management malaysia

8/3/2019 Management MALAYSIA

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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


Hospital Pulau Pinang

Pulau Pinang

Dr. Sheamini Sivasampu

Principal Assistant Director

Health Technology Assessment Section


Dr. Faisal Salikin

Emergency Medicine Specialist

Hospital Kuala Lumpur

Kuala Lumpur

Ms Sin Lian The

Nursing Sister



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


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


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


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


Medical Development Division

Ministry o Health

Dr. Tai Li Ling

Senior Consultant Intensivist & Anaesthesiologist


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


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


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


Hospital Taiping,

Perak

Dr. Tan It

Consultant Anaesthetist

Sunway Medical Centre,

Selangor

Dato Dr. Lim yu Hoe



Pulau Pinang

Dr. S Visalach Purushothaman

Senior Consultant Haematologist

Hospital Ampang

Selangor

Dr. Mahathar Abdul Wahab

Emergency Medicine Specialist


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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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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REFERENCES


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REFERENCES

1 Annual report 2007. Vector Borne Diseases Section, Mnistry o Health, Malaysia

(Unpublished)

2 Dengue hemorrhagic ever: diagnosis, treatment, prevention and control. 2nd

ed. Geneva: World Health Organization;1997. Available at http://w3.who.int/csr/

resources/publications/dengue/024-33.pd.

3 Nimmannitya S. Clinical spectrum and management o dengue haemorrhagic

ever. Southeast Asian J Trop Med Pub Hlth 1987;18(3):392-7.

4 Gubler DJ. Dengue and Dengue Haemorrhagic Fever. Clinical Microbiology

Review. 1998;11(3):480-96.

5 Kalayanarooj S, Vaughn DW, Nimmannitya S et al. Early clinical and laboratory

indicators o acute dengue illness. 1:J Inect Dis. 1997 Aug;176(2):313-21.

6 Balmaseda A, Hammond SN, Perez MA et al. Short report: assessment othe World Health Organization scheme or classifcation o dengue severity in

Nicaragua.Am J Trop Med Hyg, 2005 Dec; 73(6): 1059-62

7 Hammond SN, Balmaseda A, Perez L, et al. (2005) Dierences in dengue severity

in inants, children, and adults in a 3-year hospital-based study in Nicaragua.Am

J Trop Med Hyg. 2005;73: 1063-170.

8 Guzman MG, Alvarez M, Rodrguez R, et al. Fatal dengue hemorrhagic ever in

Cuba, 1997. Int J Inect Dis 1999; 3:1305.

9 Rigau-Perez JG, Lauer MK. Dengue-related deaths in Puerto Rico, 1992-1996:

diagnosis and clinical warning signs. Clin Inect Dis. 2006 May 1;42(9):1241-6.

10 Ong A, Sandar M, Chen MI, Sin LY. Fatal dengue haemorrhagic ever in adults

during a dengue epidemic in Singapore. International Journal o Inectious

Diseases. 2007 May;11(3):263-7.

11 Wichmann O, Hongsiriwon S, Bowonwatanuwong C, et al. Risk actors and

clinical eatures associated with severe dengue inection in adults and children

during the 2001 epidemic in Chonburi, Thailand. Trop Med Int Health. 2004

Sep;9(9):1022-9.

12 Yip WCL. Dengue Haemorrhagic Fever: Current Approaches to Management.

Medical Progress October 1980.

13 Cohen SN, Halstead SB. Shock associated with dengue inection. I. Clinical and

physiologic maniestations o dengue hemorrhagic ever in Thailand, 1964. J

Pediat 1966; 68:448-56.

14 Pongpanich B. Pathogenetic mechanism in dengue hemorrhagic ever: Report o

an international collaborative study. Bull World Hlth. 1973; 48:117.

15 Ganong WF. Cardiovascular homeostasis in health and disease. In: Review o

Medical Physiology. 22nd Edition. London: McGraw-Hill; 2005:p.630-46.

16 Bhamarapravati N, Tuchinda P, Boonyapaknavik V. Pathology o Thailand

haemorrhagic ever: a study o 100 autopsy cases.Anna Trop Med Parasitol.

1967;61:500-10.


47/67

17 Sahaphong S, Riengrojpitak S, Bhamarapravati N, et.al. Electron microscopic

study o the vascular endothelial cell in dengue haemorrhagic ever. Southeast

Asian J Trop Med Public Health 1980;11:194.

18 Chuansumrit A, Tangnararatchakit K. Pathophysiology and management o

dengue hemorrhagic ever. Transusion Alternatives In Transusion Medicine.

2006;8( Suppl 1):3-11.

19 Halstead SB. Observations related to pathogenesis o dengue hemorrhagic ever.

VI. Hypotheses and discussion. Yale J Biol Med. 1970 Apr;42(5):350-62.

20 Sangkawibha N, Rojanasuphot, S, Ahandriks, et al. Risk actors in dengue shock

syndrome: a prospective epidemiologic study in Rayong, Thailand. I. The 1980

outbreak.Am. J. Epidemiol. 1984;120:653-669.

21 Guzman MG, Kouri G, Bravo J, et al. Enhanced severity o secondary dengue-2

inections: death rates in 1981 and 1997 Cuban outbreaks. Rev Panam Salud

Publica, 2002 Apr;11:223-7.

