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GUIDELINE DEVELOPMENT AND OBJECTIVE
GUIDELINE DEVELOPMENT
The development group or this guideline consisted o a amily medicine
specialist, an emergency medicine specialist, a general physician, inectious
disease physicians, intensivists, haematologists, public health physicians,
a virologist and a nursing sister rom the Ministry o Health and Ministryo Higher Education, Malaysia. During the process o development o this
guideline, there was active involvement o a review committee.
The previous edition o the CPG (2003) was used as the basis or the
development o this present guideline.
This guidelines provides :
a. A detailed description o the clinical course o dengue illness which
reects the dynamism and systemic nature o dengue that have crucialbearing on the patients management.
b. A detailed description o the basic pathophysiological changes
o severe dengue (i.e. plasma leakage and hypovolaemia/shock)
and provide guidance on the recognition o these changes and the
appropriate action o management.
c. A brie discussion on WHO Classifcation (1997) and its limitations.
d. Some useul guides on the dierential diagnoses that can be conused
with dengue or vice versa; they were described according to the stage
o disease.
e. A more ocused guide on the disease monitoring in accordance with
the dynamic changes as the disease progresses.
. Emphasis on the importance o monitoring the plasma leakage [clinical
signs o plasma leakage and haemotocrit (HCT)] and the haemodynamicstatus o the patient.
g. Clearer algorithm on uid management in severe dengue.
h. Emphasis on the importance o recognising or suspecting signifcant
occult bleed with some useul guides.
i. A more systematic approach on the recognition o signs o recovery.
Literature search was carried out at the ollowing electronic databases:
International Health Technology Assessment Website, PUBMED, Cochrane
Database o Systemic Reviews (CDSR), Journal ull text via OVID search
engine, Comprehensive; Database o Abstracts o Reviews o Eectiveness,
Cochrane Controlled Trials Registered, CINAHL via EBSCO search engine.
In addition, the reerence lists o all relevant articles retrieved were searched
to identiy urther studies.
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Reerence was also made to other guidelines - WHO Dengue Haemorrhagic
Fever: Diagnosis, Treatment, Prevention and Control, WHO Geneva 1997;
Guidelines, Guidelines or DHF Case Management, Bangkok, Thailand
2002; Guidelines on Clinical Management O Dengue Fever / Dengue
Haemorrhagic Fever 2005 Sri Lanka; WHO Regional Publication SEARO,
1999; Guidelines or Treatment o Dengue Fever/Dengue Hemorrhagic
Fever in Small Hospitals, WHO Regional Ofce or SE Asia, New Delhi,1999. There were very ew studies carried out on dengue patients in the
adult population. Many o the studies included in this guideline are based
upon the management o dengue in children. The fndings o these studies
were then extrapolated on to the adult population, taking into consideration
our local practices.
The clinical questions were divided into major subgroups and members
o the development group were assigned individual topics within these
subgroups. The group members met a total o 15 times throughout thedevelopment o the guideline. All literature retrieved were appraised by
at least two members and presented in the orm o evidence tables and
discussed during group meetings. All statements and recommendations
ormulated were agreed by both the development group and review
committee. Where the evidence was insufcient the recommendations were
derived by consensus o the development group and review committee.
The articles were graded using the modifed version o the criteria used
by the Catalonia Agency or Health Technology Assessment and Research
(CAHTAR), Spain, while the grading o recommendation in this guideline
was modifed rom the Scottish Intercollegiate Guidelines Network (SIGN).
The drat guideline was posted on both the Ministry o Health Malaysia and
Academy o Medicine, Malaysia websites or comment and eedback. This
guideline has also been presented to the Technical Advisory Committee or
Clinical Practice Guidelines, and the Health Technology Assessment and
Clinical Practice Guidelines Council, Ministry o Health Malaysia or reviewand approval.
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OBJECTIVES
GENERAL OBJECTIVES
To provide evidence-based guidance in the management o dengue
inection in adult patients.
SPECIFIC OBJECTIVES
To improve recognition and diagnosis o dengue cases and provide
appropriate care to the patients.
To identiy severe dengue and carry out more ocused close monitoring
and prompt appropriate management.
To provide guidance on appropriate and timely uid management and
the use o blood and blood products.
To improve on early and accurate notifcation o dengue cases or
prompt public health intervention.
CLINICAL QUESTIONS
Please reer to Appendix 6
TARGET POPULATION
Adult patients with dengue ever, dengue haemorrhagic ever or dengueshock syndrome and other orms o severe dengue.
TARGET GROUP/USER
This guideline is applicable to primary care doctors, public health personnel,
nurses, assistant medical ofcers, physicians and critical care providers
involved in treating adult patients with dengue ever, dengue haemorrhagic
ever or dengue shock syndromeand other orms o severe dengue.
HEALTHCARE SETTINGS
Both outpatient and inpatient settings
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v
CLINICAL INDICATORS FOR QUALITy MANAGEMENT
PRIMARy INDICATORS
i. Case atality rate (DF & DHF)
Numerator: No o DF & DHF/DSS death
Denominator: No o DF & DHF cases (clinically diagnosed)
National target (9th Malaysian Plan):< 0.2%
ii. DHF atality rate
Numerator: No o DHF/ DSS death
Denominator: No o DHF/ DSS cases (clinically diagnosed)
National target (9th Malaysian Plan):
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v
GUIDELINE DEVELOPMENT GROUP
CHAIRPERSON
Dr. Mahiran Mustaa
Senior Consultant Inectious Disease Physician
Hospital Raja Perempuan Zainab II
Kota Bharu, Kelantan
MEMBERS(alphabetical order)
Dr. Abdul Hamid Jaaar
Assistant Director
Communicable Disease Control Division
MOH
Dr. Norita Ahmad
Consultant Inectious Disease Physician
Hospital Raja Perempuan Zainab II
Kelantan
Dr. Ainul Nadziha Mohd. Hanaah
Assistant DirectorHealth Technology Assessment Section
Medical Development Division, MOH
Dr. Salmah Idris
Consultant PathologistHospital Sungai Buloh
Selangor
Dr. Chow Ting Soo
Consultant Inectious Disease Physician
Hospital Pulau Pinang
Pulau Pinang
Dr. Sheamini Sivasampu
Principal Assistant Director
Health Technology Assessment Section
Medical Development Division, MOH
Dr. Faisal Salikin
Emergency Medicine Specialist
Hospital Kuala Lumpur
Kuala Lumpur
Ms Sin Lian The
Nursing Sister
Health Technology Assessment Section
Medical Development Division, MOH
Dato Dr. Faraizah Abdul Karim
Deputy Director
National Blood Centre,
Kuala Lumpur
Dato Dr. K. Sree Raman
Senior Consultant Physician
Hospital Tuanku Jaaar,
Negeri Sembilan
Dr. Ho Bee Kiau
Family Medicine Specialist
Bukit Kuda Health ClinicSelangor
Dr. Suresh Kumar
Consultant Inectious Disease Physician
Hospital Sungai BulohSelangor
Dr Mohamad Ikhsan Selamat
Principal Assistant Director
Communicable Disease Control Division
MOH
Dr. Tan Cheng Cheng
Senior Consultant Intensivist and
Anaesthesiologist
Hospital Sultanah Aminah, Johor
Dr. Jameela Sathar
Senior Consultant Haematologist
Hospital Ampang
Selangor
Dr. Tan Lian Huat
Lecturer and Inectious Disease Physician
University Malaya
Kuala Lumpur
Dr. Lim Chew Har
Consultant Intensivist & Anaesthesiologist
Hospital Pulau Pinang
Pulau Pinang
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v
REVIEW COMMITTEE(alphabetical order)
The drat guideline was reviewed by a panel o independent expert reerees
rom both public and private sectors, who were asked to comment primarily
on the comprehensiveness and accuracy o interpretation o the evidence
supporting the recommendations in the guideline.
