INTRODUCTION Dengue is the most rapidly spreading mosquito-borne viral disease in the world.

In the last 50 years, incidence has increased 30-fold with increasing geographic expansion to new countries and, in the present decade, from urban to rural settings. Dengue fever is classically a self-limiting, nonspecific illness. DHF is a more serious clinical entity. It emerged among children in Southeast Asia during the 1950s and has since become a major public health problem worldwide and a significant cause of pediatric morbidity and mortality. DEFINITION WHO defines dengue fever as an acute onset febrile illness that lasts 2-7 days, with two or more of the following symptoms: headache, retro-orbital pain, myalgia/arthralgia, maculopapular rash, petechiae, and positive tourniquet test. Hemorrhagic manifestations are uncommon. DISEASE BURDEN Since 2000, epidemic dengue has spread to new areas and has increased in the already affected areas of the region. Cyclic epidemics are increasing in frequency and in-country geographic expansion is occurring in Bangladesh, India and Maldives -countries in the deciduous dry and wet climatic zone with multiple virus serotypes circulating. Every year about 50-100 million cases of dengue infection, 500,000 cases of DHF and at least 12,000 deaths occur worldwide; ninety percent of these deaths occur in children less than 15 years of age. During dengue epidemics, attack rates among susceptible individuals are often 40-50%, but may reach 80-90%. An estimated 500,000 cases of DHF require hospitalization each year, of which a very large proportion are children. At least 2.5% of cases die, although case fatality could be twice as high. Without proper treatment, DHF case fatality rates can exceed 20%. ETIOLOGY Dengue virus 40- to 50-mm single-stranded RNA viruses belonging to the Flavi-virus group. Four serotypes, have been described-DEN-1, DEN-2, DEN-3, and DEN-4. Infection with one dengue virus serotype results in specific immunity to that serotype only. predominant serotype in the 1980s- DEN-2, recently it is DEN-3.

Transmission By biting and injecting infected salivary fluid into the wound of another person by an infected Aedes mosquito.

Aedes aegypti is the most important epidemic vector. A. albopictus and A. polynesiensis may act as vectors in some geographic locations. Aedes aegypti is seen in abundance in at-risk areas. It is found between latitudes

30 north and 20 south and at over 2,200 meters above the sea level. Transmission occurs in geographically diverse areas, including subtropical and tropical cities at various altitudes. The Aedes mosquito rests indoors, mainly in living rooms and bedrooms, and in small collections of water, such as flowerpots or coconut shells. This maximizes man-vector contact and minimizes contact with insecticides sprayed outdoors, hence hindering the control of this vector. Eggs can survive for long periods. Improper disposal of garbage or inadequate wastewater drainage may be responsible for high mosquito densities in endemic areas. Significant increases in the mosquito larval populations are seen during the rainy season. CASE CLASSIFICATION Dengue has a wide spectrum of clinical presentations, often with unpredictable clinical evolution and outcome. While most patients recover following a self-limiting non-severe clinical course, a small proportion progress to severe disease, mostly characterized by plasma leakage with or without hemorrhage. Dengue is one disease entity with different clinical presentations and often with unpredictable clinical evolution and outcome. WHO Symptomatic dengue virus infections were grouped into three categories as per old WHO classification: 1. Undifferentiated fever 2. Dengue fever (DF) 3. Dengue hemorrhagic fever (DHF)- with or without shock DHF was further classified into four severity grades, with grades III and IV being defined as dengue shock syndrome (DSS). There have been many reports of difficulties in the use of this classification. Therefore model for classifying dengue has been suggested by an expert group (Geneva, Switzerland, 2008)

Criteria for dengue warning signs Probable dengue Warning signs* Live in /travel to Abdominal pain or dengue endemic area. tenderness Fever and 2 of the Persistent vomiting following criteria: Clinical fluid accumulation

Criteria for severe dengue Severe plasma leakage Leading to: Shock (DSS) Fluid accumulation with respiratory

 Nausea, vomiting Rash Aches and pains Tourniquet test positive Leukopenia Any warning sign Laboratory-confirmed dengue (important when no sign of plasma leakage)

