Dengue Fever

Introduction
• 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)

 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/
REASON FOR CHANGE IN EPIDEMIOLOGY
Incidence increased 30-fold in last 50 years due to :

Climatic
change
Uncontrolled Improper
population water
growth storage

Increased
Rapid & proliferation of Increase in
unplanned vector &
increased virus air travel
urbanisation transmission
 Epidemiology
• It depends on 3 factors :
• Agent – virus.
• Environment.
• Host – man & mosquito.
Agent Environment

Host/Vector
 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.
 Vector/Intermediate Host
• 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.
Transmission & Pathogenesis

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
 Increased Probability of DHF
Hyper-endemicity

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

 Pathogenesis of DHF (ADE)
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
STEP 2- Heterologous Antibodies of first serotype
infection form Infectious Complexes with second
serotype

2 2
2

2
Dengue 2 virus
Non-neutralizing antibody to Prior DENV infection
2
Ag-Ab Complex formed by non-neutralizing antibody
and virus
 STEP 3 - Heterologous Complexes Enter More
Monocytes & macrophages, 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
 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
 Pathogenesis of DHF –Abnormal Haemostasis

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.
Dengue Clinical Syndromes

I. Undifferentiated fever

II. Classic dengue fever

III. Dengue hemorrhagic fever

IV. Dengue shock syndrome

 Natural course
The clinical course of illness passes through 3 phases:

• Febrile phase
• Critical phase
• Convalescent phase
 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.
 • During the first 24-48 hours of fever, children may develop a transient generalised 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".

Febrile rash of dengue which blanches Convalescent rash of dengue – "White

upon pressure. islands in the sea of red".
 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.

 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.
Clinical Manifestations of
DENV Infection

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
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
 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)
 WORK UP OF A PATIENT WITH DENGUE

1. Laboratory diagnosis
• Virus isolation
• Genome detection
• Antigen detection
• Serological diagnosis

2. Supportive investigations
 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
 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

 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
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
MANAGEMENT OF DF/DHF/DSS
 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

 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
 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
 INITIAL INPATIENT MANAGEMENT

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

ye
no
s
Algorithm 1 Algorithm 2
 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 Consider fresh

increase IV fluid rate BT
 ALGORITHM 2 (for deteriorating patient)
Review baseline HCT

High

Low
Give 2 bolus of crystalloid (colloid in
nd

hypotensive shock)

Algorithm Whole
1 Improvement
blood/PRBC
Yes
No

Recheck Algorithm 2*
hematocrit
If shock persists inspite of 2-3 rounds of algorithm 2, then the patient is said to be in refractory
shock
 APPROACH IN REFRACTORY SHOCK

Evaluate for unrecognised morbidities

Consider CVP if expertise available

CVP normal or high with

CVP low / HCT high
continuing shock , HCT normal

-Titrate fluid with care Consider ionotrope support depending

- consider ventilation /nasal on SBP
CPAP in cases with respiratory - Dopamine/adrenaline(for low SBP)
distress - Dobutamine (for normal/high SBP)
-Consider
ionotropes/vasopressors
Check intra abdominal pressure
 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.
 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
 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
 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
 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.

 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
 Conclusion & Future Directions
• 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.