Dr. Christopher Lee
Senior Consultant Inectious Disease Physician
Hospital Sungai Buloh
Selangor
Proessor Luc Lum Chai See
Proessor o Paediatrics
Department o Paediatrics
University Malaya Medical CentreKuala Lumpur
Datin Paduka Dr. Santha Kumari
Senior Consultant Physician
Hospital Tengku Ampuan Rahimah
Selangor
Dr. Radhakrishnan Sothiratnam
Consultant PhysicianColumbia Asia Medical Center
Negeri Sembilan
Dr. Rud yeoh Seok Ching
Consultant Haematologist
S. C. Yeoh Haemotology Consultancy Sdn Bhd
Kuala Lumpur
Datin Dr. Rugaah BakriDeputy Director
Health Technology Assessment Section
Medical Development Division
Ministry o Health
Dr. Tai Li Ling
Senior Consultant Intensivist & Anaesthesiologist
Hospital Kuala Lumpur
Kuala Lumpur
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v
EXTERNAL REVIEWERS(alphabetical order)
The ollowing external reviewers provided eedback on the drat
Dr. Alan Teh
Consultant Physician & Haematologist
Subang Jaya Medical Centre
Selangor
Dr. Maimunah Mahmud
Family Medicine Specialist
Klinik Kesihatan Jinjang
Kuala Lumpur
Dr. Chua Kaw Beng
Consultant Virologist
National Public Health Laboratory
Ministry o Health
Sungai Buloh
Selangor
Dato Dr. Ravindran Jegasoth
Head o Department and Senior
Consultant O&G
Hospital Kuala Lumpur
Kuala Lumpur
Dr. Jearam Menon
Senior Consultant Gastroenterologist
& Head o Department
Hospital Queen Elizabeth
Sabah
Dr. Rashidi Ahmad
Emergency Physician/Lecturer
Department o Emergency Medicine
Universiti Sains Malaysia
Kelantan
Dato Dr. ST Kew
Senior Consultant Physician
Internal Medicine Department
International Medical UniversityKuala Lumpur
Assoc. Pro. Dr. Shaiul Bahari Ismail
Lecturer and Family Medicine Specialist
Department o Family Medicine
School o Medical SciencesUniversiti Sains Malaysia
Kubang Kerian, Kelantan
Dr. G. R. Letchuman Ramanathan
Senior Consultant Physician
Hospital Taiping,
Perak
Dr. Tan It
Consultant Anaesthetist
Sunway Medical Centre,
Selangor
Dato Dr. Lim yu Hoe
Senior Consultant Physician
Hospital Pulau Pinang
Pulau Pinang
Dr. S Visalach Purushothaman
Senior Consultant Haematologist
Hospital Ampang
Selangor
Dr. Mahathar Abdul Wahab
Emergency Medicine Specialist
Hospital Kuala Lumpur
Kuala Lumpur
Dr. yoong Kar yaw
Consultant Physician
Hospital Sultan Ismail
Johor Bharu
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v
TABLE OF CONTENTS
GUIDELINE DEVELOPMENT AND OBJECTIVE i
GUIDELINE DEVELOPMENT GROUP v
REVIEW COMMITTEE vi
EXTERNAL REVIEWERS vii
TABLE OF CONTENT viii
1. EPIDEMIOLOGY 1
2. VIROLOGY 3
3. CLINICAL MANIFESTATIONS AND PATHOPHYSIOLOGY 3
3.1 SPECTRUM OF DENGUE INFECTION 3
3.2 CLINICAL COURSE OF DENGUE INFECTIONi. Febrile Phase
ii. Critical Phase
iii. Recovery Phase
44
4
5
3.3 PATHOPHYSIOLOGY OF PLASMA LEAKAGE IN DENGUE
HAEMORRHAGIC FEVER (DHF)/ DENGUE SHOCK SYNDROME (DSS)
6
3.4 TOURNIQUET TEST 8
3.5 WHO DENGUE CLASSIFICATION
3.5.1 Limitations o WHO classifcation
8
8
3.6 OTHER IMPORTANT MANIFESTATIONS 9
3.7 DIAGNOSTIC CHALLENGES 10
4. DISEASE NOTIFICATION 11
5. LABORATORY INVESTIGATIONS 11
5.1 DISEASE MONITORING LABORATORY TESTS 11
5.2 DIAGNOSTIC TESTS5.2.1 Dengue Serology Tests
5.2.2 Virus Isolation
5.2.3 Polymerase Chain Reaction (PCR)
5.2.4 Non-structural Protein-1 (NS1 Antigen)
1212
14
14
14
6. INVESTIGATION OF POST MORTEM CASE 15
7. MANAGEMENT OF DENGUE INFECTION 15
7.1 OUTPATIENT MANAGEMENT 15
7.2 PATIENT TRIAGING AT EMERGENCY & TRAUMA AND
OUTPATIENT DEPARTMENT
17
7.3 CRITERIA FOR HOSPITAL REFERRAL / ADMISSION
7.3.1 Reerral rom primary care providers to hospital
7.3.2 Reerral rom hospitals without specialist to hospital with
specialists
18
18
18
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x
7.4 DISEASE MONITORING
7.4.1 Principles o Disease Monitoring
7.4.2 Outpatient Disease Monitoring
7.4.3 Inpatient Disease Monitoring
19
19
19
19
7.5 FLUID MANAGEMENT7.5.1 Non-shock patients (DHF Grade I & II)
7.5.2 Dengue Shock Syndrome (DSS) (DHF Grade III &IV)
2222
23
ALGORITHM FOR FLUID MANAGEMENT FOR DSS (DHF GRADE III & IV) 25
7.6 MANAGEMENT OF BLEEDING/HAEMOSTASIS
7.6.1 Haemostatic Abnormalities in Dengue Inection
7.6.2 How to recognize signifcant bleeding?
7.6.3 Management o Bleeding in Dengue
7.6.4 Management o Upper Gastrointestinal Bleeding (UGIT)
7.6.5 The Role o Prophylactic Transusions in Dengue
7.6.6 The Role o Adjunctive Therapy in Dengue
26
26
26
26
27
27
27
7.7 INTENSIVE CARE MANAGEMENT
7.7.1 Indications or respiratory support (non-invasive and invasive
ventilation)
7.7.2 Indications or haemodynamic support
7.7.3 Guide on saety and risk o invasive procedures
28
28
28
29
8. DISCHARGE CRITERIA 30
9. PREVENTION OF DENGUE TRANSMISSION IN HOSPITALS 30
10. VACCINATION 31
11. DENGUE IN PREGNANCY 31
REFERENCES 33
APPENDIX 1 -World Health Organization Classifcation O DF And
DHF (1997)
44
APPENDIX 2 -Methods o Sample Collection 46APPENDIX 3 - Home Care Advice Leaet 47
APPENDIX 4 -Dengue Monitoring Record 48
APPENDIX 5 - Dengue Monitoring Chart 49
APPENDIX 6 - Clinical Questions 50
APPENDIX 7 - Search Strategy 52
LIST OF ABBREVIATIONS 53
ACKNOWLEDGEMENT 54
DISCLOSURE STATEMENT 54
SOURCES OF FUNDING 54
LEVELS OF EVIDENCE & GRADES OF RECOMMENDATION
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1. EPIDEMIOLOGy
Dengue is one o the most important arthropod-borne viral diseases in
terms o human morbidity and mortality. Dengue has become an important
public health problem. It aects tropical and subtropical regions around the
world, predominantly in urban and semi urban areas.
The number o reported dengue ever (DF) and dengue haemorrhagic ever
(DHF) cases in Malaysia shows an increasing trend (Figure 1). The incidence
rate also shows an upward trend rom 44.3 cases/100,000 population in
1999 to 181 cases/100,000 population in 2007 (Figure 2). This exceeds the
national target or the incidence rate o DF and DHF which is less than 50
cases/100,000 population. Dengue ever accounts or almost 95% o all
reported cases. The serologically confrmed cases are approximately 40-
50% o these cases at the time o notifcation. This relatively low percentage
o seropositivity is due to lack o convalescent samples (second bloodspecimen) being sent or confrmation.
The incidence rate is higher in the age group o 15 years and above (Figure
2). The highest incidence rate is among the working and school-going age
groups. An increase o dengue deaths in the adult population has been
observed since 2002. (Figure 3) The case atality rates or both DF and DHF
however remain well below 0.3% since 2002 (Figure 4).
Most o the dengue cases reported were rom urban areas (70 80%) wherethere is a high density o its population and rapid development activities-
actors which avour dengue transmission.
Figure 1 : Number o Dengue Cases, Malasia 1995-2007
6,543
14,255
19,429
27,381
10,146
7,103
16,368
32,76731,545
33,895
39,65438,556
46,542
79.6
43.040.9
50.2
46.5
52.5 52.9
47.348.9
39.642.5
47.3
29.5
0
1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007
0.0
10.0
20.0
30.0
40.0
50.0
60.0
70.0
80.0
90.0
SerologyPositve(%)
Total DF DHF Serology Positive (%)
6,543
14,255
19,429
27,381
10,146
7,103
16,368
32,76731,545
33,895
39,65438,556
49,173
79.7
42.540.9
50.2
46.2
52.4 53.0
47.349.0
39.6
42.7
47.348.7
0
10
20
30
40
50
60
70
80
90
100
0
10,000
20,000
30,000
40,000
50,000
60,000
SerologyConfirmed(%)
Noofcases
Year
Total (Clinical) DF DHF Serologically Confirm ed (%)
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Figure 2 : Dengue Incidence Rate b Age Group in Malasia, 1999-2007
Figure 3 : Dengue Deaths b Age Group in Malasia, 1999-2007
Figure 4 : Dengue Case Fatalit Rate (CFR) b Age Group in Malasia, 1999-20071
0
10
20
30
40
50
60
70
80
90
1999 2000 2001 2002 2003 2004 2005 2006 2007Year
NoO
fDeath
0 - 14 Years (IR) > 15 Years (IR)
0.36
0.63
0.31 0.300.23
0.30 0.280.23
0.20
0.00
0.20
0.40
0.60
0.80
1.00
1.20
1.40
1999 2000 2001 2002 2003 2004 2005 2006 2007
Incide
nce(per100,0
00)
Year
Population (CFR) 0 - 14 Years (CFR) > 15 Years (CFR)
44.330.2
68.2
133.6 125.9 132.5
151.9144.7
181
0
50
100
150
200
250
1999 2000 2001 2002 2003 2004 2005 2006 2007Year
Incidence
(per
100,
000)
Population 0 - 14 Years > 15 Years
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2. VIROLOGy
Dengue inection is caused by dengue virus which is a mosquito-borne
avivirus. It is transmitted byAedes aegypti andAedes albopictus. There
are our distinct serotypes, DEN-1, 2, 3 and 4. Each episode o inection
induces a lie-long protective immunity to the homologous serotype but
coners only partial and transient protection against subsequent inection
by the other three serotypes. Secondary inection is a major risk actor
or DHF due to antibody-dependent enhancement. Other important
contributing actors or DHF are viral virulence, host genetic background,
T-cell activation, viral load and auto-antibodies.
