A mosquito-borne viral disease occurring in tropical and subtropical areas. Spreads by animals or insects Requires a medical diagnosis Lab tests or imaging often required Short-term: resolves within days to weeks Those who become infected with the virus a second time are at a significantly greater risk of developing severe disease. Symptoms include high fever, headache, rash and muscle and joint pain. In severe cases there is serious bleeding and shock, which can be life threatening. Treatment includes fluids and pain relievers. Severe cases require hospital care.

1. Presenter: Dr.Arun Vasireddy
Dengue Fever
Subject Seminar - 6th July,2015

2. Introduction
Epidemiological Scenarios & Demographics
Etio-pathogenesis
Pathophysiology
Clinical picture
Evaluation & Diagnosis
Management of DF/DHF/DSS
Prevention & Control
Future Directions
Overview

3. • Dengue fever, a.k.a,Breakbone fever - identified as the most common
arboviral(arthropod-borne) disease worldwide by WHO.
• Transmitted by female mosquitoes of the genus Aedes,
• subtropical and tropical geographical distribution.
• 5 antigenically distinct serotypes – (DENV 1-5)
• 5TH serotype was discovered in October 2013 in malaysia.(sylvatic)
Introduction

4. GLOBAL SCENARIO (WHO,2014)
• 30-fold increase in global incidence over the last five decades.
• According to WHO, recent estimate indicates 390 million dengue infections annually ,of which
96 million manifest clinically.
• 3.5-5 lakh cases of DHF/DSS per year
• About 3900 million people, in 128 countries, are at risk of infection.
• 75% of global disease burden is in Asia-Pacific region.
• Actual no. of dengue cases are underreported/misclassified.
Source: http://www.who.int/mediacentre/factsheets/fs117/en/

6. INDIAN SCENARIO
• Dengue virus was isolated in India for the first time in 1945.
• The first recorded epidemic of clinically Dengue like illness occurred at Madras in 1780.
• The first evidence of occurrence of dengue fever in the country was reported in 1956 from
Vellore district in Tamil Nadu.
• The first dengue hemorrhagic fever(DHF) outbreak occurred in Calcutta in 1963.
• All 4 serotypes are found in Indian population
• Since 1996, the area of endemicity is increasing with about 450 million population at risk
• At present, dengue is endemic in 23 states
• Mortality rates are 10-20% (40% in case of DSS)

7. CDC Outbreak Report (southern asia) 2012-14

9. REASON FOR CHANGE IN EPIDEMIOLOGY
Incidence increased 30-fold in last 50 years due to :
Increased
proliferation of
vector &
increased virus
transmission
Rapid &
unplanned
urbanisation
Uncontrolled
population
growth
Climatic
change
Improper
water
storage
Increase in
air travel

10. Epidemiology
• It depends on 3 factors :
• Agent – virus.
• Environment.
• Host – man & mosquito.
Environment
Host/Vector
Agent

11. Agent - Dengue virus
• Dengue virus belongs the genus flavivirus.
• These viruses contain a single stranded RNA as its genome and are small in size
(30-45nm).
• There are five antigenically distinct serotypes (DENV 1-5) with abundant genetic
variation.
• These serotypes may be in circulation either in singular, or more than one can be
in circulation in any geographical area at the same time.
• Antigens can cross react with other members in the same genus.
• Infection with any one serotype confers lifelong immunity to the virus serotype.

12. • The genome encodes only 10 proteins.
• Out of ten, 3 are structural proteins that form the coat of the virus and deliver the RNA to
target cells –
• 1k4r ,the nucleocapsid of core protein,
• 1ok8, a membrane associated protein (M),
• 2r6p6, an envelope protein(E).
• 7 are non-structural (NS) proteins that orchestrate the production of new viral antigens once
the virus invades the cell - NS1, NS2A, NS2B, NS3, NS4A, NS4B and NS5
• In dengue virus infection, pts have measurable levels of NS1 protein in the blood, a diagnostic
marker of the infection.
Dengue virus
Ref: Goodsell DS. RCSB Protein Data Bank. July, 2008.

