DENGUE

SUBODH KUMAR MAHTO

PGIMER,DR.RML HOSPITAL
NEW DELHI
 Dengue fever , also known as breakbone fever, is an
infectious tropical diseases caused by the dengue
virus.
 Dengue virus belongs to flaviviridae family. The
flaviviridae are positive sense , single stranded RNA
viruses.
 AEDES MOSQUITO
Dengue is transmitted by several species
of mosquito within the genus aedes
principally Ae. Aegypti

Distinct feature is black and white stripes

on its body and legs

Bites during the day.

 Ae. aegypti females will often feed on several persons during a
single blood meal and, if infective, may transmit dengue
virus to multiple persons in a short period of time even if
they only probe without taking blood.

 Ae. aegypti prefers to lay its eggs in artificial water

containers, to live in close proximity to humans, and to feed
on people rather than other vertebrates.

 Desert coolers, Drums, Jars, Pots, Buckets, Flower vases,

Plant saucers, Tanks, Cisterns, Bottles, Tins, Tyres, Roof
gutters, Refrigerator drip pans,�Cement blocks
 With increasing spread of the vector mosquito
throughout the tropics and sub tropics, large areas of
the world have become vulnerable to the introduction
of dengue viruses.
TRANSMISSION OF DENGUE VIRUS
BY AEDES AEGYPTI
 An infection can be acquired via a single bite. A female
mosquito that takes a blood meal from a person
during the initial 2-10 days of dengue infection ,
becomes itself infected with the virus in the cells
lining its gut.
 About 8–10 days later, the virus spreads to other tissues
including the mosquito's salivary glands and is
subsequently released into its saliva. The virus seems
to have no detrimental effect on the mosquito, which
remains infected for life.
 The virus has four different types; infection with one
type usually gives lifelong immunity to that type, but
only short-term immunity to the others. Subsequent
infection with a different type increases the risk of
severe complications
FACTORS RESPONSIBLE FOR THE
RESURGENCE OF DENGUE
 Population growth

 Unplanned and uncontrolled urbanization

 Inadequate & Interrupted water supply- leading to

storage of water

 Deficient waste water management

 Failure of effective mosquito control measures

 RISK FACTORS
 Virus strain (DENV 2 and 3)
 Pre-existing anti-dengue antibody Immune
enhancement
 Previous infection
 Maternal antibodies in infants
 Hyperendemic transmission: Two or more serotypes
circulating simultaneously at high levels .
 Endemic: only one serotype prevalent in the area
 Age: more severe in children
 Ethnicity: Africans have less severe illness
 Chronic diseases (bronchial asthma, sickle cell anaemia and
diabetes mellitus)
Pathophysiology
 2 main pathophysiological changes:
 Increased vascular permeability
 Haemostatic Disorder:
 Vascular Changes
 Thrombocytopenia
 Coagulopathy
 PERSONS EXPOSED TO DENGUE VIRUS

SERUM ANTI BODIES NEUTRALIZE THE VIRUS OF

SAME TYPE.

SUBSEQUENT INFECTION --ANTIBODIES FORM

COMPLEXES BUT DO NOT NEUTRALIZE THE NEW VIRUS.

