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Guideli
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DengueFever&DengueHaemorrhagicFever
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May2023
 Ministry of Health
Sri Lanka
National Guidelines

Guidelines on Management of
Dengue Fever & Dengue
Haemorrhagic Fever
in Children and Adolescents

In Collaboration with the

Sri Lanka College of Paediatricians

Revised Edition
2023 May
 Ministry of Health
Sri Lanka
National Guidelines

Guidelines on Management of Dengue Fever & Dengue

Haemorrhagic Fever in Children and Adolescents

Developed by in collaboration with

National Dengue Control Unit

&

ISBN 978-624-6042-01-1

ii
 This guideline was revised by the following committee.
(Names appear in alphabetical order)

Dr Jagath Amarasekera Consultant Community Physician,

National Dengue Control Unit
Dr Prasad Chathurangana Senior Lecturer,
Faculty of Medicine, University of Colombo
Dr Amali Dalpatadu Secretary,
Sri Lanka College of Paediatricians
Dr Sri Lal de Silva Consultant Paediatrician,
National Dengue Control Unit
Dr D. S. Anoja F Dheerasinghe Consultant Community Physician,
National Dengue Control Unit
Dr LakKumar Fernando Clinical Head,
Centre for Clinical Management of Dengue &
Dengue Haemorrhagic Fever, Negombo
Prof Manori Gamage Professor in Paediatrics,
Faculty of Medicine, Sri Jayawardenepura
Dr Shanthini Ganesan Consultant Paediatrician,
Colombo South Teaching Hospital
Dr Nimalka Pannila Hetti Consultant Community Physician,
National Dengue Control Unit
Dr Viraj Jayasinghe Consultant Paediatrician,
Lady Ridgeway Hospital, Colombo
Dr Nalin Kitulwatte Consultant Paediatric Intensivist,
Lady Ridgeway Hospital, Colombo
Prof Guwani Liyanage President,
Sri Lanka College of Paediatricians
Prof Randula Ranawaka Professor in Paediatric Nephrology.
Faculty of Medicine, University of Colombo
Prof Deepthi Samarage Consultant Paediatrician,
Neville Fernando Hospital

iii
 Dengue guideline committee 2012

Dr LakKumar Fernando

Dr Samantha Waidyanatha

Dr Shanthini Ganesan

Dr Devan Mendis

Dr Sri Lal de Silva

Dr Lilanthi de Silva

Dr Nalin Kitulwatte

Dr Rasanayake Mudiyanse

Prof Deepthi Samarage

Prof Asvini Fernando

Dr Sunethra Gunasena

Dr Jayantha Weeraman

Dr Hasitha Tissera

iv
 Message from the Director General of Health Services,
Ministry of Health, Sri Lanka

Among many communicable diseases prevalent in the Asian region,

dengue continues to be a major health problem having continuous
epidemics in many countries, where in Sri Lanka an increasing number of
children and adolescent patients are being reported.

The revised “Guidelines on the Management of Dengue Fever and Dengue

Haemorrhagic Fever in Children and Adolescents’’, developed by the Sri
Lanka College of Paediatricians in collaboration with the National
Dengue Control Unit of the Ministry of Health, is expected to provide the
necessary knowledge for improved patient management and fill any gaps
regarding the above topic. I take this opportunity to thank all experts who
were involved in developing this guideline.

I am sure this document will help in strengthening case management in

both public and private settings in Sri Lanka and have a positive influence
in reducing the number of severe cases and deaths due to dengue among
children and adolescents in Sri Lanka.

Dr Asela Gunawardena
Director General of Health Services

v
 Message from the Deputy Director General (Public Health
Services) 1,
Ministry of Health, Sri Lanka

Dengue has become a major public health issue in recent years, with high
morbidity, and considerable mortality. It remains a major health problem
among children and adolescents as well.

Nevertheless, Sri Lanka has made notable progress in reducing the case
fatality rate as a result of improved clinical care and various intersectoral
activities on dengue prevention and control. “Guidelines on the management
of Dengue Fever and Dengue Haemorrhagic Fever in Children and
Adolescents’’, developed in 2010 have greatly contributed to this
achievement. In the context of further strengthening and reshaping clinical
management with the latest evidence, the Sri Lanka College of
Paediatricians in collaboration with the National Dengue Control Unit of
the Ministry of Health has revised the guidelines.

The latest “Guidelines on the Management of Dengue Fever and Dengue

Haemorrhagic Fever in Children and Adolescents’’ is a complete guide which
could be utilized at all levels of health care providers in both public and
private settings in Sri Lanka to provide evidence-based treatment to
children and adolescents with dengue fever, dengue haemorrhagic fever
and expanded dengue syndrome.

vi
I appreciate the immense contribution of all the stakeholders; the Sri
Lanka College of Paediatricians and National Dengue Control Unit in this
endeavour.

Dr S.M. Arnold
Deputy Director General (Public Health Services) 1

vii
 Message from the President,
Sri Lanka College of Paediatricians

In recent years Sri Lanka has successfully reduced the incidence and
mortality from dengue infection in children and adolescents. Improved
early detection and a standardized treatment protocol with enhanced
diagnostics at all medical care institutions will further reduce mortality.

The need to revise the national dengue management guidelines was a long-
standing need, and the Sri Lanka College of Paediatricians was pleased to
lead the revision. We considered this project a top priority, and I thank all
our members who contributed.

These guidelines provide recommendations for all Paediatricians and

healthcare professionals caring for children with dengue infection. This
clinical framework is intended to provide a structure for the outpatient and
in-patient management. The recommendations within this guide are based
on existing principles of management of dengue infection and expert
consensus opinion in the absence of high-quality evidence.

I hope that these guidelines will assist clinicians in saving the lives of
children with dengue in this country.

Professor Guwani Liyanage

President, Sri Lanka College of Paediatricians

viii
 Message from the Director,
National Dengue Control Unit

Dengue fever and Dengue haemorrhagic fever have made a significant

impact on disease morbidity and mortality in the country in the recent past.
The out-patient and in-ward departments of most hospitals in Sri Lanka
are observing an increase in the number of child and adolescent patients
with dengue over the recent years. The growing number of children
infected with the dengue virus can have poor outcomes if early
identification and proper medical care are overlooked.

“Guidelines on the management of Dengue fever and Dengue haemorrhagic

fever in Children and Adolescents” developed in 2010 have clearly helped to
reduce the mortality due to Dengue. With the purview of updating the
guidelines to meet emerging issues in patient management, the Sri Lanka
College of Paediatricians and the National Dengue Control Unit of the
Ministry of Health have revised the guidelines to supersede the previous
document published by the Epidemiology Unit, Ministry of Health in
2010.

