I 

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Adapted and modified from Clinical Practice Guidelines: Academy of Medicine,

Malaysia
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PREFACE
DENGUE GCP GUIDELINES – 2020
This is the second edition of Good Clinical Practice Guidelines published by Dengue
Expert Advisory Group (DEAG) for the management of dengue infection in adults,
hence forth going to be referred to as GCP dengue-guidelines-2020.

It must be emphasized that these guidelines are only meant to provide broad
recommendations for good clinical practice, based on the best evidence available at the
time of development of these recommendations - an overall management strategy in a
garden variety of dengue patient. As each patient is unique hence adherences to these
guidelines will, by no means, guarantee the best outcome in every case.

Attending healthcare provider is best suited to make appropriate decisions for his
patients, taking ground realities into consideration, regarding implementation /
modifications of these “generic” protocols. After all, he is primarily responsible,
for the management of his/her “unique patient” based on the clinical picture and
the locally available management options.

FROM CHAIRMAN DEAG

I am grateful to all people who taught me and particularly patient who allowed me to
examine them and learn from them in this process. I am also thankful to my colleagues
who patiently tolerate me. It is humbling to note that knowledge is never complete and
that a persistent effort is always needed to improve upon the existing. This new book is
part of that effort.

GUIDELINES DEVELOPMENT AND OBJECTIVE

GUIDELINES DEVELOPMENT
Primary Authors:

Prof. Faisal Masud

Assoc. Prof. Somia Iqtadar

Prof. Mohammad Ali Khan

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Review of the Guidelines

The authors have issued these GCP guidelines in 2012 and updated in 2018.
DEAG Secretariat
Services Institute of Medical Sciences,
Jail Road, Lahore
Development and Review Committee:

In addition to the primary authors, we wish to thank our contributors for participating in
the second edition of GCP guidelines 2020. We are especially grateful to

 Clinical Manifestations and Pathophysiology

Professor Faisal Masud (Professor of Medicine), Professor Muhammad Ali Khan

(Professor of Pediatrics) and Dr. Somia Iqtadar (Associate Professor of Medicine,
KEMU)

 Critical Technological Interventions

Mr. Saflain Haider (Director, PITB) and Mr. Shehzad Anwar (Program Manager,
PITB), Mr. Sheharyar Khalid (Implementation Coordinator, PITB)

 Epidemiology

Dr. Anjum Razzaq (Senior Demonstrator, Department of Entomology, IPH) and

Dr. Somia Iqtadar (Associate Professor of Medicine, KEMU)

 Dengue Fever in Pediatric Population

Professor Muhammad Ali Khan (Professor of Pediatrics), Prof. Muhammad

Haroon Hamid (Professor of Pediatrics, KEMU, Lahore), Prof. Ghulam Mustafa
(Professor of Pediatrics, NMU, Multan), Dr. Muhammad Faheem Afzal (Assoc.
Prof. of Pediatrics, KEMU, Lahore)

 Dengue Fever in Immunocompromised Patients

Dr. Faisal Sultan (CEO, SKMCH&RC), Dr. Syed Hammad Nazeer (Consultant
Infectious Diseases, SKMCH&RC) and Dr. Muhammad Ammar Shafqat
(Resident, Department of Internal Medicine, SKMCH & RC)
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 Dengue Fever in Patients on Antithrombotic Therapy & Antihypertensive

treatment in dengue Fever

Prof. Nadeem Hayat Malik (CEO, Punjab Institute of Cardiology), Dr. Muhammad
Shahzad Hafeez (Assist. Prof. of Medicine, SIMS/SHL)

 Dengue Fever in Pregnancy

Prof. Zohra Khanum (Gynecologist/Obstetrician, FJMU, Lahore)

 Dengue in Patients with Renal Disease

Prof. Hafiz Ijaz Ahmad (Chairman Nephrology & Director MED, PKLI, Lahore)

 Discharge Criteria

Professor Faisal Masud (Professor of Medicine) and Dr. Somia Iqtadar

(Associate Professor of Medicine, KEMU)

