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Introduction Dengue viruses are RNA viruses belong to the family Flaviviridae . It is the most common cause of arboviral diseases worldwide (Yasmashiro, 2004). It consists of phylogenetically and antigenically distinct four serotypes of dengue viruses , DENV 1, DENV 2, DENV 3 and DENV 4.These serotypes were classified by Albert Sabin in 1944, and infection with one type confers long-term immunity, it is to that type only and not to the other three. ( Humaira Zafar et al) Although outbreaks of disease clinically consistent with dengue have been reported for centuries, it was not until 1943 in Japan and 1945 in Hawaii that the first two dengue viruses were isolated (named DENV1 and DENV2, respectively) .In the latter half of the 20th century, DENV transmission followed the spread of its principal mosquito vector, Aedes aegypti , and was likely accelerated by urbanization and globalization. Spatial patterns in concurrent and sequential circulation of DENV1–4 should be considered along with virus and host genetics as potentially important population-level risk factors for severe dengue illness because secondary infection with a heterologous DENV type may increase the probability of severe disease . Although international transmission of disease is not new, it is notable that airline passenger numbers have increased by 9% annually since 1960, enabling infected human hosts to move the viruses long distances more quickly . Increased urbanization along with substandard housing, unreliable water supply, and poor sanitation provide an environment for Ae. aegypti proliferation in close proximity to human hosts. (Jane P. Messina et al) The WHO and US centers for disease control has considered dengue fever a major health threat for Brazil, Pakistan and India (CDC Report, 2013).The epidemiology of DF has been drastically changed, resulting in the increased incidence of disease worldwide along with the worsening of clinical symptoms. The course of epidemic is dependent upon the rate of contact between the host, the infecting vector and the threshold theory. This theory states that the introduction of few infected individuals in the community will not give rise to an outbreak unless the density of vector exceeds a certain critical level (CDC Report, 1980). Dengue viral infection is becoming a growing threat to the population of developing world (Senanayake, 2006). DF is a terrible viral disease. It has involved many tropical regions of the world. It has been estimated that about 40% of world population is at the risk for this infection (Durand, 2003). The substandard housing, crowding, and deterioration in water, sewer, and waste management systems associated with unplanned urbanization have created ideal conditions for increased transmission of mosquito-borne diseases in tropical urban centers. A third major factor has been the lack of effective mosquito control in areas where dengue is endemic. To reduce Dengue in our country the National Dengue control programmes must follow all WHO recommended Dengue control guidelines. The important focused points in WHO guidelines are the public health education, community participation, detection of breeding sites, environmental management by reactive insecticide fogging, geo referenced entomologic and clinical surveillance systems. ( Humaira Zafar et al) The four serotypes of DENV have been co-circulating in Sri Lanka for more than three decades and their distribution has not changed drastically in the last 30 years. Epidemiologically, during the 19th century DF was considered as a sporadic disease, causing epidemics at long intervals. However, dramatic changes in the epidemic pattern have occurred and DF/DHF currently is ranked as the most important mosquito-borne viral disease in the world. DF is now one of the leading causes of hospitalization and death among children in the tropical regions of the world. The rapid increase in DENV activity in India and Sri Lanka suggests its potential to cause even more severe epidemics in the future. (P.D.N.N. Sirisena et al) The principal vector of dengue, Aedes aegypti, is found worldwide between latitudes 35°N and 35°S . It is an efficient vector for several reasons: it is highly susceptible to dengue virus; it feeds preferentially on human blood; it thrives in close proximity to humans; it is a daytime feeder; its bite is almost imperceptible; and it is a restless mosquito as the slightest movement interrupts feeding, thus several people may be bitten in a short period for one blood meal. Unlike most mosquitoes, A aegypti takes more than one blood meal during a gonotropic cycle—that is, before the eggs are laid. In many areas, dengue epidemics occur during the warm, humid, rainy seasons, which favour abundant mosquitoes and shorten the extrinsic incubation period. Dengue haemorrhagic fever is distinguished from dengue by the presence of increased vascular permeability, not by the presence of haemorrhage. Patients with dengue may have severe haemorrhage without meeting WHO criteria for