13. • DENV is transmitted by the bite of female aedes
mosquito.
• In India, Aedes aegypti is the main vector in most urban
areas.
• Rarely by Ae.Albopictus, Ae.polynesiensis, Ae.niveus in
some states.
• Population & Lifespan depends on - rainfall , water
storage, temperature and humidity.
• Year round breeding - (10⁰ C Isotherm).
• 300 N to 400 S latitude distribution - Tropics and sub-
tropics
• survives best between 16 ⁰ C and 30 ⁰ C and a relative
humidity of 60–80%.
• Altitude is also a limiting factor for the distribution and is
restricted to between sea level and 1000 ft above sea
level.
Vector/Intermediate Host

14. • To find a host, these mosquitoes are attracted to chemical compounds emitted by mammals. These
compounds include ammonia, carbon dioxide, lactic acid, and octenol.
• most commonly bite at dusk and dawn, indoors & in shady areas.
• Breed in areas of stagnant water, such as flower vases, uncovered barrels, buckets, and discarded tires, but
the most dangerous areas are wet shower floors and toilet tanks, as they allow the mosquitos to breed in
the residence.
• Research has shown that certain chemicals (fatty acids associated with bacteria involved in the
degradation organic matter in water) stimulate the female mosquitoes to lay their eggs.
• Can transmit the infection trans-ovarially.
Peculiarities of A.aegypti

15. Host - Primates
• The DENV infects humans and several species of lower primates.
• People of all ages and both genders are at risk. (more in <15 yrs age groups & in females)
• Secondary dengue infection is a risk factor for DHF, including passively acquired antibodies
in infants.
• Travel to dengue endemic areas is a most important risk factor.
• Migration of a patient during viremia to a non-endemic area may introduce dengue into
that area.
• The geographical spread of dengue has been reported to occur mainly by people travelling
from endemic areas to non-endemic areas.

16. How dengue is transmitted?
Because of the high level of viraemia resulting from DENV infection of humans, the
viruses are efficiently transmitted between mosquitoes and humans without the need
for an enzootic/sylvantic amplification host.
Whitehead SS, Blaney JE, Durbin AP, Murphy BR. Prospects for a dengue virus vaccine.
Nature Reviews Microbiology 5, 518-528 (1 July 2007)
Available from: http://www.nature.com/nrmicro/journal/v5/n7/full/nrmicro1690.html

17. Transmission & Pathogenesis
Viremia Viremia
Extrinsic
incubation
period
DAYS
0 5 8 12 16 20 24 28
Human #1 Human #2
Illness
Mosquito feeds /
acquires virus
Mosquito refeeds /
transmits virus
Intrinsic
incubation
period
Illness

18. Increased Probability of DHF
Hyper-endemicity
Increased circulation
of viruses
Increased probability
of secondary infection
Increased probability of
occurrence of virulent strains
Increased probability of
immune enhancement
Increased probability of DHF

19. Neutralizing antibody to Dengue 1 virus
Dengue 1 virus
Pathogenesis of DHF (ADE)
STEP 1- Homologous Antibodies Form Non-
infectious Complexes
Non-neutralizing antibody
Complex formed by neutralizing antibody and virus

20. Non-neutralizing antibody to Prior DENV infection
Dengue 2 virus
STEP 2- Heterologous Antibodies of first serotype
infection form Infectious Complexes with second
serotype
Ag-Ab Complex formed by non-neutralizing antibody
and virus

21. STEP 3 - Heterologous Complexes Enter More
Monocytes & macrophages, Where Virus Replicates
Non-neutralizing antibody
Dengue 2 virus
Complex formed by non-neutralizing
antibody and Dengue 2 virus

22. STEP 4 –DHF pathogenesis
• The affected macrophages release vasoactive mediators that increase vascular permeability,
leading to vascular leakage, hypovolemia, and shock.
• Infants born to mothers who have had dengue, as maternally derived dengue neutralizing IgGs
wane, are also thought to be at risk for enhanced disease.
• Activation of classic complement pathway & Cross reactivity at T-cell level results in increased
production of IFN-γ & TNF-α leading to Increased vascular permeability & bleeding
• Antibody dependent enhancement (ADE) & inappropriate memory T-cell response are central to
pathogenesis of DHF/DSS

23. 1. Vasculopathy
2. Thrombopathy with impaired platelet function & moderate-severe thrombocytopenia
(due to interaction of virus with platelets through IgM antiplatelet antibody)
3. Coagulopathy, with activation of coagulation & fibrinolysis, and later in severe
disease,DIC.
4. Bone Marrow depression – reduced megakaryocyte production
Mechanism – Suppressed megakaryocytopoiesis & increased platelet
clearance by DENV induced apoptosis & antiplatelet antibodies.
Pathogenesis of DHF –Abnormal Haemostasis