 Disease Notification

 Professor Faisal Masud (Professor of Medicine), Professor Muhammad Ali Khan

(Professor of Pediatrics) and Dr. Somia Iqtadar (Associate Professor of Medicine,
KEMU)

 Epidemiology

Dr. Anjum Razzak (Senior Demonstrator, Institute of Public Health, Lahore)

 Investigation of Post Mortem Case

Professor Faisal Masud (Professor of Medicine) and Dr. Somia Iqtadar

(Associate Professor of Medicine, KEMU)

 Laboratory Investigations

Dr. Muhammad Uthman Ahmad (Associate professor of Medicine, Shaikh Zayed

Medical Complex Lahore)

 Management of Dengue Infection

Professor Faisal Masud (Professor of Medicine), Professor Muhammad Ali Khan

(Professor of Pediatrics), Dr. Somia Iqtadar (Associate Professor of Medicine,
KEMU) and Dr. Muhammad Zaman Khan Assir (Assistant Professor of Medicine,
AIMC)
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 Prevention of Dengue Transmission In Hospitals

Professor Faisal Masud (Professor of Medicine) and Dr. Somia Iqtadar

(Associate Professor of Medicine, KEMU)

 Surgery in Dengue

Prof. Mahmood Ayyaz (Principal, SIMS, Lahore)

 Vaccination

Dr. Somia Iqtadar (Associate Professor of Medicine, KEMU)

 Virology

Professor Faisal Masud (Professor of Medicine) and Dr. Somia Iqtadar

(Associate Professor of Medicine, KEMU)

These guidelines are geared to provide:

1. In-depth description of the clinical course of dengue virus related illnesses to

understand the dynamic and systemic nature of disease which has a significant bearing
upon the clinical management of the patient.

2. An understanding of the basic pathophysiology of severe dengue (DHF i.e. plasma

leakage and hypovolemia/shock) in the clinical context - and provide generic guidelines
for the recognition of these changes and subsequent clinical management.

3. A brief discussion on WHO Classification (1997-2011) and its limitations.

4. A list of differential diagnoses that can be confused with dengue fever or vice versa;
during different stages of dengue and some generic advice about it.

5. Appropriate documentation and forms for focused monitoring and management of the
dengue disease taking into account the dynamic changes during the course of illness.

6. Simple practical action plan to diagnose, monitor and manage the plasma leak – with
particular emphasis on its early signs and symptoms and on its relationship with
hematocrit (HCT) and hemodynamic status of the patients.

7. Easy to follow Algorithms for Dengue Shock Syndrome in dengue hemorrhagic fever
(compensated and decompensated shock).

8. A guideline for early detection of occult bleed – importance of recognizing it and

guide for replacing blood or its constituents.
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9. A guideline about recognition the signs of recovery and guide about when to safely
discharge a patient.

Reference has also been made to other guidelines

 WHO Dengue Hemorrhagic Fever: Diagnosis, Treatment, Prevention and
Control,

 WHO Guidelines, Geneva, 1997

 Guidelines for DHF Case Management, Bangkok, Thailand 2002;

 Guidelines on Clinical Management Of Dengue Fever / Dengue

Hemorrhagic Fever 2005 Sri Lanka; WHO Regional Publication SEARO, 1999;

 Guidelines for Treatment of Dengue Fever/Dengue Hemorrhagic Fever in

Small Hospitals, WHO Regional Office for SE Asia, New Delhi, 1999.

 Clinical Practice Guidelines: Academy of Medicine, Malaysia was used as

general framework for these guidelines and was referred to extensively.

Our literature search yielded only a very few studies that were carried out on adult
dengue patients and these could not provide us with sufficient breadth of information to
draw up evidence-based recommendations. We have had to therefore, draw upon the
studies carried out in the pediatric population. Extrapolating the results of these studies
to the adult population carries the obvious risk of reaching biased conclusions and the
committee is cognizant of this fact.

The clinical questions were divided into major subgroups and members of the
development group were assigned individual topics within these subgroups. The group
members met a total of 14 times throughout the development of the guidelines.

OBJECTIVES
GENERAL OBJECTIVES
To provide evidence-based guidance in the management of patients with dengue
infection.