dengue haemorrhagic fever. In these cases the pathogenesis probably derives from thrombocytopenia or a consumptive coagulopathy, not from the vascular leak syndrome seen in dengue haemorrhagic fever. Dengue haemorrhagic fever may (grades III and IV) or may not (grades I and II) include clinical shock, referred to as dengue shock syndrome . Dengue virus antigen has been found in a variety of tissues, predominately the liver and reticuloendothelial system.Viral replication is thought to occur primarily in the macrophages, although dendritic cells(Langerhans cells) in the skin may be an early target of infection. (Robert V Gibbons et al) All four serotypes have been associated with dengue haemorrhagic fever. Variations in virus strains within and between the four serotypes may influence disease severity. Secondary infections (particularly with serotype 2) are more likely to result in severe disease and dengue haemorrhagic fever. This is explained by the theory of antibody dependent enhancement, whereby cross reactive but nonneutralising antibodies from a previous infection bind to the new infecting serotype and facilitate virus entry into cells resulting in higher peak viral titres. In primary and secondary infections, higher viral titres are associated with more severe disease. Higher titres may result in an amplified cascade of cytokines and complement activation causing endothelial dysfunction, platelet destruction, and consumption of coagulation factors, which result in plasma leakage and haemorrhagic manifestations. (Robert V Gibbons et al) Dengue is becoming a serious public health problem in India. Although dengue infection has been endemic in India since the nineteenth century, DHF has become endemic in various parts of India since 1987, with the first major widespread epidemics of DHF and DSS occurring in 1996, involving areas around Delhi and Lucknow, Uttar Pradesh, and spreading to other regions in India. However, the epidemics of Delhi and Pune in western India in 2006 and in Kerala state in 2008 marked the changing epidemiology of dengue infection, with all four serotypes of dengue viruses found in co-circulation, leading to an increase in secondary dengue infection and, in some cases, co-infections with DENV-1 and DENV-3, DENV-2 and DENV-3 and DENV-1, DENV-2 and DENV-3. In West Bengal state, nearly 61% of dengue cases reported between 2005 and 2007 were secondary dengue infection cases. (Dengue Bulletin Vol 35,Dec 2011) Epidemiologic studies have identified young age, female sex, high body-mass index, virus strain, and genetic variants of the human major-histocompatibility- complex class I–related sequence B and phospholipase C epsilon 1 genes as risk factors for severe dengue. Secondary infection, in the form of two sequential infections by different serotypes, is also an epidemiologic risk factor for severe disease. ( Cameron P. Simmons et al) The mechanisms that have been considered to cause DHF include antibody-dependent enhancement (ADE), T cell response, and a shift from Th-1 to Th-2 response. The combined effect of all of these is cytokine tsunami resulting in movement of body fluids in extravascular space. It has been suggested that in dengue a Th1 response is linked to recovery from infection while a Th2 type response leads to severe pathology and exacerbation of the disease. ( Nivedita Gupta et al) Severe complications related to DHF may occur very early in disease, it is important to explore prognostic markers of severe disease during acute phase. The hyperendemicity with cocirculation of two or more serotypes during the same time period have been widely suspected as one of the major cause of disease severity in South East Asia.Hepatic dysfunction is common in patients with severe dengue manifestations. Liver dysfunction might be responsible for the decreased synthesis of specific factors of the intrinsic pathway, an unbalance of which may consequently cause hemorrhage.( Rajni Kumaria) One of the largest outbreaks in north India occurred in Delhi and adjoining areas in the 1996 which was mainly due to dengue-2 virus. Thereafter, in 2003, another outbreak occurred in Delhi and all four dengue virus serotypes were found to be cocirculating. However, dengue-3 was reported to predominate in certain parts of North India in 20039. Dengue has been rampant in parts of Tamil Nadu in the past two decades. The prevalence of dengue vector and silent circulation of dengue viruses have been detected in rural and urban Tamil Nadu, which is ever increasing.The vulnerability of children to dengue infection was re-established in our study, as has been reported earlier. (P. Gunasekaran et al) Upon analyzing the year-wise distribution of dengue cases in the study population, steady increase in the number of dengue patients over the past few years was noted. The study revealed that majority of the cases were in the age group of 15–44 years. (Ashwini Kumar et al) Cyclic dengue epidemics in Kerala state have been occurring since 2001, even though the first dengue report was brought on record from Kottayam