Mucosal bleed Lethargy, restlessness Liver enlargement >2 cm Laboratory: increase in HCT o Concurrent with rapid decrease in platelet count *(requiring strict observation and medical Intervention)

Distress Severe bleeding As evaluated by clinician Severe organ involvement Liver: AST or ALT >=1000 CNS: Impaired consciousness Heart and other organs

PATHOGENESIS
After the bite of an infected mosquito, the average incubation period lasts 4 to 7 days (range of 3-14 days), during which the patient may or may not experience symptoms, depending on the virus strain, age, immune status, and other factors. This is followed by viremia, which is associated with sudden onset of fever and constitutional symptoms lasting for 5-6 days (range of 2 to 12 days). The dengue virus replicates within cells of the mononuclear phagocyte lineage (macrophages, monocytes, and B cells). Additionally, infection of mast cells, dendritic cells, and endothelial cells is known to occur. The virus may infect peripheral blood leukocytes, liver, spleen, lymph node, bone marrow, thymus, heart, kidney, stomach, lung, and possibly the brain, suggesting blood-brain barrier disruption. Following the febrile (viremic) phase, the patient may either recover or progress to the leakage phase, leading to DHF and/or dengue shock syndrome. The increased number of infected cells results in increased production of cytokines, including TNF- and IFN-, and other chemical mediators. TNF- and IFN- also lead to activation of other dendritic cells, virally infected or non-infected. The release of various cytokines and mediators is responsible for increased vascular permeability, abnormal leakage of plasma, hypovolemia, shock, and hemostatic abnormalities. In addition, there is evidence to show that endothelial cells also undergo apoptosis, which causes disruption of the endothelial cell barrier, leading to the generalized vascular leak syndrome. More severe infection occurs when a person is infected for a second time with a different serotype in2-4%of individuals. How a second dengue infection causes a severe disease and why only some patients get severe disease remains unclear. It is suggested that residual antibodies produced during the first infection are unable to neutralize a second infection with another serotype, and the second infection, under the influence of enhancing antibodies, results in severe infection and disease. This phenomenon is referred to as antibody-dependent enhancement. The pre-existing non neutralizing antibodies generated from previous primary infection cross-react with viral serotypes involved in secondary infections and bind to the virions, but do not neutralize them. Such antibody-coated virions are taken up more rapidly than uncoated virus particles by tissues, dendritic cells, monocytes and macrophages. This leads to a higher viral load and enhanced antigen presentation by the infected dendritic cells to the T cells, resulting in extensive T-cell activation and proliferation of memory T-cells. This extensive T-cell activation supposedly causes the T-cells to become stunned, whereby their IFN- expression remains low.

CLINICAL MANIFESTATIONS Dengue fever Fever lasting 2-7 days Two or more among the following o Headache o Retro-orbital pain o Myalgia/arthralgia o Maculopapular rash o Petechiae o Positive tourniquet test o Itching o Prostration o Flushing commonly on the face, neck, and chest. Younger children - coryza, diarrhea, rash and seizure, and less commonly with vomiting, headache, and abdominal pain

Dengue hemorrhagic fever Hepatomegaly and splenomegaly -occasionally seen, especially in infants Positive tourniquet test petechiae, ecchymoses or purpura mucosal bleeding hematemesis or melena GI bleed- severe cases In DHF, bleeding may not correlate with the platelet counts and usually occurs once the fever has settled.

Dengue shock syndrome

WHO defines DSS as DHF plus signs of circulatory failure.

The patient is considered to have shock if the pulse pressure (i.e. the difference between the systolic and diastolic pressures) is 20 mm Hg in children or he/she has signs of poor capillary perfusion (cold extremities, delayed capillary refill, or rapid pulse rate). Child often conscious and lucid and BP initially appears normal, later with the diastolic pressure rising towards the systolic pressure and the pulse pressure narrows as the peripheral vascular resistance increases. PHASES OF DENGUE
1. Febrile phase High-grade fever sudden in onset, lasting 27 days and is often accompanied by facial flushing, skin erythema, generalized body ache, myalgia, arthralgia and headache. Some patients may have sore throat, injected pharynx and conjunctival injection. Anorexia, nausea and vomiting are common. A positive tourniquet test in this phase increases the probability of dengue. Mild hemorrhagic manifestations like petechiae and mucosal membrane bleeding (e.g. Nose and gums) Hepato-spleenomegaly and tenderness over liver and spleen. The earliest abnormality-progressive decrease in total white cell count.