The new guideline for the ‘’Management of Dengue fever and Dengue
haemorrhagic fever in Children and Adolescents’’ is developed based on the
best available evidence, which refers to the clinical management of dengue
infection among children and adolescents in Sri Lanka. Thirty per cent of
the dengue caseload currently belongs to the age group below 19 years, and
the majority of the caseload will be addressed by this guideline. These
revised national guidelines on the management of dengue fever and dengue

ix
haemorrhagic fever in children and adolescents are intended to reach all
levels of health care services to reduce morbidity and mortality due to
dengue illness.

I congratulate and thank the team of Paediatricians and members of the

National Dengue Control Unit who contributed towards developing the
updated guideline.

Dr Nalin Ariyarathne
Director, National Dengue Control Unit

x
 Contents

1 Introduction 01
2 Natural course of the illness 04
3 Diagnosis and outpatient management 06
4 In-ward management of DF/DHF 11
5 Complications of dengue 27
6 Convalescent (recovery) phase 38
7 Laboratory diagnosis 40
8 Transferring a patient to another institution 42
9 Management of dengue during infancy 43
10 Management of dengue in obese children 45
11 Annexures 47

xi
xii
1 Introduction

Many patients infected with the dengue virus remain asymptomatic

(approximately 90%). Others after an incubation period of approximately
6 (3-14) days, develop a febrile illness which could turn out to be one of
the following (Figure 1.1):

1. Undifferentiated febrile illness

2. Dengue Fever (DF)
3. Dengue Haemorrhagic Fever (DHF)
4. Expanded Dengue Syndrome

Differentiation between DF and DHF is difficult during the initial few

days.

1.1 Undifferentiated fever

Those who have been infected with the dengue virus, especially for
the first time (i.e., primary dengue infection), may develop a simple
fever indistinguishable from other viral infections.
Undifferentiated/asymptomatic individuals will still be
transmitting the disease.
Figure 1.1 Classification of dengue viral infection.

1.2 Case Definitions of DF and DHF

1.2.1 Dengue Fever (DF)

Clinical criteria that define DF include 2-7 days of illness with high
fever, headache, retro-orbital pain, myalgia, arthralgia/ bone pain,
rash and haemorrhagic manifestations e.g.: positive tourniquet test
or petechiae, with no evidence of plasma leakage.

2
1.2.2 Dengue Haemorrhagic Fever (DHF)

In the first few days of illness in DHF patients’ signs and symptoms
are similar to that of DF. However, in DHF the patients will
develop features of plasma leakage. The case definition of DHF
includes:

1. High fever or recent history of acute fever

2. Haemorrhagic manifestations
3. Thrombocytopenia of ≤100×109/L
4. Objective evidence of plasma leakage

In patients with definite evidence of plasma leakage, the presence

of haemorrhagic manifestations including a positive tourniquet
test is not essential for diagnosing DHF. However, the term
“DHF” is retained because these patients may develop overt or
concealed bleeding during the course of the illness.

Rarely there are instances where patients would start leaking before
their platelet count drops below 100×109/L.

3
2 Natural Course
of the Illness

Dengue infection is a dynamic disease. Its clinical course changes as the

disease progresses and consists of three stereotypic phases.

• Febrile phase
• Critical phase
• Convalescent phase

2.1 Febrile phase (common to both DF & DHF)

Dengue fever and dengue haemorrhagic fever are two different
clinical conditions from the beginning. They look very similar in
the first few days. Following are some features observed in the
febrile phase.

• High fever 2-7 days.

• Facial flushing, skin erythema, headache, retro-orbital pain,
myalgia, arthralgia, nausea, and vomiting.
• Haemorrhagic manifestations include petechiae, purpura, gum
or nasal bleeding, gastrointestinal bleeding, haematuria,
menorrhagia, and positive tourniquet test.

4
• Total white cell count could be high or normal initially, and in
the majority, the counts drop towards the latter part of the
febrile phase to levels below 5×109/L.
• Platelet count is normal initially and will come down to
<100×109/L in about half of DF and almost all of DHF patients.
• Tender hepatomegaly favours a diagnosis of DHF.

It is often difficult to differentiate DF from DHF in the febrile

phase of the illness. Therefore, suspected DF and DHF patients
should be closely followed up in order to identify the DHF patients
going into plasma leakage phase to ensure correct fluid
management during the critical phase.

5
3
Diagnosis &
Outpatient
Management
3.1 Suspecting dengue infection in a child with acute onset of fever
The following features would suggest dengue infection.

• Headache & retro-orbital pain

• Nausea or vomiting
• Arthralgia & myalgia
• Flushed appearance of the skin
• Rash (diffuse, erythematous, macular)
• Positive tourniquet test* (negative test does not exclude the
possibility of dengue)
• Leucopenia (WBC <5×109/L)
• Platelet count < 150×109/L

*tourniquet test is done by measuring the blood pressure using a cuff of appropriate size
for each patient (the width is to cover 2/3 of the upper arm). Raise the pressure to
midway between systolic and diastolic blood pressure for 5 minutes. Release the pressure
and wait for one minute before reading the result. A positive test is considered when
there are ≥ 10 petechiae per square inch.

Some patients may present with respiratory symptoms such as

cough, rhinitis or injected pharynx and gastrointestinal symptoms

6
 such as abdominal pain, diarrhoea or vomiting with or without the
classical clinical presentation described above.

3.1.1 Dengue NS1 Antigen test

• This is useful for early diagnosis of dengue infection.
• When available it should be performed in the first few days of
the illness. Its positivity is highest in the first 3 days of fever.
• The test is likely to be positive more in the primary than the
secondary dengue infections.
• Negative NS1 test does not exclude dengue infection.

3.2 Criteria for admission

Medical officers are expected to use clinical judgment regarding
admission. However, it is essential to admit the following patients:

• All patients with a platelet count of ≤150×109/L

• Increase in HCT >10%
• All patients with any of the following warning signs mentioned
in Box 3.1

Consider early admission in the categories of patients stated in

Box 3.2.