24. FACTORS RESPONSIBLE FOR DHF/DSS
• Presence of enhancing and non neutralising antibodies
• Age : susceptibility to DHF/DSS drops significantly after 12 yrs of age
• Sex : females more often affected than males
• Race : Caucasians more often affected than blacks
• Nutritional status : malnutrition is protective
• Sequence of infection : example, serotype 1 followed by serotype 2 is more dangerous than
serotype 4 followed by serotype 2
• Infecting serotype : type 2 more dangerous than others
• Infecting genotype : Asian type 2 causes DHF/DSS while American type is not responsible for the
illness

25. Dengue Clinical Syndromes
I. Undifferentiated fever
II. Classic dengue fever
III. Dengue hemorrhagic fever
IV. Dengue shock syndrome

27. Natural course
The clinical course of illness passes through 3 phases:
• Febrile phase
• Critical phase
• Convalescent phase

29. Febrile phase
• The onset of dengue fever is usually with sudden rise in temperature which may be
biphasic, lasting 5-8 days and commonly associated with headache, flushing and rash.
• There may be pain in retro-orbital area, muscles, joint or bone.
• Rash may be maculopapular or rubelliform and usually appear after 3 or 4 day of fever and
commonly seen in face, neck and other part of the body which generally fades away in the
later part of the febrile phase.
• Localized cluster of petechiae may appear over upper and lower limbs.

30. Febrile rash of dengue which blanches
upon pressure.
Convalescent rash of dengue – "White
islands in the sea of red".
• During the first 24-48 hours of fever, children may develop a transient generalized macular
erythematous rash which blanches upon pressure.
• The convalescent rash of dengue fever appears about 2-3 days after defervescence.
• It is characterized by generalized confluent petechial rash which does not blanch upon
pressure, with multiple small round islets of normal skin. It is otherwise called "white islands
in a sea of red".

31. Critical phase
• DF/DHF patients usually go to critical phase after 3 to 4 days of onset of fever.
• During this critical phase plasma leakage and high haemoconcentration are
documented and patients may develop hypotension.
• Abnormal haemostasis and leakage of plasma leads to shock,bleeding,
accumulation of fluid in pleural and abdominal cavity.
• High morbidity and mortality in DHF/DSS are commonly associated with various
organ involvements and metabolic derangement.
• The period of plasma leakage usually persists for 36-48 hrs.

32. Convalescent phase (recovery)
• During the recovery phase the extracellular fluid which was lost due to capillary leakage
returns to the circulatory system and signs and symptoms improve.
• This phase occurs after 6-7 days of fever and last for 2-3 days. (48-72 hours)
• Longer convalescence may be expected in some of the patients with severe shock, organ
involvement and other complications which may require specific treatment.
• Patient may develop pulmonary oedema due to fluid overload if the fluid replacement is
not optimized carefully.

33. Vascular symptoms:
Hypovolaemia
Low blood pressure
Shock
Hepatic injury
Fluid pooling in
body cavities
Gall bladder
thickening
Haemorrhaging
within organs
Infrequent
complications:
Encephalitis
Acute pancreatitis
Renal failure
Myocarditis
Splenic rupture
Pulmonary haemorrhage
Vascular symptoms:
Leukopenia
Thrombocytopenia
Neutropenia
Late eosinophilia
Reduced coagulation
Skin symptoms:
Rash
Bruising
Petechiae
Purpura
Joint pain
Altered haematopoiesis
Bleeding gums,
nose and eyes
Headache,fever
Vomiting
Intestinal bleeding
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John ALS, Abraham SN, Gubler DJ.
Barriers to preclinical investigations of anti-dengue immunity and dengue pathogenesis
Nature Reviews Microbiology 11, 420–426 (2013)
Available from: http://www.nature.com/nrmicro/journal/v11/n6/full/nrmicro3030.html

34. Clinical Evaluation in Dengue Fever
• Blood pressure
• Evidence of bleeding in skin or other sites
• Hydration status
• Evidence of increased vascular permeability-- pleural
effusions, ascites
• Tourniquet test

35. Tourniquet Test
• Inflate blood pressure cuff to a
point midway between systolic and
diastolic pressure for 5 minutes
• Positive test: 20 or more petechiae
per 1 inch2 (6.25 cm2)