THESE COMPLEXES FACILLITATES THE ENTRY OF THE VIRUS INTO THE

MONONUCLEAR CELLS BY BINDING WITH THE Fc RECEPTORS.
INCREASED VASCULAR
PERMEABILITY
Infected monocytes

Vasoactive mediators

Increased vascular permeability

Hemorrhagic manifestations DHF, DSS

Thrombocytopenia
 Infection of human haematopoietic cellsinhibits
megakaryocytopoieses
 Increased peripheral destruction of antibody coated
platelets
 Platelet destruction in the liver and spleen.
 Platelet dysfunction(Qualitative defect)
Hemorrhage in Dengue
 Vasculopathy
 Thrombocytopenia
 Platelet dysfunction
 DIC
 Coagulopathy
 WHO 1997/2011 CASE DEFINITION OF DENGUE AND LEVELS OF
SEVERITY
 DENGUE FEVER
 Probable
An acute febrile illness with 2 or more of the following:
1. Headache
2. retro-orbital pain
3. Arthralgia
4. Rash
5. Hemorhagic manifestations
6. Leukopenia AND
Supportive serology( a reciprocal antibody titre≥1280, a comparable
IgG assay elisa titer or (+) Igm antibody on a late course or acute
convalescent phase serum specium.
Confirmed: by lab criteria
 DENGUE HEMORRHAGIC FEVER
 Fever ,or history of fever lasting for 2-7 days
 Hemorrhagic tendencies evidenced by at least one of the
following
1. positive tourniquet test
2. petechiae, ecchymosis, purpura
3. bleeding from the mucosa, GIT, injection sites or other
location.
4. hematemesis or malena
 Thrombocytopenia (≤1,00,000 cells/cumm)
 Evidence of plasma leakage due to increase vascular
permeability manifested by atleast one of the following:
1. a rise in hematocrit ≥20% above average for age sex and
population.
2. a drop in the hematocrit following volume replacement
treatment ≥20% of baseline.
3. signs of plasma leakage such as pleural effusion, ascites
and hypoproteinemia.
 DENGUE SHOCK SYNDROME
 All of the four criteria for DHF must be present plus evidence
of circulatory failure manifested by
Rapid and weak pulse, AND
Narrow pulse pressure (<20mmHG)
OR
Hypotension for age AND
Cold clammy skin and restlessness
CLINICAL FEATURES
 Tourniquet test
 Blood pressure (BP) cuff should be inflated on the upper arm of
the patient to a point mid way between systolic and diastolic
pressure for 5 min, and the number of resulting petechiae in 2.5
cm2 on the volar aspect of the forearm just distal to the
antecubital fossa should be counted

 A test is considered positive when 20 or more petechiae are

observed in the 2.5 cm2 / inch2
 Test reflects both capillary fragility and thrombocytopenia
 May not be positive in severe shock associated with DSS
 Earlier DHF, now part of DF without warning signs
Unusual Manifestations of Dengue
 Acute liver failure and encephalopathy which may be
present even in the absence of plasma leakage
 Cardiomyopathy and myocarditis
 Encephalitis and rarely AIDP
 Severe gastrointestinal hemorrhage
DISEASE COURSE
FEBRILE PHASE
 Sudden onset high grade fever.
 Non specific constitutional symptoms like headache,
myalgia, arthralgia, facial flushing etc.
 It lasts for 2-7 days.
 Mild hemorrhagic manifestation may occur.
 Monitor for the warning signs.
 CRITICAL PHASE
 The warning signs marks the beginning of the
critical phase(plasma leakage).
 Patients condition worsens when the Temperature
drops to 37.5- 38 C.
 It usually lasts for 24-48 hours.
 Progressive leucopenia, thombocytopenia are present.
 RECOVERY PHASE
 Gradual reabsorption of fluid in 48-72 hours.
 Bradycardia are common during this stage.
 WBC count usually starts to rise before platelet count
improves.
 Signs of fluid overload.(respiratory distress from
massive pleural effusion and ascites, pulmonary
oedema or congestive heart failure.
 STEP-WISE APPROACH
• Overall assessment
STEP I • History-physical exam-routine lab-dengue specific lab

• Assess disease phase and severity

STEP II

• NOTIFICATION
STEP III • Management decision (A/B/C)
 Laboratory Manifestations
 Hematocrit/ Packed cell volume:
 Measured by capillary centrifugation or automated
analyzers
 Crude estimate= Hb× 3
 Capillary values may be 5-10% higher than venipuncture
values
 May be altered by bleeding/volume replacement
Increase in Hct by 20%  DHF or plasma leakage
When previous value NA > 45% is significant
Other Manifestations
 Peripheral Smear and TLC
 Normal, Leukocytosis Leukopenia
 Lymphocytosis and Atypical lymphocytes