All our serotypes can be isolated at any one time but the predominat circulating
dengue virus will show a sinusoidal pattern (Figure 5). For example, DEN-3
was the predominant serotype in the early 90s with a peak in 1993, and then
subsequently declined. It then re-emerged, reaching the peak in 2001. Otherserotypes had been observed to be co-circulating at the same time.
Figure 5 : Percentage o Dengue Serotpe in Malasia, 1991-2007
3. CLINICAL MANIFESTATIONS AND PATHOPHySIOLOGy
3.1 SPECTRUM OF DENGUE INFECTION
The incubation period or dengue inection is 4-7 days (range 3-14).2 It
may be asymptomatic or may result in a spectrum o illness ranging romundierentiated mild ebrile illness to severe disease, with or without
plasma leakage and organ impairment. Symptomatic dengue inection
is a sstemic and dnamic disease with clinical, haematological and
serological profles changing rom day to day. These changes accelerate
by the hour or even minutes during the critical phase, particularly in those
with plasma leakage (reer to section 3.3).
0
10
20
30
40
50
60
70
80
90
100
%o
fSerotype
Den 1 (%) Den 2 (%) Den 3 (%) Den 4 (%)
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Understanding the systemic and dynamic nature o dengue disease as well
as its pathophysiological changes during each phase o the disease will
produce a rational approach in the management o dengue.
3.2 CLINICAL COURSE OF DENGUE INFECTION
Dengue inection is a dynamic disease. Its clinical course changes as the
disease progresses. Ater the incubation period, the illness begins abruptly
and will be ollowed by 3 phases: ebrile, critical and recovery phase. (reer
Figure 6) 3, 4
i. Febrile Phase
Typically, patients develop high grade ever suddenly. This acute ebrile
phase usually lasts 2-7 days and oten accompanied by acial ushing,
skin erythema, generalised body ache, myalgia, arthralgia and headache.3,
4
Some patients may have sore throat, injected pharynx and conjunctivalinjection. Anorexia, nausea and vomiting are common. These clinical
eatures are indistinguishable between DF and DHF.5
Mild haemorrhagic maniestations like positive tourniquet test or petechiae
and mucosal membrane bleeding may be seen in DF and DHF.5, 6 Per
vaginal bleeding is common among young adult emales. Massive vaginal
bleeding and gastrointestinal bleeding may occur during this phase but
are not common.7, 6 The fndings o an enlarged and tender liver are more
suggestive o DHF.5
The earliest abnormality in the ull blood count is a progressive decrease
in total white cell count. This should alert the physician to a high index
o suspicion o dengue especially when there is positive history o
neighborhood dengue. This disease should be notifed as early as possible
to prevent disease rom assuming epidemic proportion.
ii. Critical Phase
The critical phase occurs towards the late ebrile phase (oten ater 3rd day
o ever) or around deervescence (usually between 3rd to 5th day o illness
but may go up to 7th day) when a rapid drop in temperature may coincide
with an increase in capillary permeability in some patients. In other viral
inections, the patients condition improves as the temperature subsides,
but the contrary happens in DHF. At this point the patient will either become
better i no or minimal plasma leak occurs, or worse i a critical volume o
plasma is lost.3, 4,8, 9
The critical phase lasts about 24-48 hours. (reer Figure 6) Varying
circulatory disturbances (reer to Table 1) can develop. In less severe cases,
these changes are minimal and transient. Many o these patients recover
spontaneously, or ater a short period o uid or electrolyte therapy. In
more severe orms o plasma leakage, the patients may sweat, become
restless, have cool extremities and prolonged capillary refll time. The
pulse rate increases, diastolic blood pressure increases and the pulse
pressure narrows. Abdominal pain, persistent vomiting, restlessness,
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altered conscious level, clinical uid accumulation, mucosal bleed or liver
enlargement >2 cm are the clinical warning signs o severe dengue or high
possibility o rapid progression to shock.9, 10, 11 The patient can progress
rapidly to proound shock and death i prompt uid resuscitation is not
instituted.
It is important to note that thrombocytopaenia and haemoconcentration(evidenced by a raised haemotocrit (HCT) rom baseline or a drop in HCT
ater rehydration) are usually detectable beore the subsidence o ever
and the onset o shock. Reer to 3.5.1 or urther details. The HCT level
correlates well with plasma volume loss and disease severity. However, the
levels o HCT may be equivocal when there is rank haemorrhage, early and
excessive uid replacement or untimely HCT determinations.
Leucopaenia with relative lymphocytosis, clotting abnormalities, elevation
o transminases [typically the level o aspartate aminotransaminase(AST) is about 2-3 times the level o alanine aminotransaminase (ALT)],
hypoproteinaemia and hypoalbuminaemia are usually observed.3, 4, 5
iii. Recover Phase
Ater 24-48 hours o deervescence, plasma leakage stops and is ollowed
by reabsorption o extravascular uid. Patients general well being improves,
appetite returns, gastrointestinal symptoms abate, haemodynamic status
stabilises and diuresis ensues. Some patients may have a classical rasho isles o white in the sea o red.3 Some may experience generalised
pruritus. Bradycardia and electrocardiographic changes are not uncommon
during this stage. It is important to note that during this phase, HCT level
stabilises or drops urther due to haemodilution ollowing reabsorption o
extravascular uid. The recovery o platelet count is typically preceded by
recovery o white cell count (WCC).
Figure 6 : CLINICAL COURSE OF DHF12
Note : Onset o deervescence usually occurs between day 3 to day 5 o illness
40
Viraemia
Course ofdengue illness FEBRILE CRITICAL RECOVERY
Shock / Bleeding Reabsorption / Fluid overloadDehydration
Days of illness
Temperature
Potential
clinical issues
Laboratory
changes
Serology
and virology
Platelet
Hematocrit
IgM/IgG
Organ Impairment
1 2 3 4 5 6 7 8 9 1 0
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Clinical deterioration oten occurs during the critical phase
(plasma leakage) and it is thereore crucial to recognise the
onset o this phase.
The onset o critical phase is marked by plasma leakage and
usually occurs around the onset o deervescence.
Evidence o plasma leakage includes raised HCT (early marker),
haemodynamic instability, uid accumulation in extravascular
space (rather late marker) or hypoproteinemia.
Abdominal pain, persistent vomiting, restlessness, altered
conscious level, clinical uid accumulation, liver enlargement
or mucosal bleed are the clinical warning signs o severe
dengue or high possibility o rapid progression to shock.
3.3 PATHOPHySIOLOGy OF PLASMA LEAKAGE IN DENGUEHAEMORRHAGIC FEVER (DHF)/DENGUE SHOCK SyNDROME (DSS)
The primary pathophysiological abnormality seen in DHF and DSS is an
acute increase in vascular permeability that leads to leakage o plasma
into the extravascular compartment, resulting in haemoconcentration and
hypovolaemia or shock.13,3,4 Hypovolaemia leads to reex tachycardia and
generalised vasoconstriction due to increased sympathetic output.14,15
Clinical maniestations o vasoconstriction in various systems are as
ollows :
a. Skin - coolness, pallor and delayed capillary refll time
b. Cardiovascular system - raised diastolic blood pressure and a narrowing
o pulse pressure
c. Renal system - reducing urine output
d. Gastrointestinal system - vomiting and abdominal pain
e. Central nervous system lethargy, restlessness, apprehension, reduced
level o consciousness
. Respiratory system tachypnoea(respiratory rate >20/min)
In patients whose consciousness is not obtunded, intense thirst is another
prominent symptom. At the same time, the inadequate perusion o the
tissue leads to increased anaerobic glycolysis and lactic acidosis. I the
hypovolaemia is not corrected promptly, the patient will progress to a
reractory shock state. By then, the tissue perusion would not respond to
vasopressor drugs, even i the blood pressure and intravascular volume
were to be restored and cardiac output would remain depressed. The
resultant lactic acidosis urther depresses the myocardium and worsensthe hypotension.15 The common late complications o prolonged shock
are massive bleeding, disseminated intravascular coagulopathy (DIC) and
multi-organ ailure which are oten atal.
