1) Dengue virus has 4 serotypes and is transmitted by Aedes aegypti mosquitoes. It causes fever, rash, and in severe cases hemorrhage and shock. 2) Antibody-dependent enhancement and cytokine storms contribute to severe dengue by increasing vascular permeability. Secondary infection by a new serotype poses the greatest risk. 3) Dengue classification includes dengue fever, dengue with warning signs (abdominal pain, vomiting, etc.), and severe dengue involving shock, organ impairment, or severe bleeding. Proper classification guides treatment and monitoring.

1. DENGUE ; DENGUE
HEMORRHAGIC FEVER ;
DENGUE SHOCK
SYNDROME
PRESENTER - Dr. ADITYA RAHANE
GUIDE - Dr. RIZWAN AHMED

2. Virus
Is an arbovirus composed of single-stranded RNA
Has 4 serotypes (DEN-1, 2, 3, 4)

3. VIRUS STRUCTURE
SINGLE STRANDED RNA VIRUSES (FLAVIVIRIDIAE) WITH
LIPID ENVELOPE
Structural proteins -
1.Capsid protein C
2.Membrane protein M
3.Envelope glycoprotein E -
• The amino acid sequences of the E proteins determine the antibody
neutralizing activity that classifies DENV into 4 serotypes: DENV1, 2, 3 and 4.
• The E protein also interacts with cellular receptor(s) which initiates viral entry.

4. 2.Non-structural proteins-
NS1, NS2a, NS2b, NS3, NS4a, NS4b, and NS5
• Function in RNA replication and assembly and in viral protein
processing.
• Can also modify the host immune system.
• NS1 is the only non-structural protein with a soluble form that
can be detected in circulation.
• Infected by one dengue serotype provides lifelong immunity to
that particular virus, but other serotypes have no cross
protective immunity. Thus, persons living in an area of endemic
dengue can be infected with three, and probably four, dengue
serotypes during their lifetime

5. Vector
• Dengue transmitted by infected female mosquito
• Primarily a daytime feeder
• Lives around human habitation
• Lays eggs and produces larvae preferentially in artificial
containers

6. Replication and Transmission
of Dengue Virus
1. Virus transmitted
to human in mosquito
saliva
2. Virus replicates
in Body
3. Virus infects white
blood cells and
lymphatic tissues
4. Virus released and
circulates in blood
3
4
1
2
Infectivity Period
(about 7 days)
Extrinsic Incubation
Period (8–12 days)
Intrinsic Incubation
Period (3–14 days)

7. Replication and Transmission of
Dengue Virus
5. Second mosquito
ingests virus with blood
6. Virus replicates
in mosquito midgut
and other organs,
infects salivary
glands
7. Virus replicates
in salivary glands
6
7
5

8. Transmission of Dengue Virus by
Aedes aegypti
Viremia Viremia
Extrinsic
incubation
period
0 5 8 20 24 28
12 16
DAYS
Human #2
Illness
Mosquito feeds /
acquires virus
Mosquito refeeds /
transmits virus
Intrinsic
incubation
period
Illness
Human #1

9. MOSQUITO BITE AND
VIRAL INFECTION
SEVERE DENGUE
PRODUCION OF
ANTIBODIES
ENDOTHELIAL DAMAGE
MACROPHAGE ACTIVATION
PLATELET DESTRUCTION
INDIRECT INJURY
DIRECT CELLULAR
INJURY
AG-AB DEPOSITION
COMPLEMENT
ACTIVATION
IMMUNE CMPLEX
DEPOSITION
INCREASED
CHEMICAL
MEDIATORS
T CELL ACTIVATION
ANTIBODY DEPENDENT
ENHANCEMENT
CYTOKINE STORM
VASCULOPATHY COAGULOPATHY ORGANOPATHY
PATHOGENESIS
OF DENGUE

10. Pathogenesis
1.Antibody-dependent enhancement (ADE) MOST
IMPORTANT MECHANISM FOR SEVERE DENGUE
Circulation of infection‐enhancing antibodies at the time of
infection 🢫 strongest risk factor for development of severe disease.
• Rapid activation of the complement system.
• Capillary damage ‐ internal redistribution of fluid, resulting in
• hemoconcentration,
• hypovolemia,
• increased cardiac work,
• tissue hypoxia,
• metabolic acidosis, and
• hyponatremia.