district in 1997 with 14 cases and 4 deaths (Unpublished observation). This was followed by a more sever dengue outbreak implicating 67 cases (nearly 5-fold increase) and a toll of 13 human lives (3-fold increase) in 1998, again in the same district. (Apr-May 2006 ICMR Bulletin) Pathogenesis and clinical manifestations Duration of viremia ranged from 1 to 7 days . Viremia during primary infection was prolonged compared with secondary infections.The patients initially develop an abrupt onset of high fever (39–40°C) with headache, retro-orbital pain, malaise, nausea, vomiting, and myalgia. The acute febrile stage lasts 2–7 days and may be followed by recovery but patients feel weakness. During defervescence some patients develop haemorrhagic manifestation that may be mild petechial haemorrhage, and bleeding at the nose, gastrointestinal tract and gums, which may be severe. . (David W. Vaughn et al) Hepatomegaly is common with soft and tender liver. Thrombocytopoenia and rising haematocrit due to plasma leakage are usually detectable before the onset of the subsequent stage of shock (DSS) with an abrupt fall to normal or subnormal levels of temperature, varying degrees of circulatory disturbances lasting for 24–48 h.( U C Chaturvedi et al) Dengue virus infection in humans causes a spectrum of illness ranging from inapparent or mild febrile illness to severe and fatal hemorrhagic disease. Important risk factors influencing the proportion of patients who have severe disease during epidemic transmission include the strain and serotype of the infecting virus and the immune status, age, and genetic background of the human host. Classic dengue fever is primarily a disease of older children and adults. It is characterized by the sudden onset of fever and a variety of nonspecific signs and symptoms. The rash usually begins on the trunk and spreads to the face and extremities. Hemorrhagic manifestations in dengue fever patients are not uncommon and range from mild to severe. Skin hemorrhages, including petechiae and purpura, are the most common, along with gum bleeding, epistaxis, menorrhagia, and gastrointestinal (GI) hemorrhage. The primary pathophysiologic abnormality seen in DHF and DSS is an acute increase in vascular permeability that leads to leakage of plasma into the extravascular compartment, resulting in hemoconcentration and decreased blood pressure. Dengue virus infections of monocytes/macrophages is enhanced by ADE. This enhancement is facilitated by the fact that the dengue virus-specific CD41 T lymphocytes produce IFN-g, which in turn up-regulates the expression of FC-g receptors. The increased number of dengue virus-infected monocytes/macrophages results in increased T-cell activation, which results in the release of increased levels of cytokines and chemical mediators. Kurane and Ennis hypothesized that the rapid increase in the levels and the synergistic effects of mediators such as TNF, IL-2, IL-6, IFNg, PAF, C3a, C5a, and histamine induce increased vascular permeability, plasma leakage, shock, and malfunction of the coagulation system, which may lead to hemorrhage.( Duane J. Gubler ) DENV is an enveloped positive-strand RNA virus belonging to the Flaviviridae family.Mature virions contain three structural proteins, the capsid protein C, membrane protein M, and the envelope protein E. Multiple copies of the C protein (11 kDa) encapsulate the RNA genome to form the viral nucleocapsid . The nucleocapsid is surrounded by a host-cell-derived lipid bilayer, in which 180 copies of M and E are anchored. The M protein is a small (approx. 8 kDa) proteolytic fragment of its precursor form prM (approx. 21 kDa). The E protein is 53 kDa and has three distinct structural domains .( Izabela A et al) Plasma leakage and coagulopathy are the fundamental pathological changes responsible for clinical manifestations, morbidity, and mortality in DHF. Both humoral and cell-mediated immune mechanisms eventually result in the release of cytokines responsible for changes in the selective microvascular permeability and the resultant plasma leakage. (Kolitha H. Sellahewa et al) Laboratory diagnosis Viremia generally lasts from 4 to 5 days. The circulating viable DENV particles remain readily detectable in the blood for up to 5 days after the onset of symptoms, and then rapidly disappear following the appearance of DENVspecific antibody. DENV-specific immunoglobulin M (IgM) antibody becomes positive on the sixth day following the onset of illness in most patients. During primary DENV infection, the IgG antibody appears a few days following IgM antibody. In secondary DENV infection, an anamnestic IgG response occurs, causing serotiter to rapidly increase initially, almost immediately following the onset of disease, and then remain high in most patients .Therefore, laboratory diagnosis must consider the timing of the clinical course of dengue patients. The most sensitive virus isolation method is in vivo amplification through mosquito inoculation, the mosquito-derived cell cultures, such as C6/36 (Aedes albopictus), AP61 (Aedes