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Dengue
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- 2. Abstract Dengue is oneof the most important emerging vector-borne viral diseases. There are four serotypes of dengue viruses (DENV), each of which is capable of causing self-limited dengue fever (DF) or even life-threatening dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). The major clinical manifestations of severe DENV disease are vascular leakage, thrombocytopenia, and hemorrhage, yet the detailed mechanisms are not fully resolved. Besides the direct effects of the virus, immunopathological aspects are also involved in the development of dengue symptoms. Although no licensed dengue vaccine is yet available, several vaccine candidates are under development, including live attenuated virus vaccines, live chimeric virus vaccines, inactivated virus vaccines, and live recombinant, DNA and subunit vaccines. . For the safety and efficacy of dengue vaccines, the immunopathogenic complications such as antibody-mediated enhancement and autoimmunity of dengue disease need to be considered.
- 3. Introduction Dengue virusbelongs to family Flaviviridae, having four serotypes that spread by the bite of infected Aedes mosquitoes. The word “dengue” is derived from the Swahili phrase Ka- dinga pepo, meaning “cramp-like seizure”. The first clinically recognized dengue epidemics occurred almost simultaneously in Asia, Africa, and North America in the 1780s. It causes a wide spectrum of illness from mild asymptomatic illness to severe fatal dengue haemorrhagic fever/dengue shock syndrome (DHF/DSS). Dengue is the most rapidly spreading mosquito-borne viral disease in the world.
- 4. Dengue feverhas become an important public health problem as the number of reported cases continue to increase, especially with more severe of the disease, dengue hemorrhagic fever and dengue shock syndrome. The Primary symptoms of dengue appear include high fever and severe headache, with severe pain behind the eyes that is apparent when trying to move the eyes. Other associated symptoms are joint pain, muscle, bone and joint pain, rashes, and mild bleeding. The first symptom of the disease appears in about 5–7 days after the infected mosquito bites a healthy person. It is possible to become infected by dengue multiple times because the virus has four different serotypes. It is estimated that there are between 50 and 100 million cases of dengue fever (DF) and about 500,000 cases of dengue hemorrhagic fever (DHF) each year which require hospitalization.
- 5. An International Threatworldwide Approximately 2.5 billion people live in dengue endemic countries.
- 6. Average number ofDengue cases in 30 most endemic countries across the globe as reported by WHO in recent years
- 7. The Virus Denguevirus (DEN) is a small single-stranded RNA virus comprising four distinct serotypes (DEN-1 to -4), belonging to the genus Flavivirus, family Flaviviridae. The mature virus is spherical with a diameter of 50nm containing multiple copies of the three structural proteins, a host-derived membrane bilayer and a single copy of a positive-sense, single-stranded RNA genome. Distinct genotypes or lineages (viruses highly related in nucleotide sequence) have been identified within each serotype, highlighting the extensive genetic variability of the dengue serotypes.
- 8. The Vector The variousserotypes of the dengue virus are transmitted to humans through the bites of infected Aedes mosquitoes, principally Ae. aegypti. The immature stages are found in water-filled habitats, mostly in artificial containers closely associated with human dwellings and often indoors.
- 9. Life cycle andtransmission
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- 11. Febrile Phase Patientstypically develop high-grade fever suddenly. This acute febrile phase usually lasts 2–7 days and is often accompanied by facial flushing, skin erythema, generalized body ache, myalgia, arthralgia and headache. Sore throat, conjunctival injection, anorexia, nausea and vomiting are common. Laboratory tests compatible with DHF are: • decrease in white cell count • decrease in platelet count • increase in haematocrit. A blood film may also show atypical haematocrit test lymphocytes.