11. 1
Pathogenesis of DHF
STEP 1- Homologous Antibodies Form Non-
infectious Complexes
Dengue 1 virus
Neutralizing antibody to Dengue 1 virus
Non-neutralizing antibody
Complex formed by neutralizing antibody and virus

12. 2
STEP2- Heterologous Antibodies of first
serotype infection form Infectious Complexes
with second serotype
Dengue 2 virus
Non-neutralizing antibody to Dengue 1 virus
Complex formed by non-neutralizing antibody
and virus
2
2

13. 2
2
2
2
2
2
2
STEP3 - Heterologous Complexes Enter More
Monocytes, Where Virus Replicates
Dengue 2 virus
2
Non-neutralizing antibody
Complex formed by non-neutralizing
antibody and Dengue 2 virus
2

14. STEP4 –DHF pathogenesis
Infected monocytes release vasoactive
mediators, resulting in increased vascular
permeability and hemorrhagic manifestations
that characterize DHF and DSS

15. 2.Role of NS 1 antigen-
• The adherence of NS1 and of the DENV E protein to the
glycocalyx (major GAG in endothelium), and the resulting
damage. could alter the permeability properties of the
microvascular layer; alterations to microvascular layer
contribute to the vascular leak
• NS1 directly activated human peripheral blood mononuclear
cells via Toll-like receptor 4 (TLR4), which leads to
generation of proinflammatory cytokines and chemokines
that are responsible for vascular leak.

16. 3.HIGH VIRAL LOAD
Hyperendemicity
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

17. 4. T CELL IMMUNE PATHOLOGY
• Due to Abnormal T-lymphocyte activation leading to cytokine storm
• Coincident with defervescence there is sudden surge of cytokines
(Cytokine Tsunami) in symptomatic secondary dengue infections. This
cytokine Tsunami is believed to be responsible for pathognomonic
DHF vasculopathy.
• Some of the noted changes are: high concentrations of soluble
interleukin 2 receptor, soluble CD4, soluble CD8, interleukin 2, and
interferon gamma, soluble tumour necrosis factor receptors, soluble
CD8, soluble interleukin 2 receptors, interleukin 10 etc. CCL2, a protein
that reduces tight junctions of vascular endothelium cells is found to
be consistently high in DHF/DSS patients.

18. • Levels of these cytokines correlate with severity of dengue
disease.
• Dengue non- structural protein NS3 is the predominant
epitopes which react with antigen responsive T lymphocytes.
• It has been hypothesized that the number of cells presenting
the dengue viral antigen to T lymphocytes is markedly
increased during a secondary infection; this in turn generates
Tcell immune pathology

19. NEW CLASSIFICATION OF DENGUE
As per new guidelines this disease is now classified into three
categories:-
(1) dengue
(2) dengue with warning signs
(3) severe dengue
whereas the clinical course of the disease is divided in three
phases: febrile, critical, and recovery.

20. Suggested dengue case classification and
levels of severity

21. DENGUE CLINICAL CASE DEFINATION BY
DISEASE SEVERITY
Probable dengue
Live in /travel to dengue
endemic area. Fever and 2
of the following criteria:
1.Nausea , vomiting
2.Rash
3.Aches and pains
4.Tourniquet test positive
5.Leucopenia
6.Any warning sign
Warning signs*
•Abdominal pain or tenderness
• Persistent vomiting
• Clinical fluid accumulation
• Mucosal bleed
• Lethargy, restlessness
• Liver enlargement > 2 cm
• Laboratory: Increase in HCT
concurrent with rapid decrease in
platelet count
*(requiring strict observation and
medical intervention)

22. CRITERIA FOR SEVERE DENGUE
1.Severe plasma leakage leading to:
• Dengue Shock Syndrome
• Fluid accumulation with resp. Distress
2.Severe bleeding as evaluated by clinician
3.Severe organ involvement
• Liver:AST orALT > 1000
• CNS: Impaired consciousness
• Heart and other organs