7
Box 3.1 Warning signs of dengue

Warning signs

• Persistent vomiting
• Lethargy, restlessness, and drowsiness
• Mucosal bleeding
• No urine output for 6 hours
• Severe abdominal pain
• Cold extremities and features of shock
• Clinical fluid accumulation: pleural effusion,
ascites
• Tender hepatomegaly

Box 3.2 Categories of patients needing early admission

Patients needing early admission

• Infants
• Obese patients
• Patients with major co-morbidities / medical
problems (such as diabetes, nephrotic syndrome,
chronic renal failure, haemolytic diseases, poorly
controlled asthma)
• Adverse social circumstances

8
3.3 Management of children who do not need admission

• Ensure adequate oral fluid intake (maintenance fluid). This

should consist of oral rehydration fluid, king coconut water,
other fruit juices, kanji or soup rather than plain water. Exclude
red and brown drinks.
• Adequate physical rest (keep at home)
• Tepid sponging for fever
• Paracetamol (Do not exceed 60mg/kg/24hrs). Warn that the
fever may not fully settle with paracetamol and advise not to
take in excess.
• Anti-emetics and H2 receptor blockers if necessary.
• All NSAIDs in any form and steroids should not be prescribed.
• First FBC should be done on completion 48 hours from the
onset of fever/illness. If the platelet count is above 200×109/L,
it should be repeated daily. If the platelet count is below
200×109/L, it should be repeated twice a day. However, the
clinician could decide the frequency of FBC based on clinical
judgment.
• The patient needs admission if the platelet count drops below
150×109/L.
• Advise parents to return immediately for review if any of the
following occur:
o Clinical deterioration with settling of fever
o Inability to tolerate oral fluid
o Severe abdominal pain/ vomiting
o Cold and clammy extremities

9
 o Bleeding manifestations including inter-menstrual
bleeding or menorrhagia
o Not passing urine for more than 6 hours
o Behaviour changes: confusion, restlessness, lethargy,
irritability

10
 In-ward
4 Management of
DF/DHF
4.1 Management of patients still in the febrile phase

• It is recommended to keep a cannula in situ.

• Ensure adequate fluid intake.
Oral fluids are recommended if oral intake is good. If the
patient is vomiting or dehydrated and not taking adequate oral
fluid, consider intravenous (IV) fluids. Total fluid requirement
(oral + IV) will depend on the degree of dehydration. The rate
of infusion has to be reduced soon after the correction of
dehydration.
When IV fluids are needed during the febrile phase, use 5%
dextrose in 0.9 % NaCl.
• Adequate physical rest.
• Do not exceed 60mg/kg/24hrs of paracetamol.
• Avoid all NSAIDS and steroids.

11
4.1.1 Monitoring during the febrile phase

• Use the monitoring chart I (febrile phase) when the platelet

count is below 150×109/L or when warning signs are present –
(Annexure III)
o Temperature
o Vital parameters - pulse, blood pressure (both systolic and
diastolic), respiratory rate, capillary refill time and urine
output 4 hourly (may need more frequent monitoring
depending on the clinical situation)
o Intake and output (maintain a urine output above
0.75ml/kg/hr)
o FBC twice daily
o Inward PCV or Hct twice daily, more frequently when
clinically indicated

4.2 Critical/ Leaking phase

Key points

• The critical phase is heralded by the onset of plasma leakage.

• Platelet count dropping below 100×109/L is the most useful and
the earliest indicator that the patient is probably entering the
critical phase.
• Plasma leakage is the main cause of shock. Prolonged shock leads
to bleeding, multi-organ failure and death.

12
Key points- contd.

• Rapid drop in temperature may occur as the patient enters the

critical phase (In DF and other viral infections as fever subsides
the patient's general condition improves, but in DHF it may get
worse). During the early phase of plasma leakage, many patients
continue to have a fever with a lower intensity.
• The rate of leaking is highly variable from patient to patient.
• The leak usually starts slowly, increases gradually, reaching a peak
usually around 24 hours then slows down and ceases altogether at
the end the of leakage phase (usually within 48 hours from the
onset). But sometimes it may last less than 48 hours or may extend
even beyond 48 hours.
• Identifying the beginning and the end of the critical phase is a key
factor in guiding fluid therapy in DHF.
• It is important to monitor patients hourly.
• If the patient presents in shock, the patient may have been in
critical phase for a significant period of time, probably up to 24
hrs. Therefore, there is a possibility that some patients will have
approximately another 24 hours remaining in the critical phase.
• If a patient is already dehydrated during the latter part of the
febrile phase (due to vomiting, diarrhoea or lack of adequate fluid
intake) and hydration is not corrected he or she might go into
shock before 24 hours. In this instance the remaining duration of
the critical phase may be more than 24 hours.
• However, until the very last stage of shock, a patient appears
conscious and alert. If the patient is not closely monitored early
shock could be missed.

13
4.2.1 Early detection of the critical phase (plasma leakage)

• Platelet count reaching towards 100×109/L should alert the

clinician that the patient may be in or entering the critical phase
of DHF.
A patient with a platelet count below 100×109/L may be in one
of the following three categories:
o DF
o DHF febrile phase
o DHF critical phase

• A progressively rising haematocrit (Hct) towards 20% from the

baseline suggests that the patient may have entered the critical
phase. Patients who have received IV fluids (sometimes even
with excessive oral fluids) or bleeding may not show a rise in
Hct.

The 20% rise in Hct is calculated by taking into consideration

the baseline haematocrit. For example, if the initial Hct is 35%,
an increase up to 42% indicates a 20% increase. When the
baseline Hct is not known, it is safe to assume that the baseline
is around 35% and may be slightly lower in young children and
infants, and higher in older children. The infants may have a
lower Hct due to physiological and iron deficiency anaemia.

• Objective evidence of fluid leak

Limited ultrasound scan (Chest and abdomen) to detect peri
cholecystic collection of fluid or ascites and pleural effusion.

14
 • When in doubt, the following biochemical parameters* would
suggest that the patient is in the critical phase:
o Serum albumin of <3.5g/dl
o Serum cholesterol of <100mg/dl (non-fasting)
*Not routinely recommended due to the costs involved, but useful when there is
doubt. Since the baseline values may vary, a significant drop during the illness is
suggestive of plasma leak

4.2.2 Monitoring during the critical phase

The total duration of leaking is highly variable from patient to
patient, and it is of paramount importance to monitor frequently
and very carefully during this phase.

Hence, it is important to maintain monitoring charts. Please refer

to the following annexures.

• Annexure IV: Monitoring chart II for patients during the

critical phase
• Annexure V: Monitoring chart III for patients during shock

Monitoring should include total fluid administered (Oral+ IV) and

the following clinical parameters:
• Pulse- Rate and Volume*
• Blood pressure (BP) and pulse pressure* (the aim is to maintain
a pulse pressure close to 30mmHg during the entire critical
phase)
• Capillary refill time (CRFT)*
• Warmth/coldness of peripheries*

15
 • Respiratory rate*
• Evidence of overt bleeding and quantification
• Regular inward PCV measurements** (6 hourly) in non-shock
patients and more regularly in patients who develop shock are
essential.