2. Critical phase Characterized by Shock from plasma leakage; severe haemorrhage; organ impairment. Around the time of defervescence, when the temperature drops to 37.538oC or less and remains below this level, usually on day 37 of illness, an increase in capillary permeability in parallel with increasing haematocrit levels may occur. This marks the beginning of the critical phase. The period of clinically significant plasma leakage usually lasts 2448 hours. Progressive leukopenia Rapid decrease in platelet count usually precedes plasma leakage. At this point patients without an increase in capillary permeability will improve, while those with increased capillary permeability may become worse as a result of lost plasma volume. The degree of plasma leakage varies. Shock occurs when a critical volume of plasma is lost through leakage. It is often preceded by warning signs. The body temperature may be subnormal when shock occurs. With prolonged shock, 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. In addition, severe organ impairment such as severe hepatitis, encephalitis or myocarditis and/or severe bleeding may also develop without obvious plasma leakage or shock . 3. Recovery phase (hypervolemia) If the patient survives the 2448 hour critical phase, a gradual reabsorption of extravascular compartment fluid takes place in the following 4872 hours. General well-being improves, appetite returns, gastrointestinal symptoms abate, haemodynamic status stabilizes and diuresis ensues. Some patients may have a rash of isles of white in the sea of red. Some may experience generalized pruritus. Bradycardia and ECG changes are common during this stage. 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. Respiratory distress from massive pleural effusion and ascites will occur at any time if excessive intravenous fluids have been administered. During the critical and/or recovery phases, excessive fluid therapy is associated with pulmonary oedema or congestive heart failure.

DIAGNOSIS
History and physical examination Complete blood count- leukopenia, hemoconcentration Hematocrit- initially rises, then decreases Platelet count- thrombocytopenia (< 1,00,000) Positive tourniquet test Chest X ray- detect pleural effusion Ultrasound abdomen- rule out GI bleed viral isolation (mosquito cell lines, mosquito inoculation technique, and vertebral cell culture) serologic diagnosis detect antibodies (hemagglutination inhibition test, ELISA, complement fixation test, neutralization test, antigen capture enzyme immunosorbent assay) Molecular diagnostic methods (RT-PCR). Additional tests should be considered as indicated (and if available)-liver function, glucose, serum electrolytes, urea and creatinine, bicarbonate or lactate, cardiac enzymes, ECG and urine specific gravity.

COMPLICATION Acute renal failure Acute liver failure CNS involvement & Encephalopathy MANAGEMENT A stepwise approach to the management of dengue- WHO Step I. Overall assessment 1. History, including information on symptoms, past medical and family history 2. Physical examination, including full physical and mental assessment 3. Investigation, including routine laboratory and dengue-specific laboratory Step II. Diagnosis, assessment of disease phase and severity Step III. Management 1. Disease notification

2.

Management decisions. Depending on the clinical manifestations and other circumstances, patients may: a. be sent home (Group A) b. be referred for in-hospital management (Group B) c. require emergency treatment and urgent referral (Group C).