23. The course of dengue illness
1. Febrile Phase
2. Critical Phase
3. Recovery Phase

24. The course of dengue illness

25. 1.Febrile Phase:-
• Following a short incubation period of two to seven days, there is an
abrupt onset of high grade fever.
• During fever whole body is invariably covered with blanchable
erythematous rash

26. • The flush deepens with advancing disease. In few of these
patients a classical macula papular exanthem may erupt on
the top of erythematous flush.
• Adolescents and older children often suffer from headache,
retro-orbital pain, photophobia, backache, myalgia and
arthralgia

27. • Mild haemorrhagic manifestations like petechiae and mucosal
membrane bleeding may be seen, however massive gastrointestinal
bleeding commonly reported in adults during febrile phase is sporadic
in children.
• Leucopenia , and mild thrombocytopenia are some of the commonly
observed haematological changes during febrile phase of dengue
illness.
• After a period of 2-7 days majority patients make a smooth and
complete recovery but some of the patients may deteriorate with
defervescence and they could pass into a critical phase. The initial
clinical features are not clearly distinguishable between severe and non-
severe dengue cases; therefore it is imperative that the patient should
be under strict monitoring for warning signs so that cases progressing to
the critical phase could be timely identified.

28. 2. CRITICAL PHASE
• Around the time of defervescence, in some of the patients an
increase in capillary permeability sets in. Extravasations of plasma,
through these leaky capillaries result into progressive
hemoconcentration.
• A parallel drop in platelets and progressive leukopenia usually
precedes plasma leakage. Together these changes mark the
beginning of the critical phase. Patients in this phase would display
many of the above mentioned warning signs.
• In majority of the cases the leak is transient lasting for a few hours,
once it stops patient quickly stabilizes and completely recovers.
According to new classification these patients should be classified
as Dengue with warning signs.

29. A new category Severe dengue is created :-This category has
three types of patients:
(1) Patients with severe plasma leakage: [A] Shock {cold
clammy peripheries, prolonged CRT, narrow pulse
pressure, fall in systolic pressure}, [B] Fluid accumulation
resulting into respiratory distress.
(2) Patients with profuse bleeding
(3) Patients with significant organ involvement: [A] Hepatic
involvement {Transaminases >1000}. [B] Patients with
neurological involvement. [C] Patients with cardiac
involvement.

30. 3.RECOVERY PHASE:-
• After a couple of days the leakage stops and the plasma which had
extravasated during the leaky phase returns to circulation. Patient
starts passing copious amount of dilute urine, develop bounding
pulse, wide pulse pressure and rise in blood pressure.
• Appetite improves and patient feels better. Hemoconcentration
resolves; due to dilutional effect hematocrit may go lower than
normal.
• Around 9th day of the sickness, platelets start increasing and it
becomes normal over next couple of days.

31. • Patients with profound leak usually need massive resuscitative
fluid therapy during critical phase. With the resolution of
vascular leak, the extravasated fluid returns to the vascular
compartment.
• This returning fluid may cause congestive heart failure
manifesting as tachycardia, tachypnea, muffling of heart sounds
and basal rales. Massive pleural effusion and ascitis may further
add to respiratory distress.
• This phase most of the times last for twelve to twenty-four
hours and intense monitoring is needed during this time. The
respiratory distress might be so intense that the patient may
need an oxygen support and decongestive (diuretics) therapy.

32. • As in recovery phase of severe dengue patient is
hemodynamically unstable and regularly needs close
clinical observations and intensive therapy; which is
against the tenet of recovery.
• In severe dengue, recovery would be considered only
after uneventful passage of this stage of disease. It
should better be named as congestive or regurgitation
phase.