*Vital signs should be monitored hourly when the patient is stable during the
critical phase. However, the frequency of monitoring should be increased to every
15 minutes when the patient is leaking rapidly or while in shock until
haemodynamic stability is achieved.
**When making decisions trend of PCV is important rather than a single value.
(Please note that there is a difference in venous Hct and capillary PCV. Thus, try
to adhere to either venous or capillary whenever possible.)
**If venous PCV is performed make sure that strict sterile techniques are used.

• Fluid input and urine output should be calculated using either

the actual weight, the ideal weight for height or the adjusted
body weight of the child in the following manner.
o If the actual weight is less than the ideal weight use the
actual weight.
o If the actual weight is a little more than the ideal weight
for the height, use the ideal weight
o If there is a marked discrepancy between the ideal weight
and the actual weight (≥2SD weight for height or BMI)
then in such instances, it is best to use the adjusted body
weight (Figure 4.1)

16
 Calculation of the adjusted body weight

Figure 4.1 Calculation of the adjusted body weight

• Indications for catheterization:

o All high-risk patients during critical phase
o Patient with shock
o Patient with complications

17
 Clinical decisions should be taken based on the combination of
parameters but not a single parameter.

Golden rules in the management of the critical phase

• Early detection of beginning and recognizing the end of plasma

leakage
• Meticulous monitoring
• Matching the fluid administration to the fluid leak
• Anticipation, early detection and treatment of concealed
bleeding and other complications

18
4.3 Fluid management in the critical phase

4.3.1 Calculation of the fluid quota for the critical phase

• Fluid quota is only a guide for the management of dengue

patients during the critical period of DHF.
• Patients managed using fluid within this safe quota, are less
likely to develop fluid overload.
• The amount of fluid recommended during the entire critical
phase (irrespective of its length) should be Maintenance + 5%
of weight (50ml/kg). Weight should be calculated as given in
section 4.2.2
• All patients will not need the full quota of M+ 5% fluid, and
many may need less than this, as the rate, peak and duration of
leaking are variable from patient to patient. Some patients may
need fluid above the calculated fluid quota to maintain vital
parameters.

19
 Examples of calculation of fluid quota

Calculation of maintenance fluid

100ml/kg for the first 10 kg
+ 50 ml/kg for the next 10 kg
+ 20 ml/kg for balance weight

Calculation of the Deficit:

5% body weight = 50ml x body weight (kg)

E.g., 1

A 7-year-old boy with a weight of 22 kg. The ideal body weight is 24

kg. Use actual body weight for calculations.
Maintenance: 100 x 10 + 50 x 10 + 20 x 2 = 1540 ml
Deficit: 5%= 50 x 22 = 1100 ml
Total fluid quota = 1540 ml + 1100 ml = 2640 ml

E.g., 2
An 8-year-old boy with a body weight of 48 kg. His BMI is more
than 2SD. His height is 145 cm. The ideal body weight for his height
is 37 kg.

In this situation, consider adjusted body weight for fluid calculations.

Adjusted BW = 0.4 x (actual BW- ideal BW) + Ideal BW

= 0.4 x (48 – 37) + 37

20
4.3.2 Guide to the rate of fluid administration:
In a patient presenting without SHOCK

• All patients entering the critical phase need IV 0.9% NaCl + 5%

dextrose or Hartmann's solution + 5% dextrose through IV
cannula (largest possible size for the age) in addition to oral
fluid. The initial fluid requirement (oral + IV) is 1.5 ml/kg/hr.
Those who can drink well may be given IV fluids as 0.5ml/kg/hr
to 'keep vein open' and the balance as oral.
• When “dextrose saline” is not available, such a solution could be
made by adding 50ml of 50% dextrose to 450ml of normal
saline.
• Calculate the total fluid quota for the patient (M+ 5%) at the
beginning of the critical phase.
• Subsequent rate of infusion will depend on the rate of leak
judged by pulse rate, BP, pulse pressure, CRFT, PCV/Hct and
UOP. Keep in mind that the rate of leaking will vary from
patient to patient, and even in the same patient from time to
time. (Figure 4.2)
• Calculate the UOP in ml/kg/hr, at each void. In a patient who
is stable, hourly urine output is the best guide to deciding the
rate of fluid infusion. A urine output of 0.75 -1 ml/ kg/hour is
sufficient to maintain renal functions during the critical period.
UOP above 1 ml/kg/hour indicates that the fluid rate is too
high. UOP less than 0.75ml/kg/hr suggests an inadequate fluid
rate.
• Consider early catheterisation if monitoring urine output is
difficult. Catheterisation is essential in high-risk categories.

21
 • If a higher rate of maintenance fluid is needed to maintain the
clinical parameters, consider Dextran 40.

Figure 4.2 Natural course of DHF: The fluid rate should be adjusted
according to the rate of leaking.

Figure 4.2 is a schematic diagram describing the pattern of leaking and the fluid
requirement in a patient with classic dengue haemorrhagic fever. The leaking will start
gradually and comes to a peak and then starts slowing down. However, this pattern may
not be seen in all patients. Individual patient’s fluid rate will depend on the rate of leaking
as determined by the clinical parameters.

• It is also worth noting that although it is possible to manage

some patients with less than M + 5% volume of fluid, it should
always be done only by maintaining a urine output of 0.75 -1
ml/kg/hour and adequate pulse pressure throughout the critical
phase with frequent monitoring.

22
4.3.3 Guide to the rate of fluid administration:
In a patient presenting WITH SHOCK

• The following clinical features are observed in shock;

Clinical features of SHOCK

• Sweating
• Dizziness
• Abdominal pain
• Restlessness
• Altered conscious level
• Cold extremities
• Prolonged capillary refill time >2 sec
• Unexplained tachycardia
• Low volume pulse
• Narrowing pulse pressure <20 mmHg or
hypotension

• In general, shock occurs at the peak of leaking, around 24 hours

from the onset. It can be assumed that the remaining time
period of leaking is another 24 hours. However, it could be more
or less than 24 hours and fluid administration should be guided
by the clinical parameters. The maximum amount of fluid that
could be used in this instance is M+5%.
• The algorithm for the management of dengue shock is shown
in figure 4.3.