 Thrombocytopenia
 Automated Platelet Counters : Giant platelets;
pseudothrombocytopenia (EDTA induced platelet
aggregates).
 between day 3 - 8 following the onset of illness
Other Manifestations
 Hypoalbuminemia
 Hyponatremia
 Mild increase in AST, ALT upto 200-250
 > 1000 Hepatic involvement and severe Dengue
 ↑ PT, APTT
 ↑ Urea / Creatinine
 Mild albuminuria
 Reduced Serum Complement
Role of Ultrasonoraphy in Dengue
 Fluid accumulation:
 Pleural effusion: Right side or B/L
 Ascites
 Pericardial effusion
 Acalculous Cholecystitis
 GB wall thickening and pericholecystic fluid
 >3mm ↑ severity
 Hepatosplenomegaly
Diagnosis of Dengue virus
infection
 Laboratory criteria for
confirmation of dengue fever
 Isolation of the dengue virus from serum or autopsy
samples
 Demonstration of a fourfold or greater change in IgG or
IgM antibody titres to one or more dengue virus antigens
in paired serum samples
 Demonstration of dengue virus antigen in autopsy tissue,
serum or CSF samples by immunohistochemistry,
immunofluorescence or ELISA
 Detection of dengue virus genomic sequences in autopsy
tissue serum or cerebrospinal fluid samples by polymerase
chain reaction (PCR).
 Serological tests for dengue are not much helpful for the
clinical management except in a minority of cases where the
diagnosis is in doubt. It is mostly done to establish the
diagnosis for epidemiological information.
 Dengue NS-1 Antigen
 NS-1 is a non structural protein associated with
intracellular organalles and transported to the surface
by secretory pathways.
 More efficient with acute phase sera of primary
infection as compared to secondary dengue infection
 Soluble hexameric form found to circulate in the blood
of patients with acute dengue
 ELISA has been developed for specific detection of
Dengue NS-1 type Antigen.
 Serological tests available for
Dengue
 Hemagglutination inhibition (HI) test
 Neutralization test
 Indirect immunofluorescent-antibody test
 Complement fixation
 Dot blotting
 Western blotting
 Rapid immunochromatography test
 ELISA
MAC-ELISA ( IgM-Antibody
Capture ELISA)
 Cross reactivity between other circulating flaviviruses.
 Can not be used to determine the type of virus.
 antigens used for this assay are derived from the
dengue virus envelope protein
 MAC-ELISA has a sensitivity and specificity of
approximately 90% and 98%, respectively but only
when used five or more days after onset of fever.
IgG ELISA
 Utilizes the same viral antigens as the MAC ELISA
 Similar principle
 10 Dengue: negative IgG in the acute phase and a positive
IgG in the convalescent phase of the infection
 20 Dengue: positive IgG in the acute phase and a 4 fold
rise in IgG titer in the convalescent phase
 Requires paired sera with at least 7 day interval between
the 2 samples
Hemagglutination inhibition (HI)
test
Hemagglutination inhibition (HI)
test
 Requires paired sera with at least 7 day interval between
the 2 samples
 Cross reaction with other flaviviruses
 HI assay does not differentiate between IgM and IgG
 10 dengue: low-undetectable levels in acute sera HI
titer < 1:1280
 20 dengue: 4 fold rise between 2 samples with peak titers
> 1:2560
Rapid Tests
 Various tests are available
 Most based on “Immunochromatography”
 Give results in 30-60 minutes.
 Various commercial kits are available
 Variable sensitivity and specificity
 Accuracy in testing for IgM antibodies is lower than
ELISA.
 However, their accuracy in testing for IgG antibodies
seems to be greater than ELISA
 Can not be used for reporting or in surveillance
 1 0 Dengue vs 2 0 Dengue
10 Dengue 20 Dengue
NS-1 High Low
IgM High Low /undetectable
IgM/IgG ratio >1.2 <1.2
HI titer < 1:2560 > 1:2560
IgG paired sample -ve  +ve Both sample +ve
ELISA with 4 fold rise
Final Interpretation of Diagnostic tests
Highly suggestive
IgM + in a single serum sample
IgG + in a single serum sample with a HI titre of 1280 or greater