Management of febrile phase Rest, oral fluids For Reduction of fever: Tepid sponge after a dose of paracetamol 10-15 mg/kg/day for high fever 39C, every 4 to 6 hours Nutritional support: Soft, balanced, nutritious diet, juice and electrolyte solution - plainwater is not adequate. Avoid black- or red-colored food or drinks (may be mistaken for bleeding) Other supportive and symptomatic treatment o Domperidone -1 mg/kg/day in three divided doses in case of severe vomiting for 1-2 days. One single dose may be adequate o H2-blockers (ranitidine) - recommended in case of gastrointestinal bleeding o Antibiotic - not necessary; it may lead to complications o Intravenous fluids: In case of doubt, provide intravenous fluids, guided by serial hematocrit, blood pressure, and urine output levels. The volume of fluid should be targeted at treating mild to moderate isotonic dehydration (5-8% deficit); just correct dehydration, and discontinue it as soon as possible. If sent home Advise about warning signs and symptoms of shock and ask to report immediately if any of the following symptoms occur Clinical deterioration in defervescence (no fever or low-grade fever) Any type of bleeding Severe vomiting/abdominal pain Intense thirst Drowsiness, desire for sleeping all the time Refusal to eat or drink Cold, clammy skin and extremities, restlessness, irritability, decreased urine output or no urine for 4-6 hours Behavioral changes e.g. confusion, use of foul language Follow up Preferably everyday - from the 3rd day until afebrile for 24-48 hours. Important points to evaluate are History of bleeding, abdominal pain, vomiting, appetite, fluid intake, and urine output Physical examination: vital signs, liver size and tenderness Blood counts: WBC 5,000 cells/mm3 with lymphocytosis and increase in atypical lymphocytes and platelet counts 100,000 cells/cumm indicates progression to critical phase. Rising Hct of 10-20% indicates that the patient has progressed to the critical phase Liver function tests in every patient who shows a change in consciousness, restlessness, confusion and irritability. Management of the critical phase/DHF and dengue shock syndrome General measures Give oxygen via face mask/nasal cannula in case of shock/impending shock. NCPAP should be preferred if there is acute respiratory failure associated with DSS

Frequent monitoring Stop bleeding with proper techniques e.g. anterior nasal packing for massive epistaxis Avoid blind invasive procedures e.g. no nasogastric tube insertion, no gastric lavage Essential nursing care Sedation is needed in some cases to restrain an agitated child. Chloral hydrate(12.5-50 mg/kg), orally or rectally, is recommended. Long-acting sedatives should be avoided Monitoring of children with DHF/DSS Vital signs should be checked every 15-30 minutes until the patient is stable, and every 1-2 hours thereafter Hematocrit levels must be checked every 2 hours for 6 hours, then every 4 hours until the patient is stable. Monitoring at every 12 hours during recovery Fluid balance sheet: type of fluid, amount, rate etc Accurate measurement of urine output Serum electrolytes and blood gases should be checked every 12 hours DIC profile and liver function tests as and when indicated Weight should be measured every 12 hours Obtain laboratory tests In uncomplicated DHF cases, Hematocrit and platelet counts are the only necessary tests. In those at high risk of complicated DHF o Blood grouping/cross matching o Blood glucose o Blood electrolyte (Na, Ca, K, CO2) o Liver function test o Renal function test (BUN, creatinine, uric acid) o Blood gas o Coagulogram (PTT, PT, TT) IV fluid IV fluids should be given only when the patient enters the critical phase: thrombocytopenia 100,000, rising Hct of 10-20%. IV fluid before critical phase cannot prevent shock, but may cause fluid overload Type of IV fluid used: isotonic salt solution (normal saline or Ringer 's lactate) In young infants without shock-N/2 saline in 5% dextrose; colloid solutions in patients who already have volume overload, i.e., massive pleural effusion Fluid replacement rate minimum necessary to maintain effective circulatory volume, excess amount will leak into the pleural and peritoneal spaces Initial rate of administration DSS grade III 10 mL/kg/hour for 1-2 hours Grade IV Free flow or 20 mL/kg/dose IV bolus until BP can be measured (usually within 5-15 minutes), then reduce the rate to 10 mL/kg/hour for 1-2 hours Non-shock patients: normal maintenance or + 5%deficit and then reduce the rate to minimum after 2-4 hours, if possible. o Body weight < 15 kg: 4-7 mL/kg/hour. Body weight 15-40 kg: 3-5 mL/kg/hour Colloids: The initial rate is 10 mL/kg/hour; this will reduce Hct by about 10 percentage points e.g. from 53 to 43%. After that, reduce to 5, then to 3 mL/kg/hour Increase or decrease the rate of IV depending on: clinical signs of shock, hematocrit level, urine output fluid