33. Probable adverse events in the course of
dengue illness
Febrile Phase
• Dehydration
• High fever
• May cause
neurological
disturbances and
febrile seizures in
young children
Critical Phase
• Shock from
plasma leakage
• Severe
haemorrhage
• Organ
impairment
• Recovery Phase
Hypervolaemia
• Worsening
effusions
• Acute pulmonary
edema

34. ORGANOPATHY AND EXPANDED DENGUE
SYNDROME
1.HEPATITIS-
• Hepatomegaly and liver impairment in form of elevated
transaminases is common occurrence in dengue illnesses
• The intensity of these enzymes increase on the third day after the
infection of the disease; it reaches its highest point on the seventh or
the eighth day and it decreases to normal values within three to
eight weeks approximately.
• This disease is self-limiting but severe hepatitis with elevated
transaminases, hemorrhages and hepatic failure culminating in to
death is also seen in some patients.

35. 2. NEUROLOGICAL COMPLICATIONS
• Dengue infections can cause variety of neurological
manifestations; prominent among them are irritability
insomnia seizures , unconsciousness, myositis, spasticity and
paresis.
• Current research suggests that dengue especially DEN- 2 and
DEN- 3 has strong neurotropism and can cause encephalitis
due to direct viral invasion of the brain.
• Most neurological events are seen early in the febrile phase
and are unrelated to the perfusion status.

36. 3. Cardiac Complications:-
• Transient benign bradycardia was known to occur with
dengue illnesses;
• Myocarditis from dengue is mainly expressed by changes
in heart rhythm (tachyarrhythmias and bradyarrhythmias)
and ventricular dysfunction (reduction of left ventricular
ejection and global hypokinesia elevated cardiac
enzymes are noted in some of the recent studies.
• Fortunately, the majority of changes are transient and
reversible.

37. 4. Neuromuscular Disorders:-
• Like other viral infections, autoimmune reaction in nervous system
can follow in dengue infection, Guillain-Barré androme (GBS),
neuromyelitis optica and optic neuritis, the acute disseminated
encephalomyelitis are some of reported immunological dysfunction
in dengue
• Three major complications: (1) myositis, (2) hypokalemic paralysis,
and (3) GBS manifest with flaccid quadriparesis. Occasionally,
these complications may be life-threatening.

38. Lab Diagnosis:-
1.Complete Blood Count
• A hematocrit test in the early febrile phase establishes the
patient's own baseline value which serves as reference figure
for any change occurring during further course of disease.
• A decreasing white blood cell count increases the probability
of a dengue diagnosis. Rapid and sequential fall in platelet
count points to disease progression; progressive rise in
hematocrit in consecutive samples suggests evolution to
critical phase (DHF) of disease.

40. 2.Rapid Immunochromatographic Tests (Screening
test).
• Offer immunochromatographic tests using rapid strips that
detect NS1. IgM, and IgG antibodies,they provide early and
quick diagnosis.
• Tests are especially useful in peripheries where ELISA or
other methods are unavailable.
• Regrettably, these rapid tests are inconsistent and offer
differing degrees of sensitivity and specificity

41. 2.Nonstructural 1 Antigen
• NS1 a soluble antigen of dengue virus appears in patient's
blood as early as second day of illness and may persist all
through the viremic phase that is febrile period of the disease.
• NS1 carries a high sensitivity and specificity for dengue
diagnosis, particularly when elicited by ELISA.
• In secondary dengue infection, exceptionally NS1 may be
falsely undetectable as IgG antibodies from first infection may
form antigen (NS1) antibody complexes and leaves hardly
any free NS1 antigen to be detected

42. 3.Immunoglobulin M Antibodies
• Detection of IgM antibodies against dengue is concurrent with
the disappearance of viremia and fever.
• Primary infection is characterized by detectable levels of IgM
antibodies by day 5 or day 6 after onset of fever; levels peak
at about 14-15 days and can remain high up to 30-60 days
later, and then decline gradually over time.
• IgM antibody capture ELISA (MAC- abo) is a fast and simple
test used for the detection of IgM antibodies

43. 4.Immunoglobulin G Antibodies
• Immunoglobulin G antibodies against dengue are elevated
after the eighth or ninth day of the onset of fever and are
detectable for life. In secondary infection, very high levels of
IgG antibodies against dengue are observed from the second
or third day of fever.
• The presence of IgG antibodies in serum generally IgG
antibody titer in a serum sample Indicates past infection
.However, the presence of high IgG antibodies in serum or a
four-fold or greater increase in the antibody titer in paired
serum samples obtained indicates recent infection or
confirmed infection, respectively.