Confirmed
PCR +
Virus culture +
IgM seroconversion in paired sera
IgG seroconversion in paired sera; or
Fourfold IgG titer increase in paired sera
 Treatment
 Management is relatively simple, inexpensive and very
effective in saving lives so long as correct and timely
interventions are instituted.
 Main Pathological Abnormality is LOSS OF PLASMA
VOLUME FROM THE VASCULAR
COMPARTMENT because of increased capillary
permeability.
 Early and effective replacement of plasma losses with
plasma expander or fluid and electrolyte solution results in
a favorable outcome in most cases.
 TREATMENT PRINCIPLE

MONITOR
vital parameters

HEMATOCRIT PLATELET COUNTS

 Management Decisions
 Depending on the clinical manifestations and
other circumstances,
 Group A : Sent Home
 Group B: In-hospital management
 Group C: Require emergency
treatment
Group A Outpatient treatment
Who?
Able to take orally
Pass urine adequately once every 6 hrs
No warning signs particularly at defervescence of fever
What to do
Review daily for disease progression ( TLC, Hct and warning
signs)
ORS, juice and other fluids
Paracetamol (max 3gm/day)
Instruct to come back in case of warning signs or decreasing
urine output
Group B In hospital management
 Warning Signs  Co-existing Conditions:
 Abdominal pain or  Pregnancy, Diabetes, renal
tenderness failure, infancy, old age,
obesity, chronic haemolytic
 Persistent vomiting
diseases.
 Clinical fluid accumulation:
 Social Circumstances
PE, ascites
 Mucosal bleed
 Lethargy, restlessness
 Liver enlargement >2 cm
 ↑ Hct with
thrombocytopenia
 Dengue without warning signs
Encourage oral fluids

If not tolerated

Start NS or RL at
maintenance rate

No warning
signs Give minimum volume required to
maintain good perfusion Warning signs or
patient
and urine output ↑ Hct
improving

*IV fluids for few hrs

*switch to oral fluids as Continue IV fluid as per next slide
soon as possible
 Obtain Hct

isotonic solutions such as NS or RL

5–7 ml/kg/hr for 1-2 hrs

3–5 ml/kg/hr for 2–4 hr

2–3 ml/kg/hr
Vital signs
worsening; Obtain Hct and reassess Hct same or
Hct rising clinically rising minimally

2–3 ml/kg/hr for 2-4 hrs

Reduce IV fluid as Hct decreases Minimum fluid to maintain

and patient improves good perfusion and urine
*IV Fluid for 24-48hrs output =0.5 ml/kg/hr.
 Monitoring
 Vital signs and peripheral perfusion 1–4 hourly

 Urine output 4–6 hourly

 Hematocrit before and after fluid replacement, then
6–12 hourly
 Blood glucose, and other organ functions as indicated