SPECIFIC OBJECTIVES
• To improve recognition and diagnosis of dengue fever and provide appropriate advice
for the care to these patients
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• To identify severe dengue infection where it becomes mandatory to provide focused

close monitoring and prompt appropriate management

• To provide guidance on appropriate and timely fluid management and the use of blood
and blood products

• To provide guidelines for early and accurate notification of dengue cases for prompt
public health intervention

CLINICAL QUESTIONS FOR SELF EVALUATION

Please refer to Appendix 19

TARGET POPULATION
Patients with dengue fever, dengue hemorrhagic fever or dengue shock syndrome and
other forms of severe dengue fever and dengue fever with pre existing co morbidities.
Adults are defined, in our GCP guideline, as patients aged 15 or more.

TARGET GROUP/USER
These guidelines are applicable to primary care family physicians, house officers,
PGRs, senior registrars, public health personnel, nurses, medical officers & consultant
physicians at DHQs, and critical care providers involved in treating patients with dengue
fever.

HEALTHCARE SETTINGS
Teaching hospitals, DHQs and private health facilities - Both outpatient and inpatient
settings.
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ACKNOWLEDGEMENT
We have all benefited from clinical wisdom and commitment of our associate authors.
Many students and physicians also have contributed useful suggestion to this and
previous edition, and we are grateful. We continue to welcome comments and
recommendations for future edition in writing or via electronic mail. The editor’ postal
and e-mail address is given below.

DEAG Secretariat

Services Institute of Medical Sciences,

Jail Road, Lahore
Contact # +92 (042) 99205404
Website: deagpunjab.com
Email: [email protected]

Secretarial Staff
The authors are indebted to the following for providing invaluable secretarial assistance
in preparation of this manuscript

 Mr. Muhammad Adil Bin Ali

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TABLE OF CONTENTS NEW

PREFACE pII

GUIDELINES DEVELOPMENT AND OBJECTIVE pII

OBJECTIVES pVI

ACKNOWLEDGEMENT pVIII

TABLE OF CONTENT pIX

LIST OF APPENDICES pXII

1. EPIDEMIOLOGY p1

2. VIROLOGY p8

3. CLINICAL MANIFESTATIONS AND PATHOPHYSIOLOGY p10

3.1 Spectrum of Dengue Infection p10

3.2 Clinical Course of Dengue Infection p10

I .Febrile Phase p10

II. Critical Phase p11

III. Convalescent Phase p12

3.3 Pathophysiology of Plasma Leak p14

3.4 Tourniquet Test p20

3.5 WHO Dengue Classification p22

3.5.1 Limitations of WHO Classification p22

3.5.2 Suggested WHO Classification 2009 p23

3.6 Other Important Manifestations p25

3.7 Diagnostic Challenges p26

4. DISEASE NOTIFICATION p27

4.1 Epidemiological Classification for Disease Reporting p27

5. LABORATORY INVESTIGATIONS p29

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5.1 Disease Monitoring Laboratory Tests p29

5.2 Diagnostic Tests p31

5.2.1 Dengue Serology Tests p31

5.2.2 Virus Isolation p33

5.2.3 Polymerase Chain Reaction (PCR) p33

5.2.4 Non-structural Protein-1 (NS1 Antigen) p34

6. INVESTIGATION OF POST MORTEM CASE p35

7. MANAGEMENT OF DENGUE INFECTION p36

7.1 Introduction p36

7.2 Triaging the patient at Emergency and Outpatient Department p39

7.3 Criteria for Hospital Referral / Admission p40

7.3.1 Referral from Primary Care Providers to Hospital p40

7.3.2 Referral from Basic Health Units / Hospitals without

Specialist to the Hospitals with Requisite Expertise p41

7.4 Disease Monitoring p41

7.4.1 Principles of Disease Monitoring p41

7.4.2 Outpatient Disease Monitoring p41

7.4.3 Inpatient Disease Monitoring p42

7.5 Fluid Management p44

7.5.1 Dengue with Warning Signs p44

7.5.2 Patients in Critical Phase without Shock p45

7.5.3 Dengue Shock Syndrome (DSS) p46

7.5.4 Principles for Fluid Resuscitation p46

7.5.5 Calculation of Fluid Quota for Adults p49

FLUID MANAGEMENT IN DENGUE SHOCK Syndrome p50

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7.6 Management of Bleeding/Hemostasis p52