44. Tourniquet Test
1. Take the patient's blood pressure and
record it, for example, 100/70.
2. Inflate the cuff to a point midway between
SBP and DBP and maintain for 5 minutes.
3. Reduce and wait 2 minutes.
4. Count petechiae below antecubital fossa.
A positive test is 10 or more petechiae per 1 square inch.
• More likely to be positive near time of effervescence
• Less likely to be positive in patients with shock
 Pan American Health Organization: Dengue and Dengue Hemorrhagic Fever: Guidelines for Prevention
and Control. PAHO: Washington, D.C., 1994: 12.

45. MANAGEMENT PROTOCOL

46. MONITORING
Frequent and through monitoring is the foundation for
successful dengue treatment done by H2 assessment-
Hematocrit
Hemodynamic
1.HEMATOCRIT-
• Monitored before and after every fluid bolus then 4-6 hourly
once patient is stabilized
• Serves as an indicator to severity of dengue; rising HCT
suggests severe dengue .

47. 2.HEMODYNAMIC ASSESSMENT-
1.Peripheral pulses: A nicely perceptible peripheral pulse is a sign of
adequate perfusion. Imperceptible or feeble peripheral lower limb
pulses (posterior tibial and dorsalis pedis) particularly during
replacement fluid therapy indicate higher fluid requirement.
2.Pulse pressure:
• Dengue shock is unusual in the term that a slow leak occurs over
several days; this permits compensatory mechanisms to come
into play.
• Before the development of overt cardiovascular collapse, the
diastolic pressure rises to meet the systolic pressure, and the
pulse pressure narrows; therefore, narrowing of the pulse
pressure is the most significant parameter for defining dengue
shock

48. • Maintaining pulse pressure of more than 20 mm Hg is one of
the most important goal for IV fluid therapy. A narrow pulse
pressure less than 20mm Hg is an indication for stepping up IV
fluid rate.
3.Urine Output
• Urine output gives vital information about end organ perfusion;
it should be checked hourly till the patient is out of shock and
there after 4-6 hourly until patient is out of risk.
• In a shocked patient continuous bladder catheter enables
correct monitoring of urine output. An acceptable urine output
would be above 0.5 mL/kg/h.

49. The “5-in-1 maneuver” magic touch – CCTV-R
Hold patient’s hand to evaluate peripheral perfusion
Save life in 30 seconds by recognizing shock
1
Color
2
Capillary
refill
3
Tempera
ture
4
Pulse
Volume
5
Pulse
Rate

50. Algorithm for management of Dengue
Warning Signs

51. Group A
Outpatient Management
Outpatient treatment of dengue entails two important aspects:
1. Management of hydration and
2. Management of fever
Parents or care takers should be given following instructions:
• Give a set goal for child's fluid intake [100- 150 mL/kg body
weight (BW). Fluids could be oral rehydration solution, water,
milk, buttermilk, fruit juices, etc.
• Instruct to collect child's urine and compare the output against
fluid intake; passing scanty urine with adequate oral fluid intake
should alert for vascular leak.

52. • Do not use aspirin, ibuprofen, mefenamic acid, nimesulide, or
other nonsteroidal anti-inflammatory drugs for fever or pain as
these drugs interfere with platelet functioning Solely use
paracetamol for pain and fever.
• Watch for warning signs, viz. scanty urine, giddiness,
restlessness, anxiety, vomiting severe abdominal pain, cold
extremities, and hemorrhage.
• A handbill in patient's own language describing warning signs
should be an integral part of dengue prescription

53. • Instruct the care-givers that the patient should be brought to
hospital, immediately if any of the following symptoms
emerge around the time of defervescence: deterioration or
no clinical improvement, severe abdominal pain, persistent
vomiting, cold and clammy extremities, lethargy or
irritability/restlessness, bleeding (e.g. black stools or coffee-
ground vomiting), not passing urine for more than 6 hours.