pseudoscutellaris) and TRA- 284 (Toxorhynchites amboinensis). The diluted serum sample is inoculated on to the cell culture monolayer on screw cap tubes, dishes or flasks. Following incubation at 28°C for 1 week, the inoculated cells are screened for DENV by use of IF stain with 4 different serotype-specific monoclonal antibodies . The disadvantages of this method are the time-consuming procedures required to obtain the culture results, and the need for cell culture facilities and experienced laboratory professionals. The presence of DENV antigen in acute sera and peripheral blood mononuclear cells (PBMC) from DENV-infected patients has been determined using biotin-streptavidine enzyme-linked immunosorbent assay (ELISA). Molecular diagnosis typically provides more sensitive and rapid detection than traditional virus isolation methods, because it amplifies nucleic acid even for inactivated virus. However, the specimens and RNA must be carefully handled to avoid RNA degradation.To minimize contamination and maximize costeffectiveness, Harris et al established a modified single tube multiplex RT-PCR. Real-time RT-PCR assay represents another choice for quantifying DENV RNA. PCR products were detected in real time on a Light Cycler. Historically, hemagglutination inhibition (HI), complement fixation test (CF) and neutralization tests were used extensively for measuring anti-DENV antibodies. Three main disadvantages of the HI test have limited its wide application. First, tested serum samples must be pretreated with acetone or kaolin, to remove nonspecific inhibitors of hemagglutination. Second, the accurate HI test requires paired (acute and convalescent) serum samples. Third, difficulty in discrimination between the DENV infections from other closely related flaviviruses.to minimize the disadvantages of HI test, the plaque reduction neutralization test (PRNT) is mainly used to determine the serotype of DENV with which the patients are infected. The disadvantages of PRNT include the time-consuming titration of DENV and the careful handling of cell culture techniques required in each step. Unlike traditionally complicated HI and PRNT tests, a simple and rapid ELISA method has been adapted to detect antibodies against DENV. Several formats of ELISA are designed for detecting DENV antibodies. Classical indirect ELISA and immunoglobulin antibody capture ELISA are the 2 most common formats. Recently, anti-human IgM capture ELISA (MACELISA) and anti-human IgG ELISA (GAC-ELISA) were developed and widely used for detecting human anti-dengue IgM and IgG antibodies.( Chuan-Liang Kao et al) Conclusion Natural concurrent infection with dengue viruses may occur in highly endemic areas where different dengue serotypes have been transmitted for many years. Many cases of simultaneous infection by more than one arbovirus species in mosquito or human hosts have been documented elsewhere. Simultaneous infection by different strains of dengue viruses in human or mosquito host cells affords the potential for virus recombination. In this regard, recent evidence provided by phylogenetic and rigorous nucleotides sequence analyses of dengue virus genomes showed that recombination is an important, yet largely ignored, mechanism responsible for generation of dengue virus diversity. Therefore, the genetic exchange between dengue strains, although rarely reported in positive-strand RNA viruses might be, in addition to mutation, important factor involved in genetic variation of dengue virus8. Due to the complexity of dengue infection and the difficulties in obtaining a safe and effective vaccine, recombination and its role in the genetic diversity of dengue virus must be investigated further. Strains isolated from cases of natural concurrent infection could be good models in such studies.( Cecília Luiza Simões dos SANTOS et al) References 1. Jane P. Messina1, Oliver J. Brady1, Thomas W. Scott2,3, Chenting Zou1, David M. Pigott1, Kirsten A. Duda1, Samir Bhatt1, Leah Katzelnick4, Rosalind E. Howes1, Katherine E. Battle1, Cameron P. Simmons5,6,7, and Simon I. Hay. Global spread of dengue virus types: mapping the 70 year history. Trends in Microbiology, March 2014, Vol. 22, No. 3 2. Humaira Zafar*1, Kiran Tauseef Bukhari1, Ghulam Mustafa Lodhi. Global prevalence of dengue viral infection, its pathogenesis diagnostic and preventive approaches.Asian J Agri Biol,2013 ,1(1): 38-42 3. P.D.N.N. Sirisena, F. Noordeen. Evolution of dengue in Sri Lanka—changes in the virus, vector, and climate. International Journal of Infectious Diseases 19 (2014) 6–12 4. Robert V Gibbons, David W Vaughn. Dengue: an escalating problem. BMJ 2002;324:1563–6 5. WHO.Dengue Bulletin Vol 35.December 2011 6. Cameron P. Simmons, Ph.D., Jeremy J. Farrar, M.D., Ph.D.,Nguyen van Vinh Chau, M.D., Ph.D., and Bridget Wills, M.D., D.M. Current Concepts Dengue. N engl j med 366;15.April 2012. 7. Nivedita Gupta, Sakshi Srivastava*, Amita Jain* & Umesh C. Chaturvedi. Dengue in India. Indian J Med Res 136, September 2012, pp 373-390 8. 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