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The ollowing table is the summary o the continuum o various
pathophysiological changes in a patient who progresses rom normal
circulatory state to hypovolaemic shock.
Table 1 : A continuum o pathophsiological changes rom normal circulation to
compensated and decompensated/ hpotensive shock(Adapted rom15)
Normal Circulation Compensated shockDecompensated /
Hpotensive shock
Clear consciousnessClear consciousness shock can be
missed i you do not touch the patient
Change o mental state restless,
combative or lethargy
Brisk capillary refll time (2 sec)Mottled skin, very prolonged
capillary reil l time
Warm and pink extremities Cool extremities Cold, clammy extremities
Good volume peripheral pulses Weak & thready peripheral pulses Feeble or absent peripheral pulses
Normal heart rate or age TachycardiaSevere tachycard ia wi th
bradycardia in late shock
Normal blood pressure or age
Normal systolic pressure with
raised diastolic pressure
Postural hypotension
Hypotension/unrecordable BP
Normal pulse pressure or age Narrowing pulse pressureNarrowed pulse pressure
(
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3.4 TOURNIQUET TEST
In DHF grade 1, a positive tourniquet test serves as the only indicator o
haemorrhagic tendency. The sensitivity o the test varies widely rom as low
as 0% to 57%, depending on the phase o illness the test was done and
how oten the test was repeated, i negative. In addition 5-21% o patients
with dengue like illness had positive tourniquet test but subsequently have
negative dengue serology.22, Level 1
A recent study demonstrated that there was 95.3% positive preditive
value i ever, positive tourniquet test, leucopenia/ thrombocytopaenia/
haemoconcentration were used as screening criteria.23, Level 8
The tourniquet test may be useul as an additional tool when the diagnosis
is in doubt, especially when the platelet count is still relatively normal.
How to perorm tourniquet test
Inate the blood pressure cu on the upper arm to a point midway
between the systolic and diastolic pressures or 5 minutes.
A positive test is when 20 or more petechiae per 2.5 cm (1 inch)
square are observed.
Recommendation
The tourniquet test may be helpul in the earl ebrile phase (less
than three days) in dierentiating dengue rom other ebrile illnesses.(Grade C)
3.5 WHO DENGUE CLASSIFICATION
Based on current WHO dengue classifcation scheme (reer Appendix 1), the
key dierentiating eature between DF and DHF is the presence o plasma
leakage in DHF. However, in the early ebrile phase o dengue inection, the
symptoms can overlap and one cannot dierentiate DF and DHF.
DHF is urther classifed as mild (grades I and II) or severe (grades III and
IV), the presence o shock being the main dierence. Grades III and IV are
classifed as Dengue Shock Syndrome (reer Appendix 1).
(Note : The existing WHO dengue classifcation is being reviewed and revised)
3.5.1 Limitations o WHO classication22, Level 1
It has been observed that the existing WHO classifcation scheme has
several limitations as the disease has spread to new regions and inectedolder age groups. For example:
1. Dengue with shock without ulflling all the 4 criteria or DHF
There have been many case reports o patients with severe dengue with shock
who do not ulfl all the 4 criteria or DHF. These patients would have been
classifed as dengue ever i the WHO criteria were to be strictly applied.
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2. Severe organ impairment
Patients with severe organ impairment such as liver, respiratory,cardiac and brain dysunction were not captured as having severe
disease based on the existing classifcation.
3. Plasma leakage in DHF
The requirement o 20% increase in HCT as one o the evidence o
plasma leakage is difcult to ulfll due to several issues:a. Baseline HCT is not available in most patients and thereore, the
interpretation o plasma leak can only be made retrospectively
b. Early uid administration may aect the level o HCT
c. Bleeding will aect the HCT level
4. The existing classifcation scheme is oten not useul or diseasemanagement because the correct disease classifcation can only be
made towards the end o the illness.
Patients can present with severe dengue without ulfllingALL the4 criteria (reer to Appendix 1) or DHF/DSS.
3.6 OTHER IMPORTANT MANIFESTATIONS
Severe bleeding or organ impairment might occur without plasma leakage.The ollowing maniestations are important in dengue inection but are
oten under-recognised or misdiagnosed
1. Acute abdomen :
Acute abdominal pain is a common symptom in dengue inection. It canbe due to hepatitis, acalculous cholecystitis and shock, and occasionallymisdiagnosed as acute appendicitis.24, Level 8; 25, Level 8 The history oonset o ever beore the abdominal pain, and laboratory fndings oleucopenia, thrombocytopenia, or prolonged APTT with normal PThelp to dierentiate acute abdominal pain due to dengue inection romother surgical causes.24, Level 8 Furthermore, in patients with shock, the
abdominal pain is relieved by intravenous uid therapy.
2. Hepatitis and liver ailure :
Hepatitis is common in patients with DF/DHF and may be mild or severeregardless o the degree o plasma leakage. In some cases, liver ailuremay occur.22,Level 1 The patients with liver ailure have a high propensity
to bleed, especially gastrointestinal bleeding. 26, Level 8; 11, Level 8
3. Neurological maniestation :Patients with dengue inection may have neurological maniestations,(
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0
3.7DIAGNOSTIC CHALLENGES
Clinical eatures o dengue inection are rather non-specifc and mimicmany other diseases, thereore can be easily misinterpreted. A high indexo suspicion and appropriate history taking, particularly with regards to arecent stay in dengue hotspots, are useul or early and accurate diagnosiso dengue. In addition, a dengue patient may have a co-inection with
another pathogen.
Using a syndromic approach, Tables 2 and 3 provide quick and helpul
reerences to the dierential diagnoses which vary at dierent stages o
dengue disease.
FEBRILE PHASE
Table 2 : Dierential diagnoses or dengue illness during ebrile phase
Clinical sndrome Dierential diagnoses
Flu-like sndrome
InuenzaMeasles
Chikungunya
Adenovirus
Inectious mononucleosis
Acute HIV seroconversion illness
Rash
Rubella
Measles
Scarlet ever
Meningococcal inection
Chikungunya
Drug
DiarrheaRotavirus
Food poisoning
Neurological maniestationMeningoencephalitis
Febrile seizures
CRITICAL PHASETable 3:Dierential diagnoses or dengue illness during critical phase
Clinical sndrome Dierential diagnoses
Acute abdomen
Acute appendicitis
Acute cholecystitis
Perorated viscus
Viral hepatitis
Diabetic ketoacidosis
Shock Septic shock
Respirator distress
(Kussmauls breathing)
Diabetic ketoacidosis
Renal ailure
Lactic acidosis
Leucopaenia &
thromboctopenia bleeding
Acute leukaemia
Immune thrombocytopaenia purpura
Thrombotic Thrombocytopenic purpura
Malaria / Leptospirosis / Typhoid / Typhus
Bacterial sepsis
SLE
Acute HIV seroconversion illness
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4. DISEASE NOTIFICATION
All suspected dengue cases must be notifed by telephone to the nearest
health ofce within 24 hours o diagnosis, ollowed by written notifcation
within a week using the standard notifcation ormat.29 Any delay in notifcation
will increase the risk o dengue transmission in the locality o the residence.
In 2007, 98.4% o dengue cases were notifed by public and private hospitals
with only 1.6% rom the government and private clinics. The average day o
illness at the time o notifcation was about 4-5 days ater the onset o illness
even though patients might have presented themselves to the healthcare
acilities at day 1-3 day o ever.
Notifcation should be done as soon as a clinical diagnosis o dengue is
suspected; serological confrmation is not necessary. Notifed cases will be
ollowed up by the health authorities or the verifcation o case defnition
and preventive measures. It is also important to note that re-notifcationhas to be done i the diagnosis has been changed rom DF to DHF or DF
to other diagnosis.
Failure to notiy is liable to be compounded under the Prevention and
Control o Inectious Diseases Act, 1988 (Act 342).30
5. LABORATORy INVESTIGATIONS
5.1 DISEASE MONITORING LABORATORy TESTS
Full Blood Count (FBC)
1. White cell count (WCC) :
In the early ebrile phase WCC is usually normal but will decrease
rapidly as the disease progresses.5, Level 8 This trend o leucopenia
should raise the suspicion o possible dengue inection.