23
 All patients in shock: call for help, give oxygen, keep flat/ head low position
** A: Acidosis, B: Bleeding, C: Calcium & electrolytes, S: Sugar
Figure 4.3 Algorithm for the management of shock in dengue
haemorrhagic fever

24
4.3.4 Indications for colloids (Dextran 40)

• During rapid leaking, 0.9% saline may leak out of the

intravascular compartment within 1-2 hours of administration.
Even fluids like fresh frozen plasma (FFP) will readily leak.
Dextran 40 will remain longer.

• The following are the indications for colloids;

o During the management of shock, after administering a
total of 20 ml/ kg of crystalloids if the vital signs are
unstable
o During the management of shock in a patient who has
already received a significant amount of fluid and is at risk
of fluid overload.
o When the amount of fluid received over a period appears
to be in the direction of exceeding M + 5% deficit

25
 Key points in colloid administration

• Dextran 40 is recommended only during the critical phase.

• It should only be given at a rate of 10ml/Kg /hour over a
maximum period of one hour.
• Dextran may sometimes interfere with grouping and cross-
matching of blood. It is advisable to preserve a sample of blood
for grouping and cross-matching before administering Dextran.
• PCV should be measured before and after administering Dextran
40. Expected PCV drop is 8-10 from the pre-infusion value. If
the drop is more than 10, suspect concealed bleeding.
• One could use up to 3 boluses of Dextran 40 (each as
10ml/kg/hour) during a 24-hour period (6 doses within 48
hours).

26
5 Complications
of Dengue

Complications of dengue are usually uncommon with proper fluid

management, monitoring and timely interventions. The following are
some of the complications that can occur.

1. Prolonged shock
2. Fluid overload
3. ABCS (acidosis, bleeding, hypocalcaemia/ electrolyte imbalance,
hypoglycaemia)
4. Secondary bacterial infection
5. Death

Following high-risk patients are more likely to develop complications:

1. Infants
2. Obese patients
3. Underlying diseases
4. Expanded Dengue Syndrome
5. Pregnancy

27
5.1 Prolonged shock

• Delayed diagnosis/ delayed resuscitation and late presentation

are the common reasons for prolonged shock.
• Shock lasting > 4 hours (prolonged shock) will lead to organ
failure and the prognosis of such a patient is poor.
• Organ failure, especially liver and kidney should be avoided at
all costs. Survival is poor in multiorgan failure.

5.2 Fluid overload

5.2.1 Causes of fluid overload

• Not paying attention to the already used and the remaining fluid
quota during the management of the leaking phase.
• Continuing IV fluids beyond the critical phase unnecessarily.
• Not using colloid and blood when indicated.
• Not adjusting the fluid to match the rate of leaking.
• Over-administration of fluids without correcting associated
complications such as acidosis, bleeding and hypocalcaemia
(ABCS, see section 5.3)
• Use of hypotonic fluids.

5.2.2 Features of fluid overload

• Early signs and symptoms include cough, puffy eyelids,

distended abdomen (ascites), tachypnoea, and dyspnoea.

28
 • Late signs and symptoms include moderate to severe respiratory
distress, wheezing (an early sign of interstitial pulmonary
oedema), tachycardia, gallop rhythm and lung crepitations.
Restlessness/agitation and confusion are signs of hypoxia and
impending respiratory failure.

5.2.3 Management of fluid overload

• Assessment of the intravascular volume status of the child is

crucial when managing fluid overload. The intravascular
compartment may be depleted despite the patient being fluid
overloaded, especially during the critical phase.
• A patient with fluid overload can be in any of the following
scenarios.

1. Fluid overload with depleted intravascular volume status

Giving furosemide alone at this stage is dangerous.
Furosemide can be administered only after restoring the
intravascular volume by giving a bolus of Dextran 40. The
patient should be on continuous monitoring during this period
for 1-2 hours.

2. Fluid overload with good intravascular volume status

Furosemide alone may be given. However, close monitoring is
still essential.

29
 • DHF patients are very sensitive to furosemide. So the dose
should be smaller than the usual dose (0.1 mg/kg as a bolus).
This can be repeated if necessary.

5.3 ABCS

• Consider ABCS when there is no improvement despite

adequate fluid therapy.

A: Acidosis
B: Bleeding
C: Calcium and electrolytes
S: Sugar

5.3.1 Acidosis

• Acidosis is not uncommon in profound shock, and prolonged

acidosis makes patients more prone to DIC which contributes
to massive bleeding.
• Metabolic acidosis in DHF is mainly due to inadequate tissue
perfusion and should improve with adequate fluid resuscitation.
Giving NaHCO3 without fluid resuscitation can lead to
intracellular acidosis.
• If the patient remains unstable and pH remains below 7.25 or
HCO3 is less than 15 mmol/L after 2 crystalloid boluses and one
colloid bolus, NaHCO3 can be considered.
• When facilities are not available for a blood gas analysis, one
may use empirical NaHCO3 1ml/kg slow bolus (max 50ml)
diluted in an equal volume of normal saline.

30
5.3.2 Bleeding

• Bleeding in dengue can be concealed or overt and may

contribute to shock. It should be treated with packed red cells,
and not with other blood products eg. platelets/ FFP
• Concealed bleeding should be suspected when,
o Hct drops without clinical improvement.
o Severe metabolic acidosis and end-organ dysfunction (liver
or renal) despite adequate fluid replacement.
o Minimal increment of Hct in a child with shock
o Exaggerated drop of Hct after a 10ml/kg bolus of dextran
(>10)
• Use of Packed Red Cells (PRC)
o Use PRC at 5ml/kg over one hour and repeat only if
needed.
o 5ml/kg of PRC will increase Hct by 5 points. (E.g.:
3035)
o Even if bleeding is likely, and if Hct is >45%, do not give
blood without bringing down the HCT first by giving
dextran.

Note:

• Even with bleeding, the Hct drop may take time (4-5 hours).
When the patient does not show improvement, it is important to
repeat Hct frequently.
• Haemoglobin level may remain normal despite significant blood
loss.

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5.3.3 Hypocalcaemia

• Hypocalcaemia is common in DHF.

• When a When a dengue patient has a convulsion, one reason
could be hypocalcaemia.
• Serum calcium level should be measured in complicated dengue
patients.
• When to give calcium?
o Give empirical calcium if the patient is having
complications and deteriorating or not showing expected
improvement with fluid.
o Dose 1ml/kg (maximum 10 ml) of 10% calcium gluconate
diluted in an equal volume of 0.9% saline as a slow IV bolus
over 15-20min (look for bradycardia).
o Can be repeated every 6 hours if the patient is not
improving.

