DENGUE ; DENGUE HEMORRHAGIC FEVER ;

DENGUE SHOCK SYNDROME

PRESENTER - Dr. ADITYA RAHANE

GUIDE - Dr. RIZWAN AHMED
Virus

Is an arbovirus composed of single-stranded RNA

Has 4 serotypes (DEN-1, 2, 3, 4)
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.
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
Vector
• Dengue transmitted by infected female mosquito
• Primarily a daytime feeder
• Lives around human habitation
• Lays eggs and produces larvae preferentially in artificial
containers
 Replication and Transmission Infectivity Period
of Dengue Virus (about 7 days)

Extrinsic Incubation
Period (8–12 days)
1. Virus transmitted
to human in mosquito 1 Intrinsic Incubation
Period (3–14 days)
saliva

2. Virus replicates 2
in Body 4
3. Virus infects white
blood cells and 3
lymphatic tissues

4. Virus released and

circulates in blood
 Replication and Transmission of
Dengue Virus

5. Second mosquito 6
ingests virus with blood

6. Virus replicates
in mosquito midgut 7
and other organs,
infects salivary
glands 5
7. Virus replicates
in salivary glands
 Transmission of Dengue Virus by
Aedes aegypti

Mosquito feeds / Mosquito refeeds /

acquires virus transmits virus

Extrinsic Intrinsic
incubation incubation
period period
Viremia Viremia
0 5 8 12 16 20 24 28
DAYS
Illness Illness
Human #1 Human
#2
PATHOGENESIS MOSQUITO BITE AND
VIRAL INFECTION
OF DENGUE

INDIRECT INJURY
DIRECT CELLULAR
INJURY
PRODUCION OF
T CELL ACTIVATION
ANTIBODIES

INCREASED
ENDOTHELIAL DAMAGE ANTIBODY DEPENDENT
CHEMICAL
MACROPHAGE ACTIVATION ENHANCEMENT
MEDIATORS
PLATELET DESTRUCTION
AG-AB DEPOSITION
COMPLEMENT CYTOKINE STORM
ACTIVATION
IMMUNE CMPLEX
DEPOSITION
SEVERE DENGUE VASCULOPATHY COAGULOPATHY ORGANOPATHY
 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.
 Pathogenesis of DHF
STEP 1- Homologous Antibodies Form Non-
infectious Complexes

1
1

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

2 2
2

2
Dengue 2 virus
Non-neutralizing antibody to Dengue 1 virus
2
Complex formed by non-neutralizing antibody
and virus
 STEP3 - Heterologous Complexes Enter More
Monocytes, Where Virus Replicates

2
2
2
2
2
2 2
2
2

2 Dengue 2 virus

Non-neutralizing antibody
2 Complex formed by non-neutralizing
antibody and Dengue 2 virus
STEP4 –DHF pathogenesis

Infected monocytes release vasoactive

mediators, resulting in increased vascular
permeability and hemorrhagic manifestations
that characterize DHF and DSS
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.
3.HIGH VIRAL LOAD

Hyperendemicity

Increased circulation Increased probability

of viruses of secondary infection

Increased probability of Increased probability of

occurrence of virulent strains immune enhancement

Increased probability of DHF

 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.
• 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
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.
Suggested dengue case classification and
levels of severity
DENGUE CLINICAL CASE DEFINATION BY
DISEASE SEVERITY
Warning signs*
Probable dengue • Abdominal pain or tenderness
Live in /travel to dengue • Persistent vomiting
endemic area. Fever and 2 • Clinical fluid accumulation
of the following criteria:
• Mucosal bleed
1.Nausea , vomiting • Lethargy, restlessness
2.Rash • Liver enlargement > 2 cm
3.Aches and pains • Laboratory: Increase in HCT
4.Tourniquet test positive concurrent with rapid decrease in
5.Leucopenia platelet count
6.Any warning sign *(requiring strict observation
and medical intervention)
 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 or ALT > 1000
• CNS: Impaired consciousness
• Heart and other organs
 The course of dengue
illness

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

MANAGEMENT PROTOCOL
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 .
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
• 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.
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

2 3 4 5
1
Capillary Tempera Pulse Pulse
Colo refill ture Volume Rate
r
Algorithm for management of Dengue
Warning Signs
 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.
• 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
• 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.
 CHILD WITH WARNING SIGNS

OBTAIN BASELINE CBC MONITOR FLUIDS INTAKE MONITOR VITALS 4 HOURLY

CONTINUE MONITORING VITALS YES DOES THE CHILD HAS

NO CHECK HEMATOCRIT
WATCH FOR WARNING SIGNS ADEQUATE ORAL ITAKE GIVE IV ISOTONIC SOLUTIONS

GIVE ISOTONIC CRYSTALLOIDS

GROUP B IN STEP WISE MANNER
5-7 ML/KG/HR FOR 1-2 HOURS
MANAGEMENT 3-5 ML/KG/HR FOR 2-4HOURS

RECHECK HCT
REASSESS CLINICAL STATUS
 CLINICALLY STABLE ;NO CHANGE
OR MINIMAL CHANGE IN HCT

CONTINUE ISOTONIC SALINES

YES IS THE PT
2-3 ML/KG/HR FOR 2-4 CLINICALLY
HOURS STABLE

NO

RECHECK HCT
REASSESS CLINICAL STATUS

WORSENING VITAL SIGNS

AND INCREASING HCT
INCREASE IV FLUIDS TO 5-
10ML/KG/HOUR FOR 1-2
ADEQ. FLUID INTAKE AND HOURS
URINE OUTPUT AND
CLINICALLY STABLE

RECHECK HCT
REASSESS CLINICAL STATUS

REDUCE IV FLUIDS
 IS THE PT
YES
IMPROVING

GIVE ISOTONIC CRYSTALLOIDSIN

STEP WISE MANNER
5-7 ML/KG/HR FOR 1-2 HOURS
3-5 ML/KG/HR FOR 2-4HOURS NO
2-3 ML/KG/HR FOR 2-4HOURS
FOLLOW STEPS FOR GROUP C
MANAGEMENT
 GROUP C MANAGEMENT

DENGUE SHOCK SYNDROME

(COMPENSATED OR HYPOTENSIVE)

OXYGEN

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

IMPROVEMENT NO IMPROVEMENT
 IMPROVEMENT NO IMPROVEMENT

REPEAT 10-20ML/KG SECOND

START IV THERAPY ;TITRATE FLOW
BOLUS OVER 30 MINS PREFRABLY
RATE FROM
COLLOIDS
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

FURTHER IMPROVEMENT

DISCOTINUE IV FLUIDS AFTER 24-

48 HOURS
FURTHER PLAN
 NO IMPROVEMENT NO IMPROVEMENT
IMPROVEMENT
HCT RISES OR >45% HCT FALLS

10-20 ML/KG BOLUS OVER 1 HOUR PREFREBALLY COLLOID SUSPECTED BLEEDING

NO IMPROVEMENT BLOOD TRANSFUSION

10ML/KG OF WHOLE BLOOD
OR
5ML/KG PACKED RBC
LOOK FOR MYOCARDIAL DYSFUNCTION CORRECT
ACIDOSIS HYPOGLYCEMIA AND ELECTROLYTE ABN.
2D ECHO
NO IMPROVEMENT

IV INOTROPES WITH FLUID REPLACEMENT THERAPY

 WHEN TO STOP INTRAVENOUS FLUIDS

 Features of intra vascular

compartment overload
• Hypertension with good volume pulse.
• Breathing difficulties, pulmonary edema.
 48 hours after defervescence.
 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.
THANK YOU