2. Haematocrit (HCT) :
A rising HCT is a marker o plasma leakage in dengue inection and
helps to dierentiate between DF and DHF but it can be masked inpatients with concurrent signifcant bleeding and in those who receive
early uid replacement.22, Level 1 Setting the patients baseline HCT in the
early ebrile phase o disease will be very useul in the recognition o
a rising HCT level.
3. Thrombocytopaenia :
Thrombocytopaenia is commonly seen in dengue inection.22,Level 1 In
the early ebrile phase, platelet count is usually within normal range
but it will decrease rapidly as the disease progresses to the late ebrilephase or at deervescence and it may continue to remain low or the
frst ew days o recovery.
There is a signifcant negative correlation between disease severity
and platelet count 3, Level 9;31Level 8 but it is not predictive o bleeding.32,
Level 8; 33, Level 1; 34, Level 6;35, Level 8; 36, Level 8
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Liver Function Test
Elevated liver enzymes is common and is characterised by greater elevation o
the AST as compared to the ALT.37,Level 8 The requency and degree o elevation
o the liver enzymes are higher with DHF compared to DF.38, Level 8;37, Level 8
Leucopaenia ollowed by progressive thrombocytopaenia issuggestive o dengue inection.
A rising HCT accompanying progressive thrombocytopaenia is
suggestive o DHF.
There is no local data available on the normal range o HCT in adults.
In the absence o a baseline HCT level, a HCT value o >40% in
emale adults and >46% in male adults should raise the suspicion
o plasma leakage.
Recommendation
The baseline HCT and WCC should be established as early as
possible in all patients with suspected dengue. (Grade A)
Serial FBC and HCT must be monitored as the disease progresses.
(Grade A)
5.2 DIAGNOSTIC TESTS
Defnitive diagnosis o dengue inection can only be confrmed in the
laboratory. However, the interpretation o laboratory diagnostic results
should be done in the clinical context. Laboratory confrmatory tests include
antibody detection (serology), virus isolation, detection o virus genetic
materials (polymerase chain reaction -PCR) and detection o dengue virus
protein (NS1 antigen).
5.2.1 DENGUE SEROLOGy TESTS
Haemagglutination Inhibition Test
The haemagglutination Inhibition (HI) test has been the gold standard or
serological diagnosis. However, because it is labour intensive and requires
paired samples or interpretation, this test is now being used mainly or
research purposes to dierentiate between primary and secondary dengue
inections.
Dengue IgM testThe IgM capture enzyme-linked immunosorbent assay (ELISA) is the most
widely used serological test. This antibody titre is signifcantly higher in
primary inections, compared to secondary inections. Once the IgM is
detectable, it rises quickly and peaks at about 2 weeks ater the onset o
symptoms, and it wanes to undetectable levels by 60 days. However in
some patients, it may persist or more than 90 days. A positive result thus
has to be intepreted and correlated cautiously with the clinical picture. I
the dengue IgM test is the only available diagnostic test in the hospital,
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then establishing a negative IgM early in the illness, and demonstrating a
positive serology later will be essential to exclude alse negative results.
In one study, IgM was detected in only 55% o patients with primary dengue
inections between day 4-7 onset o ever, and it became positive in 100%
o the patients ater day 7. However, in secondary dengue inections, IgM
was detected in only 78% o patients ater day 7.39, Level 7. In anotherstudy, 28% o secondary dengue inections were undiagnosed when IgM
was the only test perormed.4, Level 9; 40,Level 8; 41, Level 8
Indirect IgG ELISA test
In primary and secondary dengue inection, dengue IgG was detected
in 100% o patients ater day 7 o onset o ever. Thereore, dengue IgG
is recommended i dengue IgM is still negative ater day 7 in secondary
dengue.39, Level 7; 40, Level 8; 42, Level 8
Recommendation
In order to establish serological confrmation o dengue illness aseroconversion o dengue IgM needs to be demonstrated. Thereorea dengue IgM should be taken as soon as the disease is suspected.(Grade C)
Dengue IgM is usually positive ater day 5-7 o illness. Thereore, anegative IgM taken beore day 5-7 o illness does not exclude current
dengue inection. (Grade B)
I the dengue IgM is negative beore day 7, a repeat sample must betaken in the recovery phase to confrm the diagnosis. (Grade B)
Please reer to Appendix 2 or methods o sample collection
Dengue Rapid tests
Simple rapid tests such as the strip assays (immunochromatography test)
are available or qualitative detection o dengue IgM and IgG (e.g. Pan BioDengue IgM ELISA and Dengue IgM Dot Enzyme Immunoassay).
The yield o rapid tests was shown to be higher when samples were
collected later in the convalescent phase o inection, with good specifcity
and could be used when ELISA acilities were not available43,Level 1 But the
result had to be interpreted in the clinical context because o alse positive
and negative results.44,Level 8;45, Level 8; 41, Level 8; 46, Level 8 It isrecommended that
the dengue IgM Capture ELISA test be done ater a rapid test, to confrm
the status.44,Level 8
Note : False positive dengue serolog
Serological tests or dengue have been shown to cross-react with:
other avivirus Japanese Encephalitis.47, Level 9; 41, Level 8
non-avivirus malaria, leptospirosis, toxoplasmosis, syphilis48,Level ; 45, Level 8
connective tissue diseases rheumatoid arthritis44, Level 8
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5.2.2 VIRUS ISOLATION
Virus isolation is the most defnitive test or dengue inection. It can only be
perormed in the lab equipped with tissue culture and other virus isolation
acilities. It is useul only at the early phase o the illness. Generally, blood
should be collected beore day 5 o illness; i.e. beore the ormation o
neutralizing antibodies.
During the ebrile illness, dengue virus can be isolated rom serum, plasma
and leucocytes. It can also be isolated rom post mortem specimens. The
monoclonal antibody immunouorescence test is the method o choice or
identifcation o dengue virus. It may take up to two weeks to complete the
test and it is expensive.
Note: Virus isolation has a poor yield i compared with molecular tests. It is most probably due
to the viability o the virus and the quality o the samples.49,Level 8
5.2.3 POLyMERASE CHAIN REACTION (PCR)
Molecular tests such as the reverse transcriptase ploymerase chain
reaction (RT- PCR) are useul or the diagnosis o dengue inection in the
early phase (< 5 days o illness). It was shown to have a sensitivity o 100%
in the frst 5 days o disease, but reduced to about 70% by day 6, ollowing
the disappearance o the viraemia.50, Level 8;42, Level 8; 51, Level 8
An additional advantage o RT- PCR is the ability to determine dengue
serotypes 52, Level 7; 42, Level 8; 53, Level 8; 49, Level 8; 54, Level 8
Limitations o RT- PCR are:
a) This test is only available in a ew centres with acilities and trained
personnel (e.g. IMR, HKL, National Public Health Laboratory and University Malaya
Medical Centre).
b) The test is expensive
c) The specimen requires special storage temperatures and short
transportation, time between collection and extraction (reer
Appendix 1)
In view o these limitations, the use o RT- PCR should only be considered
or in-patients who present with diagnostic challenges in the early phase
o illness.
5.2.4 NON-STRUCTURAL PROTEIN-1 (NS1 Antigen)
NS1 antigen is a highly conserved glycoprotein that seems to be essential
or virus viability. Secretion o the NS1 protein is a hallmark o avivirus
inecting mammalian cells and can be ound in dengue inection as wellas in yellow ever and West Nile virus inection. This antigen is present in
high concentrations in the sera o dengue inected patients during the early
phase o the disease.55, Level 8; 56,Level 8
The detection rate is much better in acute sera o primary inection (75%-
97.3%) when compared to the acute sera o secondary inection (60% -
70%).57, Level 8;58, Level 8;59, Level 8;60, Level 8 The sensitivity o NS1 antigen detection
drops rom day 4-5 o illness onwards and usually becomes undetectable
in the convalescence phase.61,Level 8;60, Level 8; 58,Level 8;59,Level 8
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Recommendation
PCR can be used as a diagnostic tool in early dengue inection
(Grade B). It is not recommended as a routine diagnostic test due
to limited availability and cost. (Grade C)
NS1 Ag is a new diagnostic tool that may be useul in the early
phase o dengue inection. It is not useul in the convalescencephase.However, this test is still undergoing evaluation. (Grade C)
Please reer to Appendix 2 or methods o sample collection.
6. INVESTIGATION OF POST MORTEM CASE
Suitable samples or viral isolation and PCR should be obtained rom the
liver, lung, thymus, spleen, lymph nodes, CSF, pleural uid and brain tissues
in a patient suspected to have died o DF/DHF.2, Level 9; 62,Level 9 However PCR
is a more sensitive method.62 Level 9; 63, Level 7; 64, Level8
For serological confrmation o dengue illness a seroconversion o dengue
IgM needs to be demonstrated. In a patient who has died suspected o
dengue, a repeat dengue serology together with the samples mentioned
above should be obtained.
Caution : Massive blood transusion may aect the test results mentioned above.