In case of no response to IV fluids: consider and correct Massive plasma leakage Concealed internal bleeding decrease in Hct Hypoglycemia Blood sugar < 60 mg% Hyponatremia, hypocalcemia electrolytes Acidosis indicates metabolic acidosis in blood gas analysis Duration of IV fluid infusion: between 24-48 hours as plasma loss may continue for 24-48 hours. It should be discontinued when the hematocrit level falls to approximately 40%, with stable vital signs. A good urine flow indicates sufficient circulating volume. Reabsorption of extravasated plasma occurs 48 hours after the termination of shock (manifested by a further drop in hematocrit levels after intravenous fluid administration has been stopped), and hypervolemia, pulmonary edema or heart failure may occur if more fluid is given. It is extremely important that a drop in hematocrit levels at this later stage is not interpreted as a sign of internal bleeding. Strong pulse and blood pressure and adequate diuresis are good signs at this stage. The return of the patients appetite is also a sign of recovery. Blood and platelet transfusion The indications for fresh whole blood or packed red cell transfusion are significant blood loss > 10% (6-8 mL/kg), hemolysis, concealed internal bleeding Dose: Fresh whole blood 10 mL/kg/dose, packed red cells 5 mL/kg/dose Indication for platelet transfusion: significant bleeding with thrombocytopenia or if platelet count is less than 10,000/mm3 (10-20 mL/kgof platelets). Mild reductions in platelet counts are usually not associated with significant bleeding. Platelets return to normal within 7-9 days. Only 0.4% of DHF patients need platelet transfusion Criteria for the discharge of patients Absence of fever for at least 24 hours without the use of antifever therapy. Minimum of 3 days after recovery from shock: stable pulse, blood pressure and breathing rate. No respiratory distress from pleural effusion and no ascites. No evidence of external or internal bleeding. Good urinary output and stable haematocrit levels. Platelet count > 100,000/mm3. Convalescent confluent petechial rash. Treatment of complications 1. Electrolyte imbalance Hyponatremia Hypocalcemia 10% Ca gluconate 1 mL/kg/dose, IV push slowly every 6 hours 2. Fluid overload: Avoid the common causes of fluid overload, which are Early IV fluid therapy- in the febrile phase Excessive use of hypotonic solutions Non-reduction in the rate of IV fluid after initial resuscitation Blood loss replaced with fluids in cases with occult bleeding

Judicious fluid removal using colloids with controlled diuresis (furosemide 1 mg/kg infusion over 4 hours) or dialysis

3. Large pleural effusions, ascites Careful titration of intravenous fluids Large pleural effusions during the recovery phase after 48 hours - small doses of furosemide (0.25-0.5 mg/kg at 6 hours interval for 1 to 2 doses). Avoid insertion of intercostal drains and tracheal intubation 4. Disseminated intravascular coagulation Some seriously sick patients with bleeding and DIC have benefited from heparin therapy and cryoprecipitate (1 unit per 5 kg body weight) followed by platelets (4 units/m2 or 10-20 mL/kg) within 1 hour and fresh frozen plasma (FFP 10-20 mL/kg). Frequent clinical assessment and regular coagulation profile (PT, aPTT, fibrinogen, platelet and FDP) are mandatory, as indicated.

IVF therapy in DHF

IVF therapy in DSS

PREVENTION AND CONTROL ( Measures as per national vector borne disease control program, India) At present, no specific drug or vaccine is available against the dengue virus. The control is primarily dependent on vector control. 1) Environmental changes a) Environmental modification: Long lasting physical transformation of vector habitats. For example, improved water supply, mosquito proofing of overhead tanks, cisterns or underground reservoirs. b) Environmental manipulation: Temporary changes to vector habitats that involve the management of essential and non-essential containers and management of or removal of natural breeding sites. c) Changes in human habitations: Efforts are made to reduce man-virus contact by mosquito proofing of houses with screens on doors/windows.