36. WORK UP OF A PATIENT WITH DENGUE
1. Laboratory diagnosis
• Virus isolation
• Genome detection
• Antigen detection
• Serological diagnosis
2. Supportive investigations

37. LABORATORY DIAGNOSIS
• Virus isolation : - cultured mosquito cells /mammalian cells used
- “gold standard”
- low sensitivity and long detection time
• Genome detection :
• nested RT-PCR
• single step RT-PCR
• NASBA assay

38. • Antigen detection :
• E/M antigen
• NS I antigen
• Serological diagnosis : ELISA
• IgM & IgG antibody detection

39. APPROXIMATE TIME-LINE OF PRIMARY AND SECONDARY
DENGUE INFECTIONS & DIAGNOSTIC METHODS THAT CAN
BE USED TO DETECT INFECTION
-2 -1 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16-20 21-40 41-60 61-80 90 >90 Days
ONSET OF SYMPTOMS (IN DAYS)
NS1 DETECTION
VIRUS ISOLATION
RNA DETECTION
VIRAEMIA
IgM PRIMARY
IgM SECONDARY
IgG PRIMARY
IgG SECONDARY

40. COMPARISON OF DIAGNOSTIC TESTS ACCORDING TO
THEIR ACCESSIBILITY AND CONFIDENCE
DIRECT METHODS INDIRECT METHODS
ACCESSIBILITY
CONFIDENCE
VIRUS
ISOLATION
GENOME
DETECTION
NS1
ANTIGEN
SEROLOGY
IgM
SEROLOGY
IgG

41. INTERPRETATION OF DENGUE
DIAGNOSTIC TESTS
Highly suggestive Confirmed
One of the following:
• IgM + in a single serum sample
• IgG + in a single serum sample
with a HI titre of 1280 or greater
One of the following:
• PCR +
• Virus culture +
• IgM seroconversion in paired sera
• IgG seroconversion in paired sera
or fourfold IgG titer increase in
paired sera

42. ROUGH GUIDE FOR INTERPRETATION OF
DENGUE SEROLOGY REPORTS
IgM IgG INTERPRETATION
Negative Negative Early sample/not dengue
Negative Positive (low titre) Past dengue infection
Negative Positive (high titre) Secondary dengue infection
Positive Negative Primary dengue infection
Positive Positive (low titre) Recent primary dengue infection
Positive Positive (high titre) Secondary dengue infection

43. SUPPORTIVE INVESTIGATIONS
• Complete blood count (CBC)
• Metabolic panel
• Serum protein and albumin levels
• Liver panel
• Disseminated intravascular coagulation (DIC) panel
• Chest X-Rays - Effusion
• USG Abdomen - Ascites

44. Characteristic findings in dengue fever :
• Thrombocytopenia (platelet count < 100 x 109/L)
• Leukopenia
• Mild to moderate elevation of aspartate aminotransferase and alanine
aminotransferase values
In patients with dengue hemorrhagic fever:
• Increased hematocrit level secondary to plasma extravasation and/or
third-space fluid loss
• Hypoproteinemia
• Prolonged prothrombin time
• Prolonged activated partial thromboplastin time
• Decreased fibrinogen Increased amount of fibrin split products

45. MARKERS FOR SEVERE DISEASE
• Increased urinary levels of heparan sulphate
• Increased plasma levels of pentraxin 3
• Decreased serum albumin
• Increased levels of vascular endothelial growth factor (VEGF)
• Increased levels of soluble vascular cell adhesion molecule – 1
(VCAM-1)

46. DIFFERENTIAL DIAGNOSIS
• Dengue-like diseases [Chikungunya fever , West Nile fever (with rash) & Colorado tick
fever, sandfly fever, Rift Valley fever, and Ross River fever (without rash)]
• Early stages of malaria
• Mild yellow fever
• Viral hepatitis
• Leptospirosis
• Viral respiratory and influenza like diseases

47. MANAGEMENT OF DF/DHF/DSS

48. OUTPATIENT MANAGEMENT OF A PATIENT WITH
DENGUE
• Advise bed rest
• Encourage plenty of oral fluid intake (of oral rehydration solution (ORS),
fruit juice and other fluids containing electrolytes and sugar)
• Give paracetamol for high fever if the patient is uncomfortable.
• Inform the patient about the warning signs