5.3.4 Hypoglycaemia

• Prevention of hypoglycaemia: As hypoglycaemia is common in

DHF, one should try to prevent it by using 0.9% NaCl with 5%
dextrose as maintenance fluid.
• Treatment of hypoglycaemia: If the capillary blood sugar is less
than 70 mg/dL administer 10% dextrose, 2 ml/kg followed by
0.9% NaCl with 5% dextrose infusion.

32
5.3.4 Hyponatraemia

• Hyponatraemia may occur due to the inadvertent use of

hyponatraemic fluids.
• When a dengue patient has a convulsion, it could be due to
hyponatraemia.
• Prevention of hyponatraemia:
o Use 0.9% NaCl as intravenous fluids.
o Do not use hyponatraemic IV fluids (e.g. 0.45% NaCl).
o Use ORS, fruit juices and kind coconut water as oral fluids.
o Do not use water alone as oral fluids.
• Management of hyponatraemia:
o If symptomatic:
3% NaCl 3-5ml/kg as a slow IV bolus over 20 minutes
through a larger vein
o If asymptomatic,
Fluid restriction itself should correct hyponatraemia.
Repeat electrolytes regularly.

5.4 Encephalopathy
Encephalopathy in DHF is mainly due to hepatic encephalopathy.
The basic principle of management is maintaining adequate
Cerebral Perfusion Pressure (CPP) by maintaining Mean Arterial
Pressure (MAP) and reducing Intra Cranial Pressure (ICP).

CPP = MAP – ICP

33
 The following are recommended in the management.

• Adequate oxygenation (intubation may be needed for those with

respiratory failure or low GCS)
• Fluid management
o Aim for a normovolaemic state.
o Switch to colloids early.
• Maintain MAP
o Adequate fluids as above.
o Inotropes and Vasopressors
• Reduce ICP
o Keep head in midline position.
o Elevate the head end of the bed to 30- 45 degrees.
o Avoid neck flexion.
o 3% NaCl 3-5 ml/kg slow boluses.
o Controlled hyperventilation (maintain PaCO2 between 30
to 35 mmHg)
o Maintain blood sugar level > 70 mg/dL.
o Maintain sodium and potassium at normal levels.
• Use IV phenobarbitone to reduce cerebral metabolism and to
control seizures.
• When liver enzymes are markedly elevated, suspect hepatic
encephalopathy.
o Look for concealed bleeding and transfuse PRC
accordingly.
o Start liver failure regimen.

34
5.5 Haemophagocytic lymphohistiocytosis (HLH)

• HLH is a rare multisystem disorder in children which is known

to occur following dengue infections.
• HLH in DHF is treatable if identified early. Mortality is very
high with delayed diagnosis.
• HLH should be suspected when the patient is having ongoing
fever with multisystem involvement.
• Bone marrow biopsy is necessary for the diagnosis.
• Early diagnosis & treatment with steroids (dexamethasone/
methylprednisolone) will completely cure the disease.
• When in doubt better to discuss with haematologist and
paediatric oncologist.

5.6 Expanded Dengue Syndrome

• There have been some reports of 'unusual dengue' where the

patients had developed clinical manifestations which are
different to what is usually expected in DF or DHF.
• These include encephalopathy and other neurological
manifestations, and organ failure such as hepatic, renal, cardiac
and other isolated organ involvement. These could be explained
as complications of profound shock or associations of underlying
comorbidities or co-infections.
• It is important to note that expanded dengue syndrome is a rare
entity, and patients should not be categorized into this group
without detailed and careful evaluation.

35
5.7 Causes of death in dengue
The main causes of death are,

• prolonged shock
• fluid overload
• massive bleeding
• unusual manifestations e.g., encephalopathy
• dual infection/ secondary sepsis

5.6 Adjunct therapy

5.6.1 Platelet transfusion

Indications for platelet transfusion

• Prophylactic platelet transfusion is NOT recommended.

• Thrombocytopaenia is unlikely to produce spontaneous
significant bleeding in DHF/DSS. Even with a very low platelet
count, do not give platelets unless there is significant bleeding.

5.6.2 Tranexamic acid

• Tranexamic acid is an anti-fibrinolytic agent that preserves and

stabilizes fibrin’s matrix structure and thereby helps to control
bleeding.
• It can be recommended to control menstrual bleeding and
gastrointestinal bleeding in dengue.
• Haematuria is a contraindication for its use.
• However, there are no control studies on its use in dengue.

36
5.6.3 Norethisterone

• This can be administered to control menstrual bleeding along

with tranexamic acid.

5.6.4 Recombinant factor VII

• Recombinant factor VII is not routinely indicated.

• The need should be discussed with a consultant haematologist.

5.6.5 Inotropic support

• NOT INDICATED in the management of uncomplicated

DHF.

5.6.6 Steroids/ IV immunoglobulin

• Use of steroids (hydrocortisone, dexamethasone and

methylprednisolone) and/or intravenous immunoglobulin is
NOT recommended.

5.6.7 Fresh frozen plasma transfusion (FFP)

• Transfusion of FFP is NOT recommended.

37
6 Convalescent
(Recovery) phase

The convalescent phase usually lasts 2-5 days for both DF and DHF. In
DHF, the convalescent phase starts at the end of the critical phase and the
extravasated fluid will be reabsorbed during this period.

6.1 Features of convalescent phase

• Improved general well-being with the following;

A: Improved Appetite
B: Bradycardia
C: Convalescent rash (typically appears as white
patches on a red background) and itching
D: Diuresis
• The definitive indicator that the patient has entered the convalescent
phase is the progressive rise of platelets.

6.2 Complications during convalescence

• Fluid overload (Management discussed in 5.1)

• Nosocomial infections e.g., pneumonia, urinary tract infection,
thrombophlebitis, sepsis.

38
6.3 Discharge from the hospital

• The following criteria should be fulfilled before discharge from

the hospital.
o No fever for at least 36-48 hours without the usage of
antipyretic drugs.
o At least two days have lapsed after recovery from shock.
o Good general condition with improving appetite.
o No distress from pleural effusions or ascites.
o Platelet count is progressively rising, and preferably above
50 x 109/L.
o Liver enzymes are improving.
o No other complications.

39
7 Laboratory
Diagnosis

Laboratory diagnosis of dengue is achieved by isolation of the virus,

detection of antigen, detection of the genome or by detection of antibodies.
Dengue virus can be isolated from a blood sample collected during the first
4 -5 days of illness. Virus isolation and typing are mainly used in research
and surveillance.

