are more and false results can be a reason.


Detection of antigen

In patients with secondary immune response, they already contain IgG immune complexes which made the detection a bit confusing. New techniques of ELISA has showed that the protein complexes made by viruses and host Abs can be detected even at 9th day of infection too no matter either its first exposure or second.


Serological tests

MAC-ELISA test: IgM ELISA is done for the serum IgM detection on a microplate coated with anti-µ- chain antibody. Dengue specific antigens, of all types bind to their specific antibodies making protein complexes which can be checked via different dyes depending on the type of complex. Enzyme linked complexes are then visualizes in spectrophotometer.


Principal of MAC-ELISA

IgG ELISA: IgG ELISA is done to check the recent or past infection caused by dengue virus. It uses the same antibodies as used by the MAC ELISA. This method is used for the detection of IgG antibodies in plasma & serum & frozen blood samples which makes possible the detection of infection (Wiwanitkit, 2009).


IgA test: This test is performed mostly after 8 days of onset of the disease and immunoglobulin level is at its peak in this period which diminishes after 40 days and then become undetectable. No changes in IgA percentages were found among researchers in patients having primary and secondary infections. Even if the values of antibodies are very low these can be detected by various means.


Haemagglutination inhibition test

This test is performed to check the coagulation of the antibodies by the viral epitopes present in the sample. For this purpose the sample is reacted with acetone to clear the extra antibodies and after this it is reacted with the trypsinized RBC (Vaughn et al., 1998). PH is maintained and sample is taken at two times. Antibodies level differs at different levels (Kao et al., 2005).


4.3 Prevention and treatment

As there is no specific treatment mode for dengue infection because no drug or vaccine has been developed till now, so prevention is the only option to control the infection. There are many ways by which we can prevent the infection (Kyle and Harris, 2008). These are as given below.


4.3.1 Mosquito control

The best way to prevent the spread of infection is to control the mosquito. We can do this as many possible ways. For example, by draining the artificial water storage containers, by using larvicide, better disposal of plastic bottles, cups. Insect growth regulators are also available which can be used to control mosquito spread (Guzman et al., 2010).


Reducing mosquito bites: If we can overcome the chance of mosquito bite by any means, we can reduce the chance of disease development. These mosquitoes can bite any one any time any keeping these things in mind we should adopt useful strategies to avoid mosquito bite. Many mosquito repellents in the form of lotions are available commercially. But keep this thing in mind that such lotions only repel the insects, they do not kill them.


Following insect repellents are being used: DEET (N, N-diethylmetatoluamide) repells mosquitoes. It is used in a specific concentration. However care must be taken while using it as it can be dangerous chemical too.


Picaridin: This kind of repellant, also known as KBR 3023, also repels the insects.


Others: Shorter acting repelling agents are also in use to reduce bite by mosquitoes. These include oils derived from cedar, citronella etc. (Zhang and Kramer, 2014).


4.3.2 Treatment

Till now, no effective vaccine or drug has been developed against dengue. As there are four strains of dengue causative agents for disease, so development of such a vaccine is necessary which will be effective against all four strains. However, a tetravalent vaccine has been developed which is under clinical trials. It contains a live attenuated, killed inactivated virus and a recombinant protein envelope (Waggoner et al., 2013). Generally, paracetamol is recommended for treatment rather than aspirin as in most cases aspirin has enhanced internal bleeding. Moreover aspirin is dangerous if given to patients below age 12. In case of severe infection, other precautionary measures are taken which include excessive fluid intake and electrolyte therapy (Shu and Huang, 2004).


4.4 Dengue virus

There are four distinct dengue virus serotypes, all of which originate from the family Flaviviridae and genus Flavivirus (Gubler, 2002). These serotypes are named as DENV-1, DENV-2, DENV-3, and DENV-4, infections caused by these viruses causes immunity to that virus for life time (King, 2014). Each of this virus serotype is being responsible for Dengue (Halstead, 1974). Dengue is one of those diseases having complex genotype having wide spectrum, which is then misdiagnosed by the other fevers. During incubation mostly patients faces sudden attack of fever for about 2-7 days with symptoms like myalgia, sore throat, macular skin rash and anorexia (Wilder-Smith et al., 2010). Still there is no specific vaccine or can say antiviral therapy (Ferreira, 2012). But with researches it is shown that intravenous rehydration lowers the rate of fatality by 1%. But due to the lack availability of proper treatments complete control over the disease is not possible (Organization et al., 2009).


4.4.1 Dengue vector and vector control

Transmission of disease is mainly occurred by the vector Aedes aegypti (A. aegypti), Aedes albopictus (A. albopictus) is the second main cause of dengue which is less effective as compared to that of first vector. This vector feeds on different types of vertebrates but is only responsible for dengue. During day time this Aedes mosquitos becomes active due to which some difficulties are observed in the controlling of that vector A. aegypti mosquitoes breed in water containers near houses or also in disposed water. A. aegypti shows more growth in domesticated environment. So, human are the major source for spread of this disease. The best way to control the disease is to take preventive measures to control the spread of the vector. In this control biological control, environmental control strategies are included.


4.4.2 Current situation of dengue around the world

Round about 3.6 billion people are lived in tropical and subtropical areas of the world which are the most appropriate places of this virus. Estimates about the spread of the disease shown that 500 000-2 000 000 dengue infections occurs, 500 000 cases of severe dengue and for about 20 000 deaths related to dengue occurred annually.


4.4.3 Clinical severity and risk prediction

In dengue-infected patients the severe manifestations develop usually late that is for about 4-6 days from the time of diminished fever. With these, bleeding from surfaces of mucosa and organ damage in the form of hepatitis, heart attack, and encephalitis occurs. After disease occurrence, 48 hours critical for the testing of the sample gives more accurate results. WHO provides a detailed notification for the detection procedure.


4.4.4 Current therapeutic options

The present management of disease depends what the sign and symptoms are and what is the fluid level of the body. Those patients that are unable to tolerate fluids get intravenous fluid having significant hemodynamics and leakage of vessels. Use of crystalloid solutions is also recommended by WHO management. (Organization, Research et al., 2009). More trials are used to detect whether infusion of a colloid solution is effective for the patient or not. In adults fluid with morbidities is necessary, also that there is some non-effective drug’ response. Balapiravir in Vietnam and Celgosivir in Singapore are two recent antiviral trials which could not show any positive response against disease (Low et al., 2014). By research on animal models it is studied that Lovastatin interrupt DENV assembly pathway.


4.4.5 New strategies for dengue control

In the past vector is mainly controlled by eliminating container breeding site or by improving water storage. Larvicide and insecticides also used to control outbreaks but have limitations, new techniques are developed to control dengue by controlling genetics of mosquitoes like the intracellular bacterium Wolbachia, transferred into the Aedes mosquitoe, and then the influences of insects’ ability of transmitting virus, by decreasing mosquito’s lifetime and also inhibiting viral replication in mosquito. Experiments in field are done in Vietnam, Australia, Brazil and Indonesia in which it is clearly demonstrated that successful invasion of Wolbachia-infected mosquitoes into natural sites of mosquito populations lead to genetic level changes at the end we will be having new strains. A part of this, some of the promising improved results can be shown by genetically modified mosquitoes along with genetically engineered sterile male Aedes mosquitoes in the field trials of Cayman Islands. In future there is possibility of dengue drug discovery by improving animal models and human infection models.



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