2) Personal protection: protective clothing, mats, aerosol coils (pyrethrum), repellents e.g., DEET, permethrin impregnated in cloth, insecticide-treated mosquito nets and curtains. 3) Biological control: by larvivorous fish: Gambria affinis and Peorilia reticulate. Bacteria Bacillus thuringiensis H-14, Bacillus sphaericus in polluted water. 4) Chemical control: a) Larvicide: Since Ae aegypti breeds in clean water, which is stored and used for household purposes, as such all the larvicides, which are safe, without any odour or colour, have residual effect with low mammalian toxicity and do not pose any health hazard should be used. Temephos, an organophosphate compound meets all the above mentioned requirements and this insecticide is being used under the public health programme. The recommended dose for application of Temephos (50 EC) is 1 ppm (1 mg per liter of water). b) Adulticide: The following methods are recommended for the control of adult Aedes aegypti mosquitoes: I. Pyrethrum spray: It may be used in indoor situations as space spray at a concentration of 0.1% 0.2% @ 30-60 ml/1000 cu. ft. Commercial formulation of 2% pyrethrum extract is diluted with kerosene in the ratio of one part of 2% pyrethrum extract with 19 parts of kerosene (volume/volume). Thus, one litre of 2% pyrethrum extract is diluted by kerosene into 20 litres to make 0.1% pyrethrum formulation (.ready-to-spray. formulation). After dilution, pyrethrum extract is sprayed with Flit pump or hand operated fogging machine fitted with microdischarge nozzle. Malathion fogging or Ultra Low Volume (ULV) spray: In application of ULV, minimum volume of liquid insecticide formulation is applied per unit area. That is, the insecticide is broken down into small droplets of a volume median diameter (VMD) of 40-80 microns with an objective of producing a cloud of insecticide droplets that remain suspended in air for an appreciable time and driven under the influence of wind. This provides maximum effectiveness against target vectors. Since no diluent is used, the technique is more cost-effective than thermal fogging but it does not generate a visible fog. Most organophosphorus insecticides in their technical form can be applied as ULV spray. Under the public health programme, ULV spray (fogging) is undertaken by using 95% or pure technical malathion. The ground equipment mostly used for ULV spray includes portable motorized knapsack blowers and cold aerosol generators.

II.

5) Legislative Measures Suitable laws and byelaws should be enacted and implemented for regulating storage/utilization of water by communities, various agencies and avoidance of mosquitogenic conditions at construction sites, factories.

a) Model civic byelaws: Under this act fine/punishment is imparted, if breeding is detected. These measures are being strictly enforced by Mumbai, Navi Mumbai, Chandigarh and Delhi Municipal Corporations. b) Building Construction Regulation Act: Building byelaws should be made for appropriate overhead / under ground tanks, mosquito proof buildings, designs of sunshades, porticos, etc for not allowing stagnation of water vis--vis breeding of mosquitoes. In Mumbai, prior to any construction activity, the owners/builders deposit a fee for controlling mosquitogenic conditions at site by the Municipal Corporation. c) Environmental Health Act (HIA): Suitable byelaws should be made for the proper disposal/storage of junk, discarded tins, old tyres and other debris, which can withhold rain water. d) Health Impact Assessments: Appropriate legislation should be formulated for mandatory HIA prior to any development projects/major constructions. 6) Health education for community mobilization and inter-sectoral convergence 7) Vaccine A tetravalent live attenuated DEN vaccine trial has been done in Thailand. After the third dose, 89% of subjects seroconverted. The trial suggested that this vaccine has moderate, but improvable reactogenicity and high seroconversion rates against four serotypes of DEN virus. CONCLUSION Dengue is an important public health problem that causes great expenses because of temporary absenteeism from school, and undermines regional and national economic development. REFERENCES 1. Singhi S, Kissoon N, Bansal A. Dengue and dengue hemorrhagic fever: management issues in an intensive care unit. J Pediatr (Rio J). 2007;83(2 Suppl):S22-35. 2. Dengue guidelines for diagnosis, treatment, prevention and control. WHO task groupnand the Special Programme for Research and Training in Tropical Diseases (TDR). 2009. Geneva. 3. Guidelines for integrated vector management for control of dengue / dengue haemorrhagic fever. NVBDCP. Ministry of health and family welfare & DGHS. GOI. 4. http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002350/ 5. Dengue, Dengue Hemorrhagic Fever and Dengue Shock Syndrome in the Context of the Integrated Management of Childhood Illness. WHO. 2005.