22 Badyopadhyay S, Lum LCS, Kroeger A. Classiying dengue: a review o the

difculties in using the WHO case classifcation or dengue haemorrhagic ever.

Tropical Medicine and International Health. 2006; 11(8):1238-55.

23 Kittigul L, Pitakarnjanakul P, Sujirarat D, et al . The dierences o clinical

maniestations and laboratory fndings in children and adults with dengue virus

inection.J Clin Virol. 2007 Jun;39(2):76-81.

24 Khor BS, Liu JW, Lee IK, et al. Dengue hemorrhagic ever patients withacute abdomen: clinical experience o 14 cases. Am. J Trop Med Hyg 2006

May;74(5):901-4.

25 Premaratna R, Bailey MS, Ratnasena BGN, et al. Dengue ever mimicking acute

appendicitis. Trans. Roy. Soc. Trop. Med. Hyg. 2007 July;101(7):683-5.

26 Nguyen HN. Additional drug therapy in acute non-varicose upper gastrointestinal

bleeding. Dtsch Met Wochenschr. 1999 Aug;124(33):980-1.

27 Solomon T, Dung NM, Vaughn DW, et al. Neurological maniestations o dengueinection. Lancet. 2000 Mar 25;355(9209):1053-9.

28 Soares CN, Faria LC, Peralta JM, et al. Dengue inection: neurological

maniestations and cerebrospinal uid (CSF) analysis.J Neurol Sci. 2006 Nov

1;249(1):19-24.

29 Ministry o Health, Malaysia. Borang Peraturan- Peraturan Pencegahan Dan

Pengawalan Penyakit Berjangkit (Borang Notis) 2005. Akta Pencegahan dan

Pengawalan Penyakit Berjangkit 1988. Borang Health 1 Rev.2005. Available at:

http://cdc.jknsabah.gov.my/Borang.htm

30 Prevention and Control o Inecious Disease Act 1988(Act 342). Kuala Lumpur:

Percetakan National Malaysia Berhad, 2001

31 Malavige GN, Velathanthiri VG, Wijewickrama ES, et al. Patterns o disease among

adults hospitalized with dengue inections. QJM. 2006 May;99(5):299-305.

32 Lum LC, Goh AY, Chan PW, et al. Risk actors or hemorrhage in severe dengue

inections. J. Pediatr2002 May;140:629-31.


48/67

33 Mairuhu AT, Mac Gillavry MR, Setiati TE. Is clinical outcome o dengue-virus

inections inuenced by coagulation and fbrinolysis? A critical review o the

evidence.Lancet. Jan 2003;3:33-41.

34 Krishnamurti C, Kalayanarooj S, Cutting MA, et al. Mechanisms o hemorrhage in

dengue without circulatory collapse.Am J Trop Med Hyg. 2001 Dec;65(6):840-7.

35 Chuansumrit A, Philmothares V, Tardtong P, et al. Transusion requirements in

patients with dengue hemorrhagic ever. Southeast Asian J Trop Med Public

Health. 2000;3:10-14

36 Chaudhary R, Khetan D, Sinha S, et al.Transusion support to dengue patients

in a hospital-based blood transusion service in north India. Transusion and

Apheresis Science. 2006 Dec; 35:239-44.

37 Souza LJ, Alves JG, Nogueira RM, et al. Aminotranserase changes and acute

hepatitis in patients with dengue ever: analysis o 1,585 cases. Braz J Inect Dis.

2004 Apr;8(2):156-63.

38 Nguyen TL, Nguyen TH, Tieu NT. The impact o dengue haemorrhagic ever on

liver unction. Research in Virology1997 July-August;148(4):273-7.

39 Schilling S, Ludos D, An LV, et al. Laboratory diagnosis o primary and secondary

inection.Journal o Clinical Virology. 2004;31:179-84.

40 Chanama S, Anantapreecha S, A-nuegoonpipat A., et al. Analysis o specifc

IgM response in secondary dengue virus inections: levels and positive rates in

comparison with primary inections.Journal o Clinical Virology. 2004;31(3):185-

189.

41 Wichmann O, Stark K, Shu P-Y, et al. Clinical eatures and pitalls in the laboratory

diagnosis in travelers. BMC Inectious Diseases. 2006;6(120): 1-8.

42 Barkham TM, Chung YW, Tang KF, et al. The perormance o RT-PCR compared

with a rapid serological assay or acute dengue ever in a diagnostic laboratory.

Trans R Soc Trop Med Hyg. 2006;100: 142-8.

43 Blacksell SD, Doust JA, Newton PN, et al. A systematic review and meta-

analysis o the diagnostic accuracy o rapid immunochromatographic assays or

the detection o dengue virus IgM antibodies during acute inection. Trans R Soc

Trop Med Hyg. 2006 Aug;100(8):775-84.

44 Berlioz-Arthaud A. Evaluation o reagents or the serological diagnosis o Dengue

EPINET II Workshop. Institut Pasteir de Nouvelle Caledonie. March 2002.

45 Wu SJL, Paxton H, Hanson B, et al. Comparison o two rapid diagnostic assays

or detection o immunoglobulin M antibodies to dengue virus. Clinical andDiagnostic Laboratory assays or detect

management malaysia

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