Recommendation
A repeat dengue serology should be obtained at the time o death.(Grade C)
Suitable specimens or virus isolation and/ or RT-PCR and/ orantigen detection are recommended or confrmation o diagnosis.(Grade C)
Please reer to Appendix 2 or methods o sample collection.
7.MANAGEMENT OF DENGUE INFECTION
7.1 OUTPATIENT MANAGEMENT
The management o dengue inection is smptomatic and supportive.A
stepwise approach as suggested in Table 4 can be useul.
Dengue is a dynamic diseaseand management issues vary according to
the 3 phases o the clinical course (reer to section 7.4). It is crucial to
recogniseplasma leakage, shock early or severe organ impairment. This
can be achieved by requent clinical and laboratory monitoring.
Dengue patients who are managed in the outpatient setting should be
provided with a disease monitoring record (reer to Appendix 4) to ensure
that all relevant inormation is available to all health care providers.
Primary care providers with no immediate haematocrit acilities should
reer patient to the nearest health acility or urther management.
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Table 4 : A Stepwise approach on outpatient management o dengue inection
It is important to evaluate every patient in a stepwise manner as in the ollowing :
Step 1: Overall assessment1. History
Date o onset o ever/ illness
Oral intake
Assess or warning signs reer to Table 5 Diarrhoea
Bleeding
Change in mental state/seizure/dizziness
Urine output (requency, volume and time o last voiding)
Other important relevant histories:
- History o dengue amongst amily members or in the neighbourhood
- Jungle trekking and swimming in waterall (consider leptospirosis, typhus, malaria)
- Recent travel
- Recent unprotected sexual or drug use behaviour (consider acute HIV seroconversion illness)
- Co-morbidities (consider sepsis particularly in patients with diabetes mellitus)
2. Physical examination
i. Assess mental state and Glasgow Coma Scale (GCS) score
ii. Assess hydration status
iii. Assess haemodynamic status
- Skin colour
- Cold/ warm extremities
- Capillary flling time (normal
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Table 5 : Warning signs 8, Level 8 ; 9, Level 8
Abdominal pain or tenderness
Persistent vomiting
Clinical fuid accumulation (pleural eusion, ascites)
Mucosal bleed
Restlessness or letharg
Liver enlargement > 2 cm
Laborator : Increase in HCT concurrent with rapid decrease in platelet
Table 6 : Clinical and laborator criteria or those who can be treated at home
1. Able to tolerate orally, good urine output and no history o bleeding
2. Absence o warning signs (reer to Table 5)
3. Physical examination:
Haemodynamically stable-pink, warm extremities
-normal capillary flling time (normal 40% in emale adults
and >46% in male adults should raise the suspicion o plasma leakage.
Thereore admission may be required
Adapted rom65, Level 9; 66, Level 9; 67,Level 9
7.2 Patient Triaging at Emergenc & Trauma and Outpatient DepartmentThe purpose o triaging patients is to determine whether they require urgent
attention. This is to avoid critically ill patients being missed upon arrival.68,
Level 9; 65 Level 9; 69,Level 9;70, Level 9
Triage Checklist
1. History o ever
2. Abdominal pain
3. Vomiting
4. Dizziness/ ainting
5. Bleeding
Vital parameters to be taken :
Mental state,blood pressure, pulse, temperature, cold or warm peripheries
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7.3 CRITERIA FOR HOSPITAL REFERRAL / ADMISSION
7.3.1 Reerral rom primar care providers to hospital
The decision or reerral and admission must not be based on a single clinical
parameter but should depend on the Total Assessment o the patient.
Reerral rom primar care providers to hospital1. Symptoms :
Warning signs (reer to Table 5)
Bleeding maniestations
Inability to tolerate oral uids
Reduced urine output
Seizure
2. Signs :
Dehydration
Shock (reer to Table 1)
Bleeding
Any organ ailure
3. Special Situations :
Patients with co-morbidity e.g. diabetes, hypertension, ischaemic
heart disease, coagulopathies, morbid obesity, renal ailure,chronic liver disease, COPD, haemoglobinopathy
Elderly (
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7.4 DISEASE MONITORING
7.4.1 Principles o disease monitoring
1. Dengue is a systemic and dynamic disease. Thereore disease
monitoring is governed by dierent phases o the disease.
2.The critical phase (plasma leakage) may last or 24-48 hours. Monitoring
needs to be intensifed and requent adjustments in the uid regimemay be required.
3. Recognition o onset o reabsorption phase is also important because
intravenous uid regime needs to be progressively reduced/ discontinued
at this stage.
7.4.2 Outpatient disease monitoring
Every patient suspected o dengue attending the outpatient/ emergency
and trauma department should be assessed in stepwise manner asrecommended in Table 4.
Daily or more requent ollow up is necessary especially rom day 3 o
illness, until the patient becomes aebrile or at least 24- 48 hours without
antipyretics. A disease monitoring record has been developed and it is
recommended to be used or outpatient care (reer to Appendix 4.).
7.4.3 Inpatient disease monitoring
Immediately ater admission every patient with suspected dengue shouldbe reviewed thoroughly similar to the stepwise approach in outpatient (reer
to Table 4).The plan o management and monitoring should be based on
the phase o the disease and the haemodynamic status o the patient.
Table 8 summarises the parameters and requency o monitoring according
to the dierent phases o the illness.
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0
Table 7: Issues o monitoring according to dierent phases o dengue illness
Phases o illness Issues :
Febrile
- Dierentiation o dengue illness rom other ebrile
illnesses.
- Not possible to dierentiate DF rom DHF.
Critical
- Plasma leakage occurs as patient progresses to
late ebrile phase or as temperature begins to
deervescence (T < 38.0 C).
- Clinical deterioration occurs during this phase due to
plasma leakage.
- Plasma leakage results in haemoconcentration and
hypovolemia/ shock.
- Excessive plasma leakage due, in part, to intravenous
uid therapy may cause respiratory distress.
- Bleeding can be precipitated by prolonged shock and
shock can be perpetuated by bleeding.
- May mimic acute abdomen o other causes.
- May be conused with septic shock or other orms
o shock.
Reabsorption
- Cessation o plasma leakage.
- Reabsorption o uid rom extravascular compartment.
- Haemodilution occurs ollowing uid reabsorption.
- Hypervolaemia and pulmonary oedema i intravenous
uid therapy is continued.
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Table 8 : Parameters and requenc o monitoring according to dierent phases
o dengue illness
Parameter or monitoringFrequenc o monitoring
Febrile phase Critical phase Recover phase
Clinical Parameters
General well being
Appetite/ oral intake
Warning signs
Smptoms o bleeding
Neurological/ mental state
Daily or more
requently towards
late ebrile phase
At least twice a
day and more
requently as
indicated
Daily or more
requently as
indicated
Haemodnamic status
Pink/ cyanosis
Extremities (cold/warm)
Capillary refll time
Pulse volume PR
BP
Pulse pressure
Respirator status
RR
SpO2
4-6 hourly
depending on
clinical status
2-4 hourly
depending on
clinical status
In shock
Every 15-30
minutes till
stable then 1-2
hourly
4-6 hourly
Signs o bleeding, abdominal
tenderness, ascites and
pleural eusion
Daily or more
requently towards
late ebrile phase
At least twice a
day and more
requently asindicated
Daily or more
requently as
indicated
Urine output 4 hourly
2-4 hourly
In shock
Hourly
4-6 hourly
Parameter or monitoringFrequenc o monitoring
Febrile phase Critical phase Recover phase
Clinical Parameters
FBC + HCT
Daily or more
requently i
indicated
4-12 hourlydepending on
clinical status
In shock
Repeated
beore and
ater each
attempt o uid
resuscitation
and as
indicated
Daily
BUSE/ Creatinine
LFT
RBS
Coagulation prole
HCO3/ TCO
2/ Lactate
As indicated
At least daily or
more requently
as indicated
In shock
Crucial to
monitor acid-
base balance/
ABG closely
As indicated
Adapted rom 2, Level 9; 65, Level 9
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7.5 FLUID MANAGEMENT`
7.5.1 Non-shock patients (DHF Grade I & II)
There are no studies that have looked at uid therapy in non shock dengue
patients. Increased oral uid intake may be sufcient in some patients
who are haemodynamically stable and not vomiting. However IV uid
(0.9% saline is recommended) is indicated in patients with increasing HCT(indicating on going plasma leakage) despite increased oral intake. IV uid
therapy should also be considered in patients who are vomiting and not
tolerating orally.71,Level 9; 65, Level 9
The normal maintenance requirement or IV uid therapy in such patients
could be calculated based on the ormula in Table 9. Frequent adjustment
o maintenance uid regime is oten needed during the critical phase.
Oten 1.2-1.5 times the normal maintenance will be required during the
critical phase. I the uid inusion rate exceeds more than the maintenancerequirement, the inusion rate should be reviewed within 4 to 6 hours.