Till the patient is out of critical period

 Group C: Require urgent treatment
in a high dependency unit
 Early presentation with shock (on days 2 or 3 of illness)
 Severe plasma leakage and/or shock
 Undetectable pulse and blood pressure
 Severe bleeding
 Fluid overload
 Organ impairment (such as hepatic damage,
cardiomyopathy, encephalopathy, encephalitis)
 Fluid resuscitation
 Fluid resuscitation in severe dengue is different from fluid
administration.
 Larger volumes of fluids administered for a limited period
 Goal is to improve central and peripheral circulation and
maintain end-organ perfusion.
 Degree of intravascular volume deficit in dengue shock varies.
 Input/output ratio is of no utility for judging the adequacy of
fluid resuscitation.
 Instead of 5-7ml/kg/hr give @ 10-20 mkl/kg/hr, if HCT dec
consider BT, if same, then maintenance dose of IVF, if increas
then give bolus again.
 Hypotensive Shock

isotonic crystalloid or colloid 20 ml/kg for 15 min

YES Clinical Improvement NO

Crystalloid/colloid 10 ml/kg/hr Review HCT

for 1 hour

IV crystalloid 5–7ml/kg/hr for 1– HCT ↑or high HCT ↓

2hrs
3–5 ml/kg/hr for 2–4hrs 2nd Bolus: Colloid 10- Consider occult/
2–3 ml/kg/hr for 2–4hrs 20ml/kg over 30 min to 1hr significant bleed
NO BT

Patient improves, Hct Improvement Repeat 2nd HCT

stable:
↓IVF to maintenance HCT ↑or high HCT ↓
level stop after 48hrs
Monitor Hct 6 hrly 3rd Bolus: Colloid 10-
20ml/kg over 1hr
NO
Repeat Hct
 Monitoring of patient in severe
Dengue (DSS)
 Alertnesss level and comfort
 Vital signs and peripheral perfusion: 15–30 minutes
1–2 hourly
 Urine output: hourly 1–2 hourly
 Hematocrit: before and after fluid boluses until stable and
then 4-6 hrly
 ABG: 30 min to 1 hrly until stable and then as indicated
 Blood glucose: before fluid resuscitation and repeat as
indicated
 KFT, LFT as indicated
Interpretation of Hematocrit
 ↑ Hct + Unstable vitals  Active Plasma Leakage
 ↑ Hct + stable vital signs  no need for extra IV fluids

 ↓ Hct + stable vitals + adequate output

haemodilution and/or reabsorption
 ↓ Hct + unstable vitals  Continued hemorrhage
 Fluids to be used in Dengue
 Crystalloids: use isotonic solutions
 NS ( Osm= 308mOsm/L)
 suitable option for initial fluid resuscitation

 large volumes hyperchloraemic acidosis

 RL ( Osm= 273mOsm/L)
 may not be suitable for resuscitation of patients with
severe hyponatremia
 Can be used after initial fluid resuscitation with NS

 avoid in liver failure and in patients taking metformin

Fluids to be used in Dengue
 Colloids:
 Dextran
 Starch
 Gelatin Haemaccel
Benefits:
 Distributed in vascular compartment
 Increase oncotic pressure
Disadvantages:
 May effect coagulation (vWF/Factor VIII)
 Allergic reactions
 May cross into the interstitium Reverse osmosis
  WHO-2012:
 Use Crystalloids first ( NS preferred as initial
resuscitation fluid over RL).
 Colloids may be used in hypotensive patients who
do not respond to a bolus of crystalloids or
PP<10mmHg.
 Colloids may also be used in patients with
obvious fluid overload but vital signs are not
stable and high Hct.
 Avoid hypotonic fluids like 5% D, N/2

*N Engl J Med 2005; 353:877-889

 When to stop IV fluids
 IV Fluid therapy can be stopped when Hct drops to 45%
in adults, 40% in children and adult females and 35% in
infants.
 Stable blood pressure, pulse and peripheral perfusion
 Afebrile for more than 24–48 days (without the use of
antipyretics)
 Resolving bowel/abdominal symptoms
 Improving urine output
Risk factors of major bleeding
 Prolonged/refractory shock;
 Hypotensive shock and renal or liver failure and/or severe
and persistent metabolic acidosis;
 Use of NSAIDs
 Pre-existing peptic ulcer disease
 Anticoagulant therapy
 Any form of trauma, including intramuscular injection.
 Clinical indicators of severe
bleeding
 Persistent and/or severe overt bleeding in the presence of
unstable haemodynamic status
 ↓ Hct + unstable vitals after fluid resuscitation
 Refractory shock that fails to respond to consecutive fluid
resuscitation of 40-60 ml/kg
 Hypotensive shock with low/normal hematocrit before
fluid resuscitation
 Treatment of haemorrhagic
complications
 5–10ml/kg of fresh-packed red cells
 Or 10–20 ml/kg of fresh whole blood (FWB)
 Fresh Whole blood is preferred
 Where possible  Use fresh blood/Packed Cells

