Dengue fever is a mosquito-borne illness caused by the dengue virus, which belongs to the genus Flavivirus and the family Flaviviridae. Dengue is widespread throughout the tropics and its transmission is strongly influenced by certain factors like rainfall, temperature, urbanization, and distribution of the principal mosquito vector Aedes aegypti. The viral infection caused may be asymptomatic or in the form of undifferentiated fever, dengue fever, dengue hemorrhagic fever, or dengue shock syndrome. Globally, dengue fever is responsible for 100 million new cases annually with 500,000 hospitalizations and 25,000 deaths. There is no vaccine available at present to prevent this disease. The increase in global cases is associated with urbanization, increased international travel, insufficient water supplies, and climate change. This article provides a general overview of dengue, the epidemiology of dengue infection, and covers the clinical features, pathogenesis, control, diagnosis, and treatment of these infections.
Dengue infection is a most common vector-borne viral infection that has emerged and re-emerged in recent years causing break-bone fever, dandy fever, dengue hemorrhagic fever(DHF), dengue shock syndrome. Dengue Fever (DF), is transmitted mainly by Aedes aegypti and Aedes albopictus. It of major public health concern in the tropics with a potential of expansion to other geographical areas. The incidences of dengue infections have increased >30 times in recent decades. It poses high costs to health services and the financial systems of the country.
Dengue was considered a sporadic disease during the 19th century which used to cause epidemics at long intervals. At present, it is endemic in almost 112 countries of the world. The pathogen dengue virus(DENV) is fully adapted to humans, and the highly domesticated principal vector Aedes aegypti emerged long ago from sylvatic cycles that involved non-human primates and canopy dwelling Aedes mosquitoes in the rainforests of Asia and Africa. During the slave trade to America in the 1600s, Aedes aegypti was introduced and it spread worldwide as the shipping industry stretched out. The largest number of dengue infections are unapparent with no clinical symptoms. The Aedes live in close proximity of humans, feeds and rest in their homes, and lays their eggs in water containers or at stagnant water sites. The female mosquito during the viraemic phase of illness takes a blood meal and gets infected. The virus first infects midgut cells and then disseminates to replicate in several mosquito tissues, finally, it infects the salivary glands in an average of 8-10 days. This period is known as the extrinsic incubation period and apparent infection generally develops during this phase. The process is influenced by certain factors like favorable temperature and the viral strain and many more. When the salivary glands of mosquitoes get infected, they can transmit the virus to the host while feeding on their blood. The time from infection to the onset of illness is known as the intrinsic incubation period. In humans, the incubation period ranges somewhere between 3-14 days with an average of 4-7 days. The classical dengue cases manifest as three natural courses that include febrile, critical, and recovery phases.
Following malaria, dengue is ranked the second most lethal vector-borne disease worldwide. Almost 120 countries and places in tropical and subtropical areas verified the endemicity of dengue that includes Southeast Asia, Central, and South America, Africa, Western Pacific, and eastern Mediterranean regions. In the 1950s, the pandemic of dengue in Southeast Asia spread rapidly due to urbanization, and an increase in economic activity was observed after the Second World War. The geographical expansion of DENVs and mosquito vectors dramatically amplified in 20-30 years, leading to an increase in frequency and magnitude of epidemics. The jet airplane that became the principal mode of human travel during the 1970s led to an increase in the frequency of epidemics. Recent morbidity of dengue has increased significantly, which suggests that more than half of the world's population is at risk of DENVs infection with 390 million total DENV infections, 96 million symptomatic infections,2 million cases of severe disease, and 21,000 deaths annually. According to recent estimates, the cost resulting from DENV infections is considerable, it averages US$2.2billion per year in the USA between 2000 to 2007, US$1.2 billion in South-East Asia every year between 2001 and 2010, and US$76 million per year in Africa. The roughly estimated annual global cost of dengue is US$8.9 billion.
DENVs are a single-stranded RNA virus belonging to the genus Flavivirus of the Flaviviridae family. There are four serotypes (DEN 1-4) that are classified according to biological and immunological criteria. These four serotypes are enveloped, spherical viral particles with a diameter of approximately 500 Armstrong. The viral genome of each serotype comprises approximately 11 kb in the length of a positive sense of single-stranded RNA, that encodes 10 proteins. The three structural proteins that encode mature virions are the membrane(M)protein, envelope (E)protein, and capsid(C)protein; the non-structural proteins (NS) are NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5. The E protein is arranged on the surface of DENVs as 90 tightly packed monomers and facilitates viral entry into host cells by binding to cellular receptors and it mediates fusion of viral and cellular membranes. The envelope protein is also associated with haemagglutination of erythrocytes, induction of neutralizing antibodies, and protective immune responses. The NS proteins are involved in the function of viral replication and packaging, processes that are closely linked to host endoplasmic reticulum(ER) and secretory pathway function.NS1 is gets expressed on the surface of infected cells and does not form a part of the virion like other viral glycoproteins. Its role in viral replication is suggested from certain shreds of evidence. High levels of NS1 protein are detected in acute-phase samples from patients with secondary dengue infections suggests that NS1 protein may contribute to the formation of circulating immune complexes that plays a crucial role in the pathogenesis of severe dengue infections.
The acute phases of DENV infections affects multiple systems including the liver, blood coagulation, complement, hematopoiesis, and the vascular systems. Dengue infections can be inapparent or give rise to undifferentiated fever, dengue fever, DHF, or dengue shock syndrome.
Dengue vascular permeability syndrome that is usually referred to as DHF/DSS includes various abnormalities in which the vascular system is affected severely. Capillary permeability and plasma leakage are certain factors proven to affect most cases with severe dengue illness in DHF/DSS patients. Moreover in these patients increased micro-vascular permeability has been reported when patients experience defervescence.