A rising HCT AND/ OR haemodynamic instability indicates on-going plasma
leakage and will require an increase in the IV uid inusion rate. I patients
deteriorate and progress to shock, uid resuscitation is indicated (reer to
the section on 7.5.2).71, Level 9; 65 Level 9
Reduce or consider discontinuation o IV uid therapy when patients begin
to show signs o recovery (usually ater 24-48 hours o deervescence, orthe HCT drops in a stable patient).
Table 9 : Calculations or normal maintenance o intravenous fuid inusion
* Normal maintenance fuid per hour can be calculated based on
the ollowing ormula (Equivalent to Hallida-Segar ormula) :
4 mL/kg/h or frst 10kg body weight
+ 2 mL/kg/h or next 10kg body weight
+ 1 mL/kg/h or subsequent kg body weight
* For overweight/obese patients calculate normal maintenance uid
based on ideal body weight(Adapted rom 2, Level 9)
Ideal bodweight can be estimated based on the ollowing ormula: 72,Level9
Female: 45.5 kg + 0.91(height -152.4) cm
Male: 50.0 kg + 0.91(height -152.4) cm
Recommendation
Encourage adequate oral uid intake. (Grade C)
IV uid is indicated in patients who are vomiting or unable to tolerate oral
uids. (Grade C)
IV uid is also indicated in patients with increasing HCT (indicating on-
going plasma leakage) despite increased oral intake. (Grade C)
Crystalloid is the uid o choice or non shock patients. (Grade C)
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7.5.2 Dengue Shock Sndrome (DSS) (DHF Grade III & IV)
Dengue shock syndrome is a medical emergency. Recognition o shock in
its early stage (compensated shock) and prompt uid resuscitation will give
a good clinical outcome.73,Level 2 Reer Table 1 or details. However, ailure to
recognise the compensated shock phase will ultimately lead to decompensated
(hypotensive) shock and a more complicated disease course.
Pulse pressure o < 20 mmHg and systolic pressure < 90 mmHg are late
signs o shock in adults.
All patients with dengue shock should be managed in high dependency
intensive care units. Fluid resuscitation must be initiated promptly
and should not be delayed while waiting or admission to ICU or high
dependency unit.
Following initial resuscitation there maybe recurrent episodes o shock
because capillary leakage can continue or 24-48 hours.
IV uid therapy is the mainstay o treatmentor dengue shock.2, Level 9; 73, Level
2; 74,Level 2To date, only three randomised controlled trials studying dierent
types o uid regime in DSS in children aged rom 5 to 15 years o age
are available.73, Level 2; 74, Level 2;75, Level 2Our recommendations are extrapolated
rom these studies. These studies showed no clear advantage o using any
o the colloids over crystalloids in terms o the overall outcome.However,
colloids may be preerable as the uid o choice in patients with intractable
shock in the initial resuscitation. Colloids seem to restore the cardiacindex and reduce the level o HCT aster than crystalloids in patients with
intractable shock. 74Level 2 The choice o colloids includes gelatin solution
(e.g. Gelausine) and starch solution (e.g. Voluven).
Principles or fuid resuscitation
The volume o initial and subsequent uid resuscitation depends on the
degree o shock and can vary rom 10-20 ml/kg ideal body weight. The
volume and rate o uid replacement should be careully titrated to the
clinical response to maintain an eective circulation while avoiding an over-replacement.
Improvement in the ollowing parameters indicates adequate uid resuscitation:
Clinical parameters
Improvement o general well being/mental state
Warm peripheries
Capillary refll time
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I the frst two cycles o uid resuscitation with crystalloids (about 40 ml/
kg) ails to establish a stable haemodynamic state and HCT remains high,
colloids should be considered or the third cycle 2, Level 9; 65, Level 9 (reer to
Algorithm or uid management or DSS).
I the repeat HCT drops ater two cycles o uid resuscitation and the
patient remains in shock, one should suspect signifcant bleed (otenoccult) and blood transusion should be instituted as soon as possible
(reer to Algorithm or uid management or DSS).
In patients with persistent shock despite three cycles o uid resuscitation
(60ml/kg IV uid), other causes o persistent shock must be considered, the
commonest being signifcant bleeds (oten occult) or which blood blood
products transusion needs to be instituted promptly, (reer to Algorithm or
uid management or DSS).
Other possible causes o persistent shock include sepsis and cardiogenic
shock (due to myocarditis or ischaemic heart disease).
Fluid therapy has to be judiciously controlled to avoid uid overload which
could result in massive pleural eusion, pulmonary oedema or ascites.2, Level
9; 65, Level 9
Reer to the algorithm on IV uid management or DSS patient or details.
Recommendation
For initial resuscitation
Crystalloids are the uid o choice in patients with DSS. (Grade A)
Colloids may be preerred as the uid o choice in patients with
severe shock. (Grade B)
When two cycles o initial resuscitation with crystalloids ail torestore haemodynamic stability, colloids should be considered.
(Grade C)
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ALGORITHM FOR FLUID MANAGEMENT FOR DSS
Compensated shock
0-0 ml/kg bolus (crystallod)
Decompensated (hypotensive) shock
0 ml/kg rapd bolus (crystallod/collod)
FBC, HCT beore and ater fud resusctaton
BUSEC, LFT, RBS, PT/APTT, Lactate/HCO, GXM
HCT
Warm perpheres, CRT secPR ncreases, PP narrows
Urne output reduces
Worsenng/ persstent metabolc acdoss
**Reduce IV fud to ml/kg/hr
**Reduce IV fud to ml/kg/hr
Reduce IV fud urther as pa-
tent contnues to mprove
Stop IV fud about hr o de-
ervescence
Clinical parameters must be monitored every 15-30 minutes during shock
**Fluid regime must be reviewed and readjusted every 30 -60 minutes.
2 IV lines (largest branula possible)
1st line: or replacement/bolus
2nd line: or blood taking OR blood transusion
HCTHCT
Administer 2nd bolus uid
0-0ml/kg bolus (crystallod) OR
0ml/kg rapd bolus (crystallod/collod)
Administer 3rd
bolus uid
0 ml/kg bolus collod
Signifcant occult/
overt bleed
Intate blood blood
product transuson
Consider other causes
Septc shock
Cardogenc shock
I deterorates to shock
I mprovement present
I mprovement present
Not
Improved
Further Improvement
Further Improvement
Further Improvement
Improvement
YES NO
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7.6 MANAGEMENT OF BLEEDING/HAEMOSTASIS
7.6.1 Haemostatic Abnormalities in Dengue Inection
The haemostatic changes that occur in dengue inection are a result o
endothelial activation.76Level 9; 77, Level 8; 78, Level 5 This leads to thrombocytopaenia
and coagulation activation which are an intrinsic part o the disease.76, Level
9;
77, Level 8; 78, Level 5
Thrombocytopaenia and coagulation abnormalities do not reliably predict
bleeding in dengue inection.34, Level 6;33, Level 1; 36, Level 8
Markers o endothelial activation such as elevated levels o thrombomodulin,
tissue actor and Von Willebrand actor are more oten seen in severe
dengue.79, Level 6; 80, Level 6 Increased levels o these proteins may promote
microvascular thrombosis and end-organ damage.81,Level 9
7.6.2 How to recognize signicant occult bleeding?
Bleeding is considered signifcant when it results in haemodynamic
instability. Bleeding rom the gums or per vagina, epistaxis and petechiae are
common but will usually cease spontaneously and are oten not signifcant.2,
Level 9 Signifcant bleeding or disseminated intravascular coagulation usually
occurs ollowing prolonged shock and acidosis.32, Level 8
Suspect signicant occult bleeding in the ollowing situations:Haematocrit not as high as expected or the degree o shock to beexplained by plasma leakage alone. 32, Level 8
A drop in HCT without clinical improvement despite adequate uidreplacement (40-60 ml/kg).32, Level 8; 66, Level 9
Severe metabolic acidosis and end-organ dysunction despite
adequate uid replacement.32, Level 8
7.6.3 Management o Bleeding in Dengue
Mild bleeding such as rom the gums, per vagina, epistaxis or petechiae,
usually cease spontaneously and do not require blood transusion.2, Level 9
Transusion o blood and blood components in dengue is indicated when
there is evidence o signifcant bleeding.32, Level 8
Recommendation
Patients with mild bleeding such as rom the gums, per vagina,
epistaxis or petechiae do not require blood transusion. (Grade C)
Blood transusion with whole blood or packed cell (preerably less
than 1 week) blood components is indicated i there is signifcant
bleeding. (Grade C)
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7.6.4 Management o Upper Gastrointestinal Bleeding
No studies have looked at the use o proton pump inhibitor in upper GIT
bleeding in dengue.
Endoscopy and endoscopic injection therapy in upper GIT haemorrhage
increases the risk o bleeding and must be avoided.82, Level 7
Generally, most o the GIT bleed will improve ater 48-72 hours o the
deervescence. A persistent bleed beyond this time will require urther
investigation.
