Management of Dengue

TUESDAY UNIT
 Introduction
• Most rapidly spreading mosquito-borne viral disease in
the world
• Approximately 390 million cases per year
• Incidence has increased 30-fold with increasing
geographic expansion to new countries and, in the
present decade, from urban to rural settings
• Number of cases have increased by eight fold
• Vast majority of cases are asymptomatic and hence
actual numbers of dengue cases are under reported
and many cases are misclassified.
• The disease is now endemic in more than 100
countries
• The first case of dengue was reported in 2004.
In 2006, large number of probable
cases and 32 laboratory-confirmed cases were
reported across hospitals in central and western
Terai
• Since 2010, dengue epidemics
have continued to affect lowland districts as well
as mid-hill areas
 Epidemiology- agent
• Members of the genus Flavivirus in the
family Flaviviridae
• 1943, Ren Kimura and Susumu Hotta first
isolated the dengue virus in 1943 from cases of
Nagasaki Epidemic
• In 1944 ,Albert B. Sabin and Walter isolated
DEN1 -1
 Agent (contd.)
• Four serotypes: DEN1/DEN2/DEN3 and DEN4
• Called serotypes because each has different
interactions with the antibodies in human blood
serum
• Share approximately 65% of their genomes

• Despite these variations, infection with each of

the dengue serotypes results in the same
disease and range of clinical symptoms
Distribution of serotypes
 Dengue virus- structure

• Ss 50 nm in size NS genes help in viral replication and assembly

• 180 copies of EM
protein
• Entry into the cells

Nature Publishing Group Guzman, M. G. et al. Dengue: A continuing global threat. Nature Reviews

Microbiology 8, S7–S16 (2010)
 Transmission
• Mosquito to human transmission
– The virus is transmitted to humans through
the bites of infected female mosquitoes,
primarily the Aedes aegypti mosquito
• Maternal to fetal

• Blood transfusion/organ transplantation

 Vector characteristics- Aedes
• Lives in urban habitats and breeds mostly in man-
made containers and a day-time feeder; its peak
biting periods are early in the morning and in the
evening before sunset 
• Female A.aegypti frequently feed multiple times
between each egg-laying period 
• Aedes albopictus: is vector is some places
• In Nepal,the dengue closely follows monsoon
season with seasonal cases occurring between
September and November
 Dengue virus replication

Mukhopadhyay, S., Kuhn, R. J., & Rossmann M. G. A structural perspective of the flavivirus life cycle. Nature Reviews Microbiology 3, 13–22 (2005)
 Host: Risk factors for severe disease

• Secondary infection
• Age: young children
• Possibly chronic diseases
– bronchial asthma,
– sickle cell anaemia and
– diabetes mellitus
Pathogenesis mechanisms
 Plasma leakage

• Functional destructive effects on endothelial cells.

– Activation of infected monocytes and T cells, the
complement system
– Production of cytokines ,monokines and mediators
– Production of mediators
 DHF & Bleeding
Thrombocytopenia, vasculopathy, platelet
dysfunction, DIC
Bleeding may occur from any site, but commonest
site of severe bleed is GIT
Does not always correlate with platelet counts
 Mechanism of thrombocytopenia
• Alterations in megakaryocytopoieses by the
infection of human haematopoietic cells and
impaired progenitor cell growth, resulting in
platelet dysfunction (platelet activation and
aggregation)
• Increased destruction or consumption (peripheral
sequestration and consumption).
 Dengue: mechanism of
thrombocytopenia
• Dengue virus can enter platelets but replicate viral
ribonucleic acid to a minimal extent and, therefore,
cannot produce infectious virus
• Increase in CD14+CD16+monocyte-platelet complexes
• Immune clearance of these complexes may
contribute to thrombocytopenia

Open Forum Infect Dis. 2017 Mar 23;4(2):ofx051.

 Bleeding and platelets
• Thrombocytopenia: alterations in
megakaryocytopoieses by the infection of human
haematopoietic cells and impaired progenitor cell
growth
• Platelet dysfunction (platelet activation and
aggregation)
• Increased destruction or consumption (peripheral
sequestration and consumption).
 Dengue infection: clinical features
• Dengue is one disease entity with different clinical
presentations and often with unpredictable clinical
evolution and outcome
• Incubation period: 4-10 days
• Most infections are subclinical.
• The illness begins abruptly and is followed by the
three phases
– febrile,
– critical and
– recovery
 Dengue: febrile phase
• Sudden onset high-grade fever lasts for 2–7 days
• Facial flushing, skin erythema, generalized body ache,
myalgia, arthralgia, headache, eye pain, anorexia, nausea
and vomiting
• Occasionally : sore throat, inflammed pharynx and
conjunctival congestion
• A positive tourniquet test in some patients
• Haemorrhagic manifestations: petechiae and mucosal
bleeding (e.g. nose and gums) may be seen
• Easy bruising and bleeding at venipuncture site in some
• Enlarged tender liver from 2-5 days
• Progressive decrease in total white cell count
 Dengue critical phase
• Between 3-7 days of onset of fever when defervescence
sets in
• Bleeding and Shock
• Hemoconcentration, progressive fall in platelets
• Severe organ impairment such as severe hepatitis,
encephalitis or myocarditis and/or severe bleeding (may
also develop without obvious plasma leakage or shock)
 Dengue recovery phase
• After 24–48 hour critical phase, a gradual reabsorption of
extravascular compartment fluid takes place in 48–72 hrs
• General well-being improves, appetite returns, gastrointestinal
symptoms abate, haemodynamic status stabilizes and diuresis
ensues.
• Some patients may have a rash of “isles of white in the sea of
red”
• Some may experience generalized pruritus, bradycardia and
electrocardiographic changes .
• Occasionally respiratory distress due to pulmonary edema
• HCT stabilizes or may be lower due to the dilution.
• TLC starts to rise soon after defervescence
• Recovery of platelet count : takes longer
Clinical course of dengue infection
Skin rashes in dengue fever