Detection of the genome by PCR from blood can be performed during the
acute phase of the illness and used in routine diagnosis as well as in research
and surveillance. However, the cost of the assay and its availability limit its
use in clinical practice. Dengue serotypes can be identified from virus
isolation and detection of the genome by PCR.

Detection of NS-1 antigen from blood (by ELISA or by

immunochromatography) is a useful method which can be performed
during the first few days of fever. The highest positivity is observed within
the first 3 days. The sensitivity of these tests varies and ranges between
60% to 90%. Therefore, a negative test result will not exclude dengue
illness and treating the patient on clinical grounds is important.

40
Detection of Dengue IgM and IgG are performed on blood samples
collected preferably after the 5th day of illness. The range of tests available
for the detection of antibodies includes ELISA, immunochromatography
and haemagglutination inhibition assay with varying sensitivity and
specificity. Detection of IgM antibodies or demonstration of a four-fold
rise in IgG antibodies (seroconversion) confirm the diagnosis of dengue.

Figure 7.1 Dengue virus, antigen and antibody response used in the
diagnosis (Reproduced from Guzman et al.)

41
 Transferring a
8 patient to
another
institution
Facilities in some peripheral hospitals may not be adequate to manage
a patient with DHF. Furthermore, a patient in prolonged shock may
need intensive care facilities. Hence, these patients may be transferred
to an institution with such facilities after stabilising.

If the patient has signs of shock, resuscitate the patient as per the
algorithm in figure 4.3 before transfer. Correct hypoglycaemia and
continue IV fluids and oxygen during the transfer. Ensure that the
receiving paediatrician is kept informed.

Proper resuscitation before transferring is important. A medical officer

and a nurse familiar with the patient should accompany the patient.
Adequate information regarding the patient should be provided in the
transfer form and this should include daily fluid balance, investigation
results and treatment given. It is important to send copies of the
temperature and monitoring charts as well.

42
9
Management of
Dengue during
infancy

DHF has been documented in primary infection among infants whose

mother was infected during pregnancy. Vertical transmission has been
reported leading to neonatal DF or DHF.

Infants who develop primary dengue infection may have a simple fever
indistinguishable from other viral infections. It may have a wide range of
clinical presentations. Maculopapular rashes (blanching erythema) may
accompany the fever or may appear during defervescence. Upper
respiratory and gastrointestinal symptoms are common. They may also
present with febrile convulsions.

Splenomegaly has been observed in young infants (especially under six

months) clinically or by ultrasound scan. Infants have less respiratory
reserves, therefore would not tolerate large effusions or pulmonary oedema.
They are more susceptible to liver impairment and electrolyte imbalance
leading to hyponatremia.

43
DHF in infancy may not have leucopenia. Often total WBC is > 10 x
109/L. Infants can have physiological or iron deficiency anaemia and
therefore their baseline Hct could be lower than older children. Liver
enzymes are elevated early in the disease. Electrolyte abnormalities
including hyponatraemia are also common. They are more prone to
develop hypoglycaemia, so regular monitoring of blood sugar is important.

Key points in managing Dengue in infancy

• Infants may have a shorter duration of plasma leakage (lasts for <
24 hours - may be as short as 6 to 12 hours) and usually respond
quickly to fluid resuscitation. Optimal fluid management from
the entry into the critical phase is vital. Infants should be
evaluated frequently for oral fluid intake (i.e., breastfeeding) and
urine output (hence the early need for catheterization).
• 0.9% saline + 5% dextrose should be used as the crystalloid in all
infants.
• Dextran 40 should be considered early when high rates of
crystalloids are required.
• Discontinue IV fluids soon after the leaking phase as the risk of
fluid overload is high.
• Continuing on-demand breastfeeding is recommended.

44
 Management of
10 Dengue in
obese children

Obesity is a high-risk category in DHF. Obese children are more prone to

go into shock and fluid overload. Therefore, careful fluid management is
vital. The following are recommended to prevent both shock and overload.

• Calculate fluid for the adjusted body weight.

• Calculate UOP for the adjusted body weight.
• Catheterize early.
• Consider colloid early if high rates of crystalloids are needed or
poor response to crystalloids.
• Consider blood transfusion early when indicated.
• Empirical calcium gluconate to prevent hypocalcemia
• Consider expert opinion early if the patient is not improving.

45
 Calculation of the adjusted body weight

Figure 10.1 Calculation of the adjusted body weight

46
Annexures

I: Ideal body weight for height: Boys

II: Ideal body weight for height: Girls
III: Monitoring chart I: Febrile phase monitoring
IV: Monitoring chart II: Critical phase monitoring
V: Monitoring chart III: Peak of leaking and shock
VI: Dengue vaccine
Annexure I:
Ideal body weight for height: Boys
(Ideal weight taken as the weight for height on the 50th centile)

Height Ideal Body Weight Height Ideal Body Weight

(cm) (kg) (cm) (kg)
100 15.50 138 31.50
101 15.75 139 32.33
102 16.00 140 33.00
103 16.33 141 34.00
104 16.66 142 35.00
105 17.00 143 35.50
106 17.33 144 36.33
107 17.66 145 37.00
108 18.00 146 38.00
109 18.50 147 39.00
110 18.75 148 39.66
111 19.00 149 40.50
112 19.50 150 41.33
113 20.00 151 42.00
114 20.25 152 42.66
115 20.50 153 43.33
116 21.00 154 44.00
117 21.33 155 45.00
118 21.66 156 45.50
119 22.00 157 46.33

48
Height Ideal Body Weight Height Ideal Body Weight
(cm) (kg) (cm) (kg)
120 22.50 158 47.00
121 22.75 159 47.75
122 23.33 160 48.50
123 23.50 161 49.00
124 24.00 162 49.75
125 24.50 163 50.50
126 25.00 164 51.00
127 25.33 165 52.00
128 25.66 166 53.00
129 26.00 167 53.75
130 26.66 168 54.50
131 27.33 169 55.25
132 27.66 170 56.33
133 28.33 171 58.00
134 28.66 172 58.75
135 29.50 173 60.00
136 30.00 174 62.00
137 30.66 175 64.00

49
Annexure II:
Ideal body weight for height: Girls
(Ideal weight taken as the weight for height on the 50th centile)

Height Ideal Body Weight Height Ideal Body Weight

(cm) (kg) (cm) (kg)
90 13.00 127 25.25
91 13.25 128 26.00
92 13.50 129 26.33
93 13.66 130 27.00
94 13.75 131 27.66
95 14.00 132 28.33
96 14.25 133 29.00
97 14.75 134 29.66
98 15.00 135 30.50
99 15.25 136 31.50
100 15.50 137 32.00
101 16.oo 138 32.75
102 16.25 139 33.5
103 16.50 140 34.50
104 17.00 141 35.00
105 17.25 142 36.00
106 17.50 143 36.50
107 17.75 144 37.00
108 18.00 145 37.75
109 18.33 146 38.50