- 12. A positiveTourniquet test in this phase increases the probability of dengue This is done by first measuring the blood pressure. Then inflate the cuff to a pressure half way between systolic and diastolic pressures. Now keep the pressure inflated for 5 minutes. After releasing the cuff look carefully for small red or purple bleeding points in the skin known as petechiae. These might be tiny, the size of a pinhead. If there are 10 or more bleeding points in 1 square inch area, then the test is positive, But can be negative especially early in the disease. In addition to the above, Doctors and nurses should also measure: • Capillary refill time (CRT) • Heart rate • Respiratory rate • Blood pressure
- 13. Critical Phase Aroundthe time of defervescence, when the temperature drops to 37.5–38C or less and remains below this level, usually on days 3–7 of illness, an increase in capillary permeability in parallel with increasing haematocrit levels may occur. This marks the beginning of the critical phase. Progressive leukopenia followed by a rapid decrease in platelet count usually precedes plasma leakage. Increase in capillary permeability may become worse as a result of lost plasma volume. Pleural effusion and ascites may be clinically detectable depending on the degree of plasma leakage and the volume of fluid therapy. Hence chest x-ray and abdominal ultrasound can be useful tools for diagnosis. Shock occurs when a critical volume of plasma is lost through leakage. It is often preceded by warning signs.
- 14. With prolongedshock, the consequent organ hypoperfusion results in progressive organ impairment, metabolic acidosis and disseminated intravascular coagulation. This in turn leads to severe haemorrhage causing the haematocrit to decrease in severe shock. Instead of the leukopenia usually seen during this phase of dengue, the total white cell count may increase in patients with severe bleeding. Those who improve after defervescence are said to have non- severe dengue. Some patients progress to the critical phase of plasma leakage without defervescence and, in these patients, changes in the full blood count should be used to guide the onset of the critical phase and plasma leakage.
- 15. Recovery Phase Ifthe patient survives the 24–48 hour critical phase, a gradual reabsorption of extravascular compartment fluid takes place in the following 48–72 hours. The haematocrit stabilizes or may be lower due to the dilutional effect of reabsorbed fluid. White blood cell count usually starts to rise soon after defervescence but the recovery of platelet count is typically later than that of white blood cell count. Bradycardia and electrocardiographic changes are common during this stage. General well-being improves, appetite returns, gastrointestinal symptoms abate, haemodynamic status stabilizes.
- 16. Capillary leakage Oneof the cardinal features of severe dengue is capillary leakage resulting into accumulation of fluids in various body cavities. CF and CF2 appear to be pathogenesis-related proteins, that can produce DHF-like pathological lesions, such as capillary leakage, cerebral oedema, and blood leukocyte changes. Progressive leukopenia followed by a rapid decrease in platelet count usually precedes plasma leakage. This may lead to severe Dengue Haemorrhagic Fever.
- 17. Dengue Hemorrhagic Fever As dengue vascular permeability progresses, hypovolemia worsens and results in shock. It usually takes place around defervescence, usually on day 4 or 5 (range days 3–7) of illness, preceded by the warning signs. There is evidence of plasma leakage, such as: – high or progressively rising haematocrit – pleural effusions or ascites – circulatory compromise or shock, tachycardia There is an altered level of consciousness (lethargy or restlessness, coma, convulsions). There is severe organ impairment, acute liver failure, acute renal failure, encephalopathy or encephalitis, or other unusual manifestations.
- 18. Pathogenesis Helper Tcells (ThF) : DV induces generation of helper T cells (ThF). DV-specific ThF secrete a cytokine, the helper factor (HF) which is composed of two chains, one has antigen and the other has I-A determinants; both chains are essential for helper activity. Cytotoxic factor (TCF) : Cytotoxic factor (CF), a unique cytokine, is produced by CD4+ T cells. Most of the patients with dengue virus infection have CF in their sera, with peak amounts in the most severe cases. CD4+ T cells and H-2A- macrophages are killed by CF while it induces H-2A+ macrophage to produce another cytokine, the macrophage cytotoxin which amplifies the effect of CF. Suppressor T cells : DV-specific suppressor T cell (TS) cascade has three sequential subpopulations of TS1, TS2, TS3 cells and their secretary soluble suppressor cytokines (SF1, SF2, SF3). DV-infected macrophage transmits the signal to recruit TS1 cells, which secrete a suppressor cytokine, SF1. Macrophage : Macrophages are the primary component of the host innate immune system. But in dengue viral infection, these are the main cells which replicate dengue virus. These are responsible for processing and presentation of DV antigen to B lymphocytes leading to their clonal expansion and immune response
- 19. Antibody Dependent Enhancement(ADE) The mechanisms that have been considered to cause DHF include antibody- dependent enhancement (ADE). A high-affinity memory B cell, specific for Virus A, is preferentially activated by a new serotype, Virus A, to produce antibodies that ineffectively bind to the A serotype. The presence of these antibodies inhibits activation of a naïve B cell that produces more effective antibodies against Virus A. This effect leads to a diminished immune response against Virus A, and heightens the potential for serious infection.