Maculopapular rashes on day1-3 of illness

Erythematous rash with central clearing

Positive Tourniquet Test
Mucosal bleeds in severe Dengue fever
 CNS Involvement
• Diagnosis: demonstration in CSF
– anti-DENV immunoglobulin (Ig)M
– viral RNA or
– NS1
– virus from the CSF
• Excluding other causative agents of viral brain diseases
• Morbidities: encephalitis, encephalopathy, menigitis,
stroke, cerebellar syndrome, transverse myelopathy

Front. Cell. Infect. Microbiol. 2017; 7:449.

 Dengue in immunocompromized
children
• Diagnostic problems: Neutropenia, thrombocytopenia
due to chemotherapy or other opportunistic
infections: need for high index of suspicion.
• Clinical features:
– More severe illness
– Higher requirement of fluids
– More hepatic dysfunction
– Delayed recovery of platelet counts

Indian Pediatr. 2017 Apr 15;54(4):330-331

Dengue case definition and
severity
 Investigations
• CBC- Hct, WBC count, platelet count
 Falling WBC f/b falling platelet count by Day 3 or
4 of illness is almost surely dengue
 Steep drop in platelet count with rising HCT
compared to baseline  progression to plasma
leakage/critical phase
 A normal CBC in the febrile phase does not
exclude dengue.
Dengue specific diagnostic tests
Antigen detection- NS1
• Serum sample
• Fever < 5 days
• Early diagnosis (acute
phase samples)
• Low sensitivity for
secondary infection (due to
preexisting antivirus IgG
antibody).
Antibody detection- IgM ELISA
• Serum sample
• Fever ≥ 5 days
• Does not differentiate
between serotypes.
• Batch testing increases
reporting time.
 Management Approach
• Classify:
– Dengue fever
– Dengue with warning signs
– Severe dengue

• Hemodynamic assessment
• Treatment according to classification
 Classification
Dengue ± warning signs Severe dengue

1. Severe plasma leakage

With
Without 2. Severe haemorrhage
warning signs 3. Severe organ impairment

Criteria for dengue ± warning signs Criteria for severe dengue

Probable dengue Warning signs 1. Severe plasma leakage
Live in or travel to dengue- •
Shock (DSS)

Abdominal pain or
endemic area. Fever and 2 of
•
Fluid accumulation with resp
tenderness distress
the following: 
Persistent vomiting

Nausea, vomiting  Mucosal bleed
2. Severe bleeding

Rash

Aches and pains  Lethargy; restlessness 3. Severe organ involvement
 Tourniquet test positive  Liver enlargement >2 cm
•
Liver: AST or ALT ≥1000
 Leucopenia  Clinical fluid accumulation
•
CNS: Impaired consciousness
Any warning sign
•
Impaired cardiac function/ other
Increase in HCT with


organ dysfunction
concurrent rapid decrease in
Lab-confirmed dengue
(important when no sign of plasma leakage)
platelet count
 Treatment of dengue
without warning signs
• Symptomatic ambulatory treatment
– Bed rest
– Oral hydration- ORS, milk, coconut water, rice water
– Paracetamol for fever- avoid NSAIDs
• Daily monitoring: Clinical, PCV, platelet count
• Refer for admission in presence of
– Cold extremities,
– Restlessness, confusion, extreme lethargy/ drowsiness
– Acute abdominal pain, frequent vomiting
– Decreased urine output, (adequate: 4-6 times/day i.e. once every 4-
6 h)
– Bleeding
– Rising PCV and thrombocytopenia without clinical symptoms.
 Treatment

Dengue with
warning signs
Hospitalization
Severe dengue
IVF in dengue- when, what, how much
and how fast?
• Febrile phase: limit IVF, encourage oral
• Critical phase: IVF required for ~ 24 to 48 h
• Recovery phase: IVF should be stopped
• Isotonic crystalloid solutions (RL, NS)
• Colloids-
– Profound hypotensive shock (PP< 10mm Hg)
– After 20-30 ml/kg of crystalloids
– Persistently high Hct after crystalloid
administration in shock state
 Treatment of dengue
with warning signs (not in shock)
• Initiate IVF RL/NS
– 5-7 ml/kg/h for 1-2 h
– 3-5 ml/kg/h for 2-4 h
– 2-3 ml/kg/h  taper and stop over 24- 48 h