50
Height Ideal Body Weight Height Ideal Body Weight
(cm) (kg) (cm) (kg)
110 18.66 147 39.00
111 19.00 148 39.75
112 19.50 149 40.50
113 19.75 150 41.00
114 20.00 151 41.50
115 20.33 152 42.00
116 20.66 153 42.50
117 21.00 154 43.66
118 21.50 155 44.00
119 21.75 156 45.00
120 22.25 157 45.66
121 22.50 158 46.75
122 23.00 159 47.75
123 23.33 160 49.00
124 23.75 161 50.00
125 24.25 162 52.50
126 24.66 163 56.00

51
52
53
54
55
Annexure VI:
Dengue Vacccine

Prof. Neelika Malavige DPhil (Oxon), FRCP (Lond), FRCPath (UK)

AICBU, Department of Immunology and Molecular Medicine, Faculty of Medical Sciences,
University of Sri Jayewardenepura, Sri Lanka

Dengue was named one of the top ten threats to global health in 2019 and
there have been many efforts to develop a safe and effective dengue vaccine
[1]. The ideal dengue vaccine should induce long-lasting immunity to all
four-dengue virus (DENV) serotypes so that severe disease would not
occur at a later date due to waning of immunity. Dengvaxia (CYD-DTV)
was the first dengue vaccine to be registered in 2015 in Mexico and was
subsequently approved by the FDA in 2019 [2]. This was a recombinant
vaccine where the envelope and PrM proteins of the DENV were
incorporated into a yellow fever virus backbone [3]. Unfortunately, this
vaccine showed poor efficacy for DENV2 serotype and was more likely to
cause severe disease in dengue seronegative vaccinees [3]. Although the
exact reasons occurrence of more severe disease in seronegative individuals
was not clear, it was attributed to waning of DENV specific antibodies
leading to severe disease by antibody dependent enhancement [3]. In
addition, as this vaccine did not contain NS1 of the DENV, failure to
induce adequate levels of NS1-specific antibody and T cell responses by
this vaccine was also thought to contribute to its suboptimum performance
[4]. Due to the safety signals of this vaccine, this vaccine was recommended
to be given only to DENV seropositive individuals by the WHO [5].

56
Subsequent vaccine developers having learnt lessons from the suboptimum
immune responses generated by CYD-TDV (Dengvaxia), have developed
vaccines either using the DENV as a backbone or developing a live
attenuated vaccine, which incorporates all four DENV serotypes. TAK-
003 (QDENGA) developed by Takeda, having finished its phase 3 trials
in many Asian and Latin American countries, has now been approved by
the European Medicines Agency and registered in Indonesia. This vaccine,
which is a live attenuated vaccine, has DENV2 as its backbone and
incorporates the envelope and PrM proteins of the three other DENV
serotypes [6]. It was shown to induce immune responses to all four DENV
serotypes and showed an overall efficacy of 80.2% against virologically
confirmed dengue with an efficacy rate of 83.6% against hospitalizations
[6]. However, this vaccine did not induce equal efficacy against all four
DENV serotypes. For instance, in baseline DENV seronegatives, the
efficacy for DENV2 was 91.9%, for DENV1 was 43.5%, while and no
efficacy against DENV3 (-23.4%) [6]. Unpublished data on the
manufacturer’s website states that the vaccine efficacy at 4.5 years was 84%
against hospitalization without any safety signals [7]. As there was a lower
number of dengue infections during the years 2020 and 2021 in the
countries where this vaccine underwent trials, due to the COVID-19
pandemic, it would be important to see any potential safety signals during
dengue outbreaks, especially due to DENV3.

Lastly, NIH TV003 developed by NIH USA is currently undergoing

phase 3 trials in several countries in Asia and Latin America. This live
attenuated vaccine was shown to induce high levels of neutralizing
antibodies and controlled human challenge models showed that the

57
vaccine completely protected against infection [8, 9]. There was no
viramiae observed in the vaccinees who were later challenged with the
DENVs. It would be important to see the effectiveness of this vaccine in
phase 3 clinical trials.

In summary, due to the presence of four DENV serotypes, and potential

of enhancing disease for different serotypes in the presence of sub-
neutralising levels of antibodies, an ideal vaccine should induce durable,
long lasting immunity to all four DENV serotypes. Due to the safety
signals.

1. WHO. Ten threats to global health in 2019. World Health

Organization, 2019.
2. Paz-Bailey G, Adams L, Wong JM, Poehling KA, Chen WH,
McNally V, et al. Dengue Vaccine: Recommendations of the
Advisory Committee on Immunization Practices, United States,
2021. MMWR Recomm Rep 2021; 70:1-16.
3. Halstead SB. Safety issues from a Phase 3 clinical trial of a live-
attenuated chimeric yellow fever tetravalent dengue vaccine. Hum
Vaccin Immunother 2018; 14:2158-62.
4. Lee PX, Ting DHR, Boey CPH, Tan ETX, Chia JZH, Idris F, et
al. Relative contribution of nonstructural protein 1 in dengue
pathogenesis. J Exp Med 2020; 217.
5. Dengue vaccine: WHO position paper, September 2018 -
Recommendations. Vaccine 2018.
6. Rivera L, Biswal S, Saez-Llorens X, Reynales H, Lopez-Medina
E, Borja-Tabora C, et al. Three-year Efficacy and Safety of

58
 Takeda's Dengue Vaccine Candidate (TAK-003). Clin Infect Dis
2022; 75:107-17.
7. Takeda. Takeda’s Dengue Vaccine Candidate Provides Continued
Protection Against Dengue Fever Through 4.5 Years in Pivotal
Clinical Trial. Takeda, 2022.
8. Nivarthi UK, Swanstrom J, Delacruz MJ, Patel B, Durbin AP,
Whitehead SS, et al. A tetravalent live attenuated dengue virus
vaccine stimulates balanced immunity to multiple serotypes in
humans. Nat Commun 2021; 12:1102.
9. Kirkpatrick BD, Whitehead SS, Pierce KK, Tibery CM, Grier PL,
Hynes NA, et al. The live attenuated dengue vaccine TV003 elicits
complete protection against dengue in a human challenge model.
Sci Transl Med 2016; 8:330ra36.

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