Recommendation
Endoscopy and endoscopic injection therapy in upper GIT
haemorrhage should be avoided. (Grade C)
Blood transusion with whole blood or packed cell (as resh as is
available, preerably less than 1 week old) blood components is
indicated in signifcant bleeding. (Grade C)
7.6.5 The Role o Prophlactic Transusions in Dengue
Prophylactic transusion with platelets and resh rozen plasma do not
produce sustained changes in the coagulation status and platelet count in
patients with DHF/DSS.83,Level 8 ; 84, Level 8
Prophylactic transusion with platelets and resh rozen plasma do not
change or reduce the bleeding outcome in DHF. 83, Level8; 84, Level 8 ; 36, Level 8
Inappropriate transusion o blood components increases the risk o
pulmonary oedema and respiratory embarrassment.83,Level 8
Recommendation
There is no role or prophylactic transusion with platelets and reshrozen plasma in dengue patients. (Grade C)
7.6.6 The Role o Adjunctive Therap in Dengue
There is insufcient evidence to support the use o recombinant activated
actor VII in dengue patients with signifcant bleeding.85, Level 3; 86, Level 9 The
coagulation system is activated in dengue and inusion o activated actor
concentrates may increase the risk o thrombosis.87, Level 9
There is insufcient evidence to support the use o intravenousimmunoglobulin88, Level 3and steroids89, Level 1 in the management o dengue
patients.
However there are anedoctal reports,72, Level 9 that demonstrated a dramatic
response when pulse methylprednisolone and high dose immunoglobulin
G was used in the early phase o haemophagocytic syndrome.
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7.7 INTENSIVE CARE MANAGEMENT
The management o DSS in the intensive care unit (ICU) ollows the general
principles o management o any critically ill patient in the ICU. However,
certain aspects which are o particular relevance to the management
o DSS are discussed here. There are several papers reviewing dengue
patients who were admitted to ICU. Several indications or ICU care were
observed as listed in the box below.90, Level 8; 91, Level 8; 10, Level 8
Indications or reerral to Intensive Care:
1. Recurrent or persistent shock
2. Requirement or respiratory support (non-invasive and invasive ventilation)
3. Signifcant bleeding
4. Encephalopathy or encephalitis
7.7.1 Indications or respirator support (non-invasive and invasive ventilation)
The main objectives o respiratory support are to support pulmonary gas
exchange and to reduce the metabolic cost o breathing.
In general, respiratory support should be considered early in a patients
course o illness and should not be delayed until the need arises. The
decision to initiate respiratory support should be based on clinical
judgement that considers the entire clinical situation.92,Level 9
In patients with metabolic acidosis, respiratory support should be
considered despite the preservation o relatively normal arterial blood pH.
When PaCO2
is higher than expected to compensate or the acidosis, the
patient should be promptly intubated.
Formula to calculate the expected PaCO2
= 1.5 x [HCO3-] + 82 mmHg
In patients with encephalopathy and GCS o
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Formula : MAP ( Mean Arterial Pressure)
= DBP + 1/3 (SBP - DBP)DBP = diastolic blood pressure
SBP = systolic blood pressure
7.7.3 Guide on saet and risk o invasive procedures
a. Central venous catheter (CVC) insertion
Volume resuscitation does not require a CVC i sufcient peripheral
intravenous access can be obtained (e.g. 14- or 16-gauge intravenous
catheters). In act, peripheral intravenous catheterisation may be preerable
because a greater ow rate can be achieved through a shorter catheter,
assuming the catheters are o equal diameter.96, Level 8 When a CVC o 8.5
French or larger (i.e. an introducer) is used, the length o tubing becomes
the rate limiting actor, not the CVC.
There are no studies on dengue patients with regards to invasiveprocedures and bleeding risks. In general, thrombocytopaenia and other
bleeding diathesis are relative contraindications to CVC placement as
high emoral, low internal jugular, and subclavian venous punctures are
difcult to compress and coner an increased risk o uncontrolled bleeding.
However, studies have shown that the incidence o bleeding in patients
with coagulopathy varies (0-15.5%).97, Level 8; 98, Level 8; 99, Level 8; 100, Level 8; 101,Level 8
When CVC is indicated in dengue patients (e.g. poor peripheral venous
access, requirement o vasopressors) it should be inserted by anexperienced operator and under ultrasound guidance i available.102, Level 8;
103, Level 1
There are multiple insertion sites to choose rom: emoral vein, external
jugular vein, internal jugular vein, subclavian vein, brachial vein and cephalic
vein. However, because the subclavian vein and artery are not accessible
to direct compression, the subclavian site is least appropriate or a patient
with a bleeding diathesis104, Level 9;105, Level 9
Recommendation
Volume resuscitation does not require a central venous catherisation
(CVC) i sufcient peripheral intravenous access can be obtained.
(Grade C)
When CVC is indicated it should be inserted by a skilled operator,
preerably under ultrasound guidance i available. (Grade C)
Subclavian vein cannulation should be avoided as ar as possible.
(Grade C)
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0
b. Arterial catheter insertion
Intra-arterial cannulation is useul as it enables continuous arterial pressure
monitoring and repeated arterial blood gas sampling. It has a very low
incidence o bleeding (1.8 2.6%)106,Level 8
Recommendation
An arterial catheter should be inserted in DSS patients who require
intensive monitoring and requent blood taking or investigations.
(Grade C)
c. Gastric tube
I a gastric tube is required, the nasogastric route should be avoided.
Consider orogastric tube as this is less traumatic.
d. Pleural tap and chest drainIntercostal drainage o pleural eusions should be avoided as it can lead to
severe haemorrhage and sudden circulatory collapse.107,Level 9
Recommendation
Intercostal drainage or pleural eusion is not indicated to relieve
respiratory distress. Mechanical ventilation should be considered.
(Grade C)
8. DISCHARGE CRITERIA
The ollowing should be taken into consideration beore discharging a patient.65,
Level 9; 66,level 9
Aebrile or 48 hours
Improved general condition
Improved appetite
Stable haematocrit
Rising platelet count
No dyspnoea or respiratory distress rom pleural eusion or ascites
Resolved bleeding episodes
Resolution/recovery o organ dysunction
9. PREVENTION OF DENGUE TRANSMISSION IN HOSPITALS
Patients are viraemic and hence potentially inectious during the ebrile
phase.108, Level 8; 109,Level 8 There are a ew small studies that demonstrate higherlevels and prolonged duration o viraemia in patients with DHF.110, Level 6; 111, Level 8
There are no scientifc studies that address the efcacy o mosquito
repellents or mosquito netting in reducing dengue transmission in
hospitalised patients. However several community studies have shown
that the use o mosquito netting/ screening was efcacious in preventing
transmission o dengue in the community.112, Level 3; 113, Level 8
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Generally, repellent products with higher concentrations o DEET (N,N-
diethyl-m-toluamide) were ound to have longer repellence times.114, Level 8
A consensus dengue guideline advised the use o mosquito netting
or repellent day and night or hospitalised dengue patients to reduce
nosocomial inection.66, Level 9
10. VACCINATION
There is no eective vaccine available or dengue.115, Level 8; 116, Level 9
11. DENGUE IN PREGNANCy
There are very ew studies addressing the management o dengue in
pregnancy. Generally the presentation and clinical course o dengue in
pregnant women is similar to that in non-pregnant individuals.117, Level 8;
118, Level 8 However, the signs and symptoms may be conused with othercomplications o pregnancy such as toxaemia, Haemolysis, Elevated Liver
Enzymes, Low Platelets (HELLP) syndrome.119, Level 9
There are some reports o an increased incidence o prematurity, in-utero
death and abruptio placenta in these women.120, Level 8;117, Level 8
The ollowing physiological changes in pregnancy may make the diagnosis
and assessment o plasma leakage challenging :
Elevation o HCT in dengue is masked by haemodilution due to increasein plasma volume especially in the 2nd and 3rd trimester. Serial HCT
measurement is crucial or disease monitoring in pregnancy.
The detection o third space uid accumulation is difcult due to the
presence o gravid uterus.
Baseline blood pressure is oten lower and pulse pressure wider
Baseline heart rate may be higher.
Management o inected pregnant patients close to delivery :
Risk o bleeding is at its highest during the period o plasma leakage
(critical phase).
I possible, avoid Lower Segment Caesarean Section (LSCS) or induction
o labour during critical phase (plasma leakage).119, Level 9
Procedures/manoeuvres that may provoke or augment labour should be
avoided during this critical phase.
Care or the mother should be provided in a multidisciplinary way in an area
o the hospital where there are trained personnel available to handle labour
and its complications.
The baby should be observed or vertical transmission o dengue ater
delivery.119, Level 9
Recommendation
All pregnant women with suspected dengue inection must be admitted.
(Grade C)
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