49. INDICATIONS OF HOSPITALISATION
Suspect severe dengue and the need for hospitalisation when patient
develops :
• Giddiness
• cooler extremities compared to trunk & extremities
• Oliguria with dark urine
• Rt. hypochondriac pain or severe abdominal pain
• Bleeding from any site
• Persistent vomiting
• Lethargy or irritability/restlessness

50. MANAGEMENT PRIORITIES OF A PATIENT
WITH SEVERE DENGUE
1) Replacement of plasma losses
2) Recognition & management of hemorrhage
3) Prevention and management of fluid overload
4) Prevention of iatrogenic infections

51. INITIAL INPATIENT MANAGEMENT
• Establish IV access
• Collect samples for blood group, Hb, PCV and platelets
• Monitor :
- Pulse volume
- Blood pressure
- Abdominal girth
- Urine output

52. Choice of fluids: Crystalloid vs colloid
• Colloids provide volume expansion over and above actual fluid volume infused.
• Crystalloids have no added volume effect.
• Major concerns with use of colloids are impact on coagulation and allergic reaction.
 Hence, crystalloids are ideal for initial resuscitation & colloids better serve in severe shock
with undetectable blood pressure.

53. Choice of fluids: NS vs RL
• NS preferred over RL due to risk of worsening tissue acidosis and lactate accumulation
when large volumes of RL is infused repeatedly
• Large volumes of 0.9% saline may lead to hyperchloraemic acidosis (this may aggravate or
be confused with lactic acidosis from prolonged shock)
• When serum chloride level the normal range, it is advisable to change to Ringer’s
Lactate.

54. APPROACH TO A PATIENT OF SEVERE DENGUE &
COMPENSATED SHOCK
- Stabilise ABC
- Fluid resuscitation (with 1-3 ml/kg/h of NS/RL
over 1 hr )
Observe for improvement (2 hours)
Algorithm 1 Algorithm 2
yes no

55. APPROACH TO A PATIENT OF SEVERE DENGUE &
HYPOTENSION
- Stabilise ABC
- Fluid resuscitation (with 10-20 ml/kg of isotonic
crystalloid /colloid over 15 min ; 1-2 bolus
-Obtain baseline HCT (before fluids)
- Correct hypoglycemia & hypocalcemia
Observe for improvement
Algorithm 1 Algorithm 2
yes no

56. ALGORITHM 1 (for improving patient)
-Maintainance IV crystalloid / colloid @ 1-3ml/kg/hr after every 2-4 hrs
- Monitor HCT 6 hrly
Check for recurrence of clinical
instability & review HCT
HCT increases HCT decreases
Bolus fluid or
increase IV fluid rate
Consider fresh
BT

57. ALGORITHM 2 (for deteriorating patient)
If shock persists inspite of 2-3 rounds of algorithm 2, then the patient is said to be in refractory
shock
Review baseline HCT
High
Low
Improvement
Whole
blood/PRBC
Algorithm
1
Recheck
hematocrit
Algorithm 2*
Yes
No
Give 2nd bolus of crystalloid (colloid in
hypotensive shock)

58. APPROACH IN REFRACTORY SHOCK
Evaluate for unrecognised morbidities
Consider CVP if expertise available
CVP low / HCT high
CVP normal or high with
continuing shock , HCT normal
-Titrate fluid with care
- consider ventilation /nasal
CPAP in cases with respiratory
distress
-Consider
ionotropes/vasopressors
Consider ionotrope support depending on
SBP
- Dopamine/adrenaline(for low SBP)
- Dobutamine (for normal/high SBP)
Check intra abdominal pressure

59. UNRECOGNISED MORBIDITIES THAT MAY
CONTRIBUTE TO REFRACTORY SHOCK
CLINICAL CONDITION TREATMENT
• Occult bleed
• Co-existing bacterial septic shock
/malaria
• Myocardial dysfunction
• Elevated intra-abdominal pressure
• Positive pressure ventilation
contributing to poor CO
• Widespread hypoxic ischemic injury
with terminal vasoplegic shock
• Whole blood/PRBC transmission
• Antibiotics/antimalarial plus BT plus
cardiovascular support
• ECHO plus cadiovascular support
• Cautious drainage
• Titrated fluid plus cardiovascular support
• No treatment effective