- 20. Isolation and Diagnosis: Sera that have been collected from suspected dengue cases in the first 3–5 days of fever (the viraemic phase) can be used for virus isolation. viral identification is performed using dengue-specific monoclonal antibodies in immunofluorescence and PCR assays. Serum is often used for virus isolation but plasma, leukocytes, whole blood and tissues obtained at autopsy can also be used. Serological Testing : When a dengue infection occurs in individuals who have experienced a previous dengue infection, a secondary immune response occurs, which generates high levels of IgG through the stimulation of memory B cells from the previous infection as well as an IgM response to the current infection. Because high levels of IgG compete with IgM for antigen binding, an IgM capture assay can be used.
- 21. Other methods ofdiagnosis are : MAC-ELISA IgG ELISA IgM:IgG ratio. Neutralization assays Nucleic acid amplification tests Reverse transcriptase PCR (RT-PCR) Nucleic acid-sequence based amplification assay (NASBA).
- 22. What to do Whatever be the cause, a very high temperature can be dangerous and cause fits known down the fever as febrile convulsions. To bring down high fever to below 39°C, gently sponge with cloth soaked in water and give paracetamol. Maintain hydration and electrolyte balance using oral fluids. Thirst is common but many need help to drink. Avoid giving from a bottle only water as this will not replace lost electrolytes. Continue breast feeding if possible. Keep mosquitoes away, for example, using nets, to stop spread of the disease from a person with dengue. Remember mosquito net is unlike malaria, the mosquitoes that spread the paediatric ward dengue will usually bite during the day.
- 23. What not todo Avoid certain drugs, like, aspirin, NSAIs (non steroidal inflammatory drugs such as ibuprofen) which may to lead to bleeding and other complications. Avoid inappropriate intravenous (IV) fluids. Always use oral fluids if the patient is able to drink. If IV fluids are given when not necessary or too quickly, the extra fluid can pour out of the leaky capillaries into the tissues. The fluid easily leaks into the pleural space causing pleural effusions and by pressing on the lungs this makes breathing difficult. An X ray of chest is enough to locate these pleural effusions. There is another possibility that if a wrong kind of fluid, for example, too much 5% dextrose without any balanced salt solution, can also cause problems such as convulsions due to brain edema or swelling.
- 24. Vaccine for Dengue A primary immunological mechanism that confers protection from dengue illness is virus neutralization through antibodies, and all current dengue vaccine candidates aim to elicit high levels of neutralizing antibody. The increasing co-circulation of the four dengue virus types means that a vaccine is needed that protects against all four of them; hence, the vaccine needs to be tetravalent. Moreover, the induction of protective, neutralizing antibody responses against all four serotypes of dengue virus simultaneously should avoid the theoretical concern of vaccine-induced antibody-dependent enhancement in vaccine recipients. Dengue vaccines in development are of four types: live attenuated viruses, chimeric live attenuated viruses, inactivated or sub- unit vaccines, and nucleic acid-based vaccines.
- 25. Live attenuatedvaccines (LAVs) can induce durable humoral and cellular immune responses since they most closely mimic a natural infection. Several parameters are crucial for LAVs: • The viruses must be sufficiently attenuated and viral replication reduced so that viraemia is low and symptoms of illness are minimal. • Transmission of the viruses by mosquitoes is reduced or eliminated. • The viruses should replicate well in cell culture and be sufficiently I mmunogenic to provide long-lasting immunity in humans, so that low doses can be used. • A balanced immune response to all four dengue viruses must be elicited. • The genetic basis for attenuation must be known and must be stable
- 26. Challenges for Vaccines& Antiviral Drugs For Development Purpose • Several potential viral targets, of which the most advanced are NS3/NS2B protease and NS5 polymerase; work in progress on E, NS3 helicase, and NS5 methyltransferase. • Must be active against all serotypes. • Must be effective in both primary and secondary DEN infections. • Must be active orally, stable to heat and humidity, have a long shelf-life, and have low/reasonable production costs. • Exploration of cellular targets. • Should provide good safety profile, including few or no secondary effects. • Must be useful in infants, children and adults.