The complement system becomes activated to control DENV infection which certainly leads to pathogenesis through interaction with the coagulation system. The temporal and peak production of complement split products are associated with increased blood fibrinogen levels and thrombocytopenia in children with DHF/DSS.
Liver enlargement and liver failure
During DENV infection liver enlargement and dysfunction are commonly seen as hepatocytes and Kupffer cells support viral replication. The other reason given for enlargement of the liver is generalized edema due to vascular permeability. Despite the prevalence of liver enlargement, jaundice is rarely seen in severe cases of dengue, while changes in enzyme levels are common. Levels of aspartate aminotransferase and alanine aminotransferase are significantly higher in a majority of cases of DHF while the globulins level significantly lowers in the severe cases. Levels of serum bilirubin, alkaline phosphatase, and gamma-glutamyl transpeptidase were observed to be raised in the patients. Liver failure is frequently present with convulsions and in the neurological examination may show hyperreflexia or an extensor plantar response.
In a study, 16.7% of children have shown left ventricular dysfunction when assessed by two-dimensional and color Doppler echocardiography. Acute reversible myocarditis and left ventricular failure contributing to hypotension are observed in patients with dengue infection.
Coagulopathy and thrombocytopenia
There is an increase in activated partial thromboplastin time(APTT) and a lessening in the level of fibrinogen is observed frequently in DHF/DSS. There is an increase in the concentration of procoagulant marker which leads to a reduction in the concentration of anticoagulant proteins. It is observed in some of the children with severe shock, the minor coagulopathy condition leads to prolonged hypotension and tissue hypoxia and bleeding occurs by erythrocyte extravasation in the gastrointestinal tract. The platelet counts can lower down to 5,000 per ml (the normal count is 20,000 platelets per ml ). There is a remarkable decrease in the production of all types of blood cells during the early febrile phase of DENV infection and it is observed in the autopsy studies that when the febrile phase of DENV comes to an end the bone marrow cells recover to normal count and leaves residual megakaryocyte.
There are several methods involved in the diagnosis of dengue infections like viral isolation, serology, and molecular techniques such as reverse–polymerase chain reaction (RT-PCR). The dengue virus can be isolated from serum, plasma, or leucocyte and blood is usually collected during the febrile period that is before the formation of neutralizing bodies against the virus, preferably before the fifth day of illness. The methods involved for serological diagnosis are haemagglutination inhibition tests, complement fixation tests, neutralization tests, enzyme-linked immunosorbent assay (ELISA). The observed sensitivity of IgM ELISA by the 5th day of infection is at the range of 83.9% -98.4% with a specificity of 100%. The molecular detection with the RT-PCR techniques can detect the dengue viral material when the antibodies are undetectable in the serum at early phases. The PCR technique can also detect dual viremia from DEN-1 and DEN-3 infection.
There is no licensed vaccine for dengue, therefore, vector control is of utmost importance for the prevention of dengue. Singapore was highly successful in the control of Ae. Aegypti, as a control program was implemented in 1968 for almost 20 years in the country and is still working till present. However, it has failed to stop the re-emergence of DENV transmission in the last 20 years. A similar control program was highly successful in Cuba for almost 30 years, but it eventually failed because of economic problems. Biological control methods are generally embattled against the larval stages of the vector. Bacillus thuringiensis serotype H-14 is shows effectivity against A aegypti and therefore used in household control of the vector. Several biological control methods includes the use of Gambusia affinis and Poecilia reticulate( both are larvivorous fishes), endotoxins producing bacteria( such as Bacillus thuringiensis and Bacillus sphaericus), and copepod crustaceans. Space spraying and larvicidal insecticides are used as chemical control.
Vaccine development faces numerous challenges, as the vaccine should be immunogenic against all four serotypes and long term protection is obligatory, for several vaccines developed till now like live attenuated, chimeric, DNA, subunit, and viral vector vaccines, none of them are sufficiently immunogenic for routine use. Live attenuated dengue vaccine was developed by passaging wild–type DENVstrains through various types of primary cells or cell lines, that includes primary dog kidney(PDK) and African green monkey kidney(GMK) cells. It was observed when 7 formulations of tetravalent live attenuated vaccines were evaluated, it showed that 58% of recipients seroconverted( neutralizing antibody titer is >=1:10) to three or more serotypes after taking the first dose and it increased to 78% in the second dose. Monovalent DEN-2 and tetravalent vaccines shows T-cell responses against all dengue serotypes and proliferation responses are more for DEN-1 and DEN-3 in comparison to DEN-2 and DEN-4, while cytotoxic T-lymphocyte responses are higher to DEN-2 and DEN-3 in opposition to DEN-1. Subunit vaccines are protein vaccines that require adjuvant and numerous doses to achieve an optimum immune response. They are comparatively safer than live attenuated vaccines.DNA vaccines are other cost-effective vaccines that are easy to produce and have temperature stability. In the majority of cases, DNA vaccine-based approaches in dengue infections are directed towards eliciting immune responses to prM protein and E protein in mice and monkeys. Various viral vectors like vaccinia virus, adenovirus, and alphavirus vectors have been used as delivery vehicles for DENV antigens. But no viral vector vaccine has reached to first clinical phase yet.
Generally, there is no specific treatment available for dengue currently. Patients are usually given supportive therapy and management is mainly symptomatic. Fluid therapy plays a central role in dengue management. Moreover, analgesics and antipyretics can be prescribed at accustomed doses, and aspirin and NSAIDs are not recommended (may result in gastric irritation or aggravate gastrointestinal bleeding). Platelet transfusion is done in severe cases that develop hemorrhagic manifestation or have low platelet counts.