60. TREATMENT OF HEMORRHAGIC COMPLICATIONS
OF DF/DHF/DSS
• Give 5–10ml/kg of fresh-packed red cells or 10–20 ml/kg of fresh whole blood at an appropriate
rate and observe the clinical response
• Infusion of 600 ml FFP may contribute to a significant increase in platelet count in the first 12 hours,
but not thereafter. (Fc receptor blocade inhibiting Immune-mediated platelet destruction)
• Consider repeating the blood transfusion if there is further blood loss or no appropriate rise in
haematocrit after blood transfusion.
• Factor VIIIa (100 microg/kg) - effective in restoring hemostasis in a limited series of patients with
Dengue Shock Syndrome exhibiting life-threatening bleeding episodes.
• There is little evidence to support the practice of transfusing platelet concentrates and/or fresh-
frozen plasma for severe bleeding. It is being practised when massive bleeding can not be managed
with just fresh whole blood/fresh-packed cells, but it may exacerbate the fluid overload.

61. MANAGEMENT OF CONGESTIVE PHASE
• Change over to hypotonic fluid
• Decrease infusion rate to 3-5 ml/kg BW/hr
• Diuretics & digitalisation needed in patients with cardiac
overload due to regurgitant fluid

62. DOs & DON’Ts OF DF/DHF/DSS
DOs DON’Ts
• Avoid IM injections
• Administer paracetamol for high
fever
• Use isotonic intravenous fluids for
severe dengue
• Give intravenous fluid volume just
sufficient to maintain effective
circulation during period of plasma
leakage for severe dengue
• Tight glycemic control
• Administer aspirin or ibuprofen for
fever
• Use hypotonic intravenous fluids for
severe dengue
• Excessive or prolonged intravenous
fluid during severe dengue

63. SPECIAL CONSIDERATIONS
• Insertion of following carries risk of hemorrhage
• Nasogastric tube – Orogastric tube preferred
• Intercostal drain - Judicious use of I.V fluids and furosemide avoids ICDs
• Central venous line– Intra osseous route preferable
• Corticosteroids are of no benefit in reducing complications.
• Efficacy of heparin not documented.

64. SIGNS OF RECOVERY
• Stable pulse, BP & breathing rate
• Normal temperature
• No evidence of external/internal bleeding
• Return of appetite
• No vomiting
• Good urinary output
• Stable hematocrit
• Convalescent confluent petechial rash

65. PROGNOSIS
• Poor prognostic indicators include :
• Early & profound shock with no detectable diastolic pressure or unrecordable BP.
• Delayed admission to hospital
• DSS with gastrointestinal hemorrhage
• Causes of death in a case of DHF/DSS :
• Failing to recognize that a patient is in shock
• Hemorrhages
• Failing to recognize that patient has entered congestive phase

66. HOW TO PREVENT DENGUE?
• There is no vaccine for preventing dengue.
(Currently, a tetravalent live attenuated CYD dengue vaccine is in stage III of trial in
over 30,000 volunteers in >10 countries of asia & america)
• Best preventive measure – Eliminate Mosquito breeding spots.

67. Change water in vases on alternate days
Remove water from flower-
pot plates on alternate day
Turn over water
storage containers
Clear blockages and put
insecticide in roof gutters
monthly

68. • Proper application of mosquito repellents containing 20% to 30% DEET as
the active ingredient on exposed skin and clothing decreases the risk of
being bitten by mosquitoes
• Biologic & Genetic manipulation of mosquitoes to reduce life span.
• The risk of dengue infection for international travelers appears to be small.
• There is increased risk if an epidemic is in progress or visitors are in housing
without air conditioning or screened windows and doors.

69. • Dengue is one of the world’s most imp emerging diseases
• Rising global incidence & explosive epidemics – Major challenge.
• Further advances :
• Further understand immunopathogenisis & pathophysiology
• Identification of better therapeutic agents.
• Improved diagnostics – early detection to guide evidence based practice.
• To Predict epidemics early.
• Develop an effective & balanced functional Vaccine for all serotypes.
• To address the public about the disease as a global threat.
Conclusion & Future Directions

70. References:
 Harrison’s principles of Internal Medicine 18th Ed.
 Manson's Tropical Infectious Diseases 23rd Ed.
 Park's Textbook of Preventive and Social Medicine 22/e
 Api textbook of medicine 10th Ed.
 Ferri's Clinical Advisor 2015
 Online Source:
 WHO & CDC Factsheets (2013-15)
 Medscape reference.