54. CHILD WITH WARNING SIGNS
MONITOR FLUIDS INTAKE MONITOR VITALS 4 HOURLY
OBTAIN BASELINE CBC
DOES THE CHILD HAS
ADEQUATE ORAL ITAKE
CONTINUE MONITORING VITALS
WATCH FOR WARNING SIGNS
CHECK HEMATOCRIT
GIVE IV ISOTONIC SOLUTIONS
YES NO
GIVE ISOTONIC CRYSTALLOIDS
IN STEP WISE MANNER
5-7 ML/KG/HR FOR 1-2 HOURS
3-5 ML/KG/HR FOR 2-4HOURS
RECHECK HCT
REASSESS CLINICAL STATUS
GROUP B
MANAGEMENT

55. WORSENING VITAL SIGNS
AND INCREASING HCT
INCREASE IV FLUIDS TO 5-
10ML/KG/HOUR FOR 1-2
HOURS
IS THE PT
CLINICALLY
STABLE
CONTINUE ISOTONIC SALINES
2-3 ML/KG/HR FOR 2-4
HOURS
RECHECK HCT
REASSESS CLINICAL STATUS
ADEQ. FLUID INTAKE AND
URINE OUTPUT AND
CLINICALLY STABLE
REDUCE IV FLUIDS
CLINICALLY STABLE ;NO CHANGE
OR MINIMAL CHANGE IN HCT
YES
NO
RECHECK HCT
REASSESS CLINICAL STATUS

56. IS THE PT
IMPROVING
YES
NO
FOLLOW STEPS FOR GROUP C
MANAGEMENT
GIVE ISOTONIC CRYSTALLOIDSIN
STEP WISE MANNER
5-7 ML/KG/HR FOR 1-2 HOURS
3-5 ML/KG/HR FOR 2-4HOURS
2-3 ML/KG/HR FOR 2-4HOURS

58. DENGUE SHOCK SYNDROME
(COMPENSATED OR HYPOTENSIVE)
IMPROVEMENT
IMMEDIATE RAPID VOLUME REPLACEMENT 10-20ML/KG OF IV FLUIDS AS RAPID BOLUS OVER 30 MINS
10ML/KG FOR COMPENSATED SHOCK
20ML/KG FOR HYPOTENSIVE SHOCK
NO IMPROVEMENT
GROUP C MANAGEMENT
OXYGEN

59. DISCOTINUE IV FLUIDS AFTER 24-
48 HOURS
FURTHER IMPROVEMENT
START IV THERAPY ;TITRATE FLOW
RATE FROM
10-7ML/KG/HR FOR 2-4 HOURS
5-3ML/KG/HR FOR 2-4 HOURS
3-1.5/KG/HR FOR 2-4 HOURS
NO IMPROVEMENT
IMPROVEMENT
REPEAT 10-20ML/KG SECOND
BOLUS OVER 30 MINS PREFRABLY
COLLOIDS
FURTHER PLAN

60. NO IMPROVEMENT
HCT FALLS
NO IMPROVEMENT
HCT RISES OR >45%
IMPROVEMENT
NO IMPROVEMENT
10-20 ML/KG BOLUS OVER 1 HOUR PREFREBALLY COLLOID
NO IMPROVEMENT
BLOOD TRANSFUSION
10ML/KG OF WHOLE BLOOD
OR
5ML/KG PACKED RBC
SUSPECTED BLEEDING
LOOK FOR MYOCARDIAL DYSFUNCTION CORRECT
ACIDOSIS HYPOGLYCEMIA AND ELECTROLYTE ABN.
2D ECHO
IV INOTROPES WITH FLUID REPLACEMENT THERAPY

62. WHEN TO STOP INTRAVENOUS FLUIDS
 Features of intra vascular compartment
overload
• Hypertension with good volume pulse.
• Breathing difficulties, pulmonary edema.
 48 hours after defervescence.

63. Discharge criteria
(all of the following conditions must be present)
Clinical • No fever for 48 hours.
• Improvement in clinical status
• General well-being,
• Good appetite,
• Haemodynamic status,
• Normal urine output,
• No respiratory distress
Laboratory • Increasing trend of platelet count(above
50,000)
• Stable haematocrit without intravenous
fluids.

64. THANK YOU