In cases of severe bleeding, use of blood is

preferable instead of platelets and FFP
Issues in Platelet transfusion
Platelet rich plasma (PRP) when managing
thrombocytopenia

Platelets present a strong antigenic stimulus

Evoking an exaggerated immune response

Further immune mediated platelet destruction

 Criteria for Platelet Transfusion
Platelet counts of dengue patients fluctuate in an
unpredictable manner despite platelet transfusion
 Prophylactic platelet transfusions are not necessary
 Stable patients with Platelet Count <10,000/cc*
 Patients with Platelet Count < 20,000/cc with minor
bleeding
 Patients with Platelet Count < 50,000/cc with significant
bleeding

*Lyons V, Triulzi D. Transfusion Medicine Update September 1999.

Platelet Concentrate vs Apheretic
Platelets
Platelet Concentrate(Random Donor) Apheretic Platelet(SDP)

5 x 1010/unit 3.5 x 1011

1 unit increases by 5k-10k/µL 1 unit increase by 30k-60k
Loss of platelet function little loss of platelet function
Differential centrifugation from freshly by platelet-pheresis technique
drawn blood units
Cheaper Costly
More exposure to TTI Less exposure to TTI
 Dose of Platelet Transfusion
 If using Platelet Concentrate:
 10-20 ml/kg or 4 units/m² BSA over 1 hour

 If using apheretic platelet:

 1 unit of apheretic platelet over 1 hr

WHO does not recommend use of FFP in bleeding in

Dengue
 Fluid Overload: Causes
 Excessive and/or too rapid intravenous fluids
 Incorrect use of hypotonic rather than isotonic crystalloid
solutions
 Inappropriate use of large volumes of intravenous fluids in
patients with unrecognized severe bleeding
 Inappropriate transfusion of FFP, PRP and Cryoprecipitate
 Continuation of intravenous fluids after plasma leakage has
resolved
 Co-morbid conditions: CHD, IHD, COPD,CKD
 Fluid overload: recognition
 Early:  Late :
 Respiratory Distress  Pulmonary oedema
 Tachypnea  Irreversible shock
 Wheezing
 Large Pleural Effusion
 Tense Ascites
 ↑ JVP
 Management of fluid overload

O2 Inhalation

Out of Critical
Critical Phase Phase

Reduce IV fluids
Hemodynamic Shock with Shock with May give furosemide
ally stable low Hct high Hct 0.1–0.5 mg/kg OD or BD

Reduce IV May have occult Consider

fluids bleeding slow colloids
Avoid diuretics cautious BT
Criteria for discharging inpatients
 Absence of fever for at least 24 hours without the use of
antipyretic therapy
 Return of appetite
 Visible clinical improvement
 Good urine output
 Stable haematocrit
 Passing of at least 2 days after recovery from shock
 No respiratory distress from pleural effusion or ascites
 Platelet count >50 000 per mm3.
 Prevention of mosquito bite
• Install Iron Mesh at doors and
Window
• Sleep under mosquito net
• Use mosquito repellant coil
/mats
• Apply mosquito repellant oil/
cream on skin
• Cover your body with clothes as
much as possible
• Allow indoor insecticide spray
by health staff
• tetravalent, live attenuated,
recombinant vaccine, which is
currently in Phase III clinical
trials.
Thank You