• PCM

• Monitoring-
– Hourly vitals- PR, RR, BP
– Oral intake, urine output 4-6 hrly,Hct

• CBC 4-6 hourly depending on trend and severity of clinical

condition
Management of
severe dengue
 Algorithm for management of compensated shock
Compensated shock (SBP maintained+ signs of poor perfusion)

Initiate IV therapy 10-20ml/kg/h crystalloid solution over 1 h

No Improvement

Improvement Check Hct

Hct rises or >45% Hct falls

Successively reduce IVF:
10ml/kg/h for 1-2 h
IVF colloid/crystalloid Suspect bleed
7ml/kg/h for 2 h
10-20ml/kg over 1 h
5ml/kg/h for 4 h
3ml/kg/h Blood transfusion
No Improvement 10ml/kg WB or
PRBC @5ml/kg/h
Further improvement

Improvement No Improvement
Discontinue IVF
after 24-48 h IV inotropes with
maintenance fluid
Algorithm for management of uncompensated shock
Hypotensive shock

O2, Rapid bolus 20ml/kg crystalloid/colloid solution over 15-30 min

No Improvement

Improvement Check Hct

Successively reduce IVF: Hct rises or >45% Hct falls

10ml/kg/h for 1-2 h
7ml/kg/h for 2-4 h IVF colloid/crystalloid 10- Suspect bleed
5ml/kg/h for 2-4 h 20ml/kg over 30-60 min
3ml/kg/h for 2-4 h Blood transfusion
No Improvement 10ml/kg WB or
PRBC
Further improvement

No Improvement
Improvement
Discontinue IVF at
IV inotropes with
48 h
maintenance fluid
Treatment of hemorrhagic manifestations

• Petechial spots or mild mucosal bleed but

hemodynamically stable:
– No role of prophylactic PRP
– Supportive care: bed rest, no IM injections,
monitoring.
– If indicated insert NG tube with great care and
avoid trauma.
Treatment of hemorrhagic manifestations

• Severe bleeding: hemodynamic instability, excessive

mucosal bleed
– Blood transfusion with monitoring.
– Little evidence to support transfusing platelets and/or FFP
for severe bleeding.
– When massive bleeding can not be managed with fresh
whole blood/fresh-packed cells: FFP and PRP may be
considered.
– Platelet transfusion-
• < 10,000/cumm without bleeding
• < 40,000/cumm with bleeding
Monitoring in severe dengue
• Monitoring intravascular volume and circulation- the most
crucial aspect of management
• Severe dengue patients should be admitted to
HDU/PICU– continuously monitor ECG, pulse oximetry ±
arterial pressure
• Bladder catheterization
• “5-in-1 magic touch”: Colour of extremities, CFT,
Temperature, pulse volume, pulse rate (CCTV-R) and
BP–
– Every 15–30 min until out of shock, then every 1–2 h
 Monitoring in severe dengue
• Respiration – Excessive fluid accumulation or metabolic
acidosis.
• Strict intake-output charting

• Bedside IVC measurement, ECHO

• Lung USG for pleural effusion, fluid overload

• HCT every 2 h for 6 h, then every 4 h

• Serum electrolytes, blood gases every 12 h

• DIC profile, RFT, LFT as & when indicated
• No improvement: look for cardiac dysfunction
(myocarditis), anemia, acidosis and treat accordingly.
 When to stop IV fluid
• signs of cessation of plasma leakage
• stable BP, pulse and peripheral perfusion
• hematocrit decreases in the presence of a good
pulse volume
• apyrexia (without the use of antipyretics) for more
than 24–48 hours
• resolving bowel/abdominal symptoms;
• improving urine output.
 Discharge criteria
• Afebrile for 48 h, atleast 24 h.
• Clinically stable with stable hematocrit and rising
trend in platelet count.
– Platelet count >50,000/cumm.
– Adequate urine output.
 Prognosis in DHF
• Mortality: 40 – 50 % if left untreated
• Early recognition of illness, careful monitoring
and appropriate fluid therapy alone < 1 %
• Prognosis depends on: duration and severity
of peripheral circulatory failure
• Poor in severe dengue (DSS), adolescent
girls, prolonged shock and associated
complications (DIC, acidosis, cardiac
dysfunction)
 Take home messages
• Dengue is not merely a platelet deficiency disease-
multiorgan involvement.
• Diagnosis- NS1 Ag in febrile phase, IgM thereafter.
• Management supportive.
• Cautious fluid administration.
• No role of prophylactic platelet transfusion.
• Monitoring: clinical and HCT (frequently in first 6 h).
• No improvement- think of myocardial dysfunction,
acidosis, anaemia.
THANK YOU