- 27. For Implementation Purpose •Need for rapid point-of-care diagnostic tool to apply antiviral most effectively. • Short window of viraemia. • Possible development of resistance: use cocktails of multiple drugs to avoid this eventuality. • Must be tested in acute DEN infection, and a prophylactic trial is not an option.
- 28. Vector Management Integrated vectormanagement (IVM) is the strategic approach to vector control promoted by WHO and includes control of the vectors of dengue. Defined as “a rational decision-making process for the optimal use of resources for vector control”, IVM considers five key elements in the management process, namely: 1. Advocacy, social mobilization and legislation 2. Collaboration within the health sector and with other sectors 3. Integrated approach to disease control 4. Evidence-based decision-making 5. Capacity-building
- 29. Preventing orreducing dengue virus transmission depends entirely on control of the mosquito vectors or interruption of human–vector contact. Activities to control transmission should target Ae. aegypti (the main vector) in the habitats of its immature and adult stages in the household and immediate vicinity, as well as other settings where human–vector contact occurs (e.g. schools, hospitals and workplaces) Ae. aegypti proliferates in many purposely-filled household containers such as those used for domestic water storage and for decorative plants, as well as in a multiplicity of rain-filled habitats – including used tyres, discarded food and beverage containers, blocked gutters and buildings under construction. Control of Ae. aegypti is mainly achieved by eliminating container habitats that are favorable oviposition sites and which permit the development of the aquatic stages. The habitats are eliminated by preventing access by mosquitoes to these containers or by frequently emptying and cleaning them, by removing the developing stages using insecticides or biological control agents, by killing the adult mosquitoes using insecticides, or by combinations of these methods.
- 30. Conclusion Scientists are investigatingthe mechanisms by which the dengue virus causes disease by focusing on understanding dengue pathogenesis, the virus itself, and vector biology. Researchers also aim to improve diagnostics for patients with dengue so that they can receive effective treatments sooner. In addition, by improving surveillance of dengue cases and mosquito vectors, researchers hope to reduce the effect of dengue epidemics.
- 31. Refrences Indian JMed Res 136, September 2012, pp 373-390; Dengue in India; Nivedita Gupta, Sakshi Srivastava*, Amita Jain* & Umesh C. Chaturvedi WHO. Dengue: Guidelines for diagnosis, treatment, prevention, and control in sub-Saharan Africa and 13 countries in South America. Geneva: World Health Organization; 2009. Parasitol Res (2012) 110:669–678; Bioefficacy of larvicdial and pupicidal properties of Carica papaya (Caricaceae) leaf extract and bacterial insecticide, spinosad, against chikungunya vector, Aedes aegypti (Diptera: Culicidae); Kalimuthu Kovendan & Kadarkarai Murugan & Arjunan Naresh Kumar & Savariar Vincent & Jiang-Shiou Hwang; Published online: 13 July 2011# Springer-Verlag 2011 Dar 47. L, Gupta E, Narang P, Broor S. Cocirculation of dengue serotypes, Delhi, India, 2003. Emerg Infect Dis 2006; 12 : 352-3. 48. Gupta E, Dar L, Kapoor G, Broor S. The changing epidemiology of dengue in Delhi, India. Virol J 2006 ; 3 : 92-6.
- 32. Bhattacharjee 10.N, Mukherjee KK, Chakravarti SK, Mukherjee MK, De PN, Sengupta M, et al. Dengue haemorrhagic fever (DHF) outbreak in Calcutta - 1990. J Commun Dis 1993; 25 : 10-4. Journal of Biomedical Science 2013, 20:37 doi:10.1186/1423-0127-20-37; Current progress in dengue vaccines; Shu-Wen Wan, Chiou-Feng Lin, Shuying Wang, Yu-Hung Chen, Trai-Ming Yeh, Hsiao-Sheng Liu, Robert Anderson and Yee-Shin Lin