7.6.1 Hemostatic Abnormalities in Dengue Infection p52

7.6.2 How to Recognize Significant Occult Bleeding? P52

7.6.3 Management of Bleeding in Dengue p53

7.6.4 Management of Upper Gastrointestinal

Bleeding (UGIT) p54

7.6.5 MANAGEMENT OF CARDIAC COMPLICATIONS

IN DENGUE INFECTION p54

7.6.6 The Role of Prophylactic Transfusions in Dengue p56

7.6.7 The Role of Adjunctive Therapy in Dengue p56

7.7 MANAGEMENT IN HIGH DEPENDENCY UNIT (HDU) p56

7.7.1 Indications for Respiratory Support (Non-invasive

and Invasive Ventilation) p57

7.7.2 Indications for Hemodynamic Support p58

7.7.3 Safety & Risk – A Guideline for Invasive Procedures p58

8. DISCHARGE CRITERIA p62

9. PREVENTION OF DENGUE TRANSMISSION IN HOSPITALS p63

10. VACCINATION p64

11. DENGUE FEVER IN PAEDIATRIC POPULATION p65

11.1.1 Calculation of Ideal Body Weight p65

11.1.2 Choice of Fluid p66

11.1.3 Rate of Administration of IV Fluids in Critical Phase -

– without Shock p66

11.1.4 Intravenous fluid replacement – during shock p67

11.2 Special Considerations for Infants p68

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12. DENGUE FEVER IN PREGNANCY p70

13. DENGUE FEVER IN IMMUNOCOMPROMISED PATIENTS p71

14. ANTIHYPERTENSIVE TREATMENT IN DENGUE FEVER p74

15. DENGUE FEVER IN PATIENTS ON ANTITHROMBOTIC THERPY p75

16. DENGUE IN PATIENTS WITH RENAL DISEASE p77

17. SURGERY IN DENGUE FEVER p78

18. CRITICAL TECHNOLOGICAL INTERVENTIONS IN

DENGUE CONTROL PROGRAM p79
REFERENCES p86

APPENDICES
APPENDIX 1a – Dengue Fever Proforma APPENDIX 11 – Clinical Case Classification
After Admission
APPENDIX 1b – Radiology Request Form
APPENDIX 2: 2a, 2b – Dengue Monitoring APPENDIX 12 – Home Care Advice
Charts
APPENDIX 3a – OPD “Form O” APPENDIX 13 –Leaflet & Patient
APPENDIX 3b – Inpatients “Form I” Information Brochure in Urdu
APPENDIX 4 a – Reporting “Form R” APPENDIX 14 - List of Abbreviations
(Suspected/Probable case)
APPENDIX 4 b – Reporting Form
(Confirmed Case)
APPENDIX 4 c – SOP for Reporting
Dengue Patients
APPENDIX 5 – Diagnostic criteria – Non
APPENDIX 15 – Acknowledgements
Epidemic Setting & Epidemic Setting
APPENDIX 6a – Referral Form Primary
APPENDIX 16 – Disclosure Statement
Care Providers to Hospital
APPENDIX 6b – Discharge Form
APPENDIX 7 – Dengue Temporary APPENDIX 17 – Source of Funding
Regulations (by the Govt. of the Punjab)
APPENDIX 8a –Design for Dengue counter APPENDIX 18 – Outcome & management
APPENDIX 8b –Requirement for indicators
Establishment of HDU at Teaching
Hospital/DHQ
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APPENDIX 9 – WHO – Classification of DF APPENDIX 19 Self-Evaluation – Review

& DHF (1997)
APPENDIX 10 – Methods of Sample
Collection
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1. EPIDEMIOLOGY
Dengue in history dates back to 3rd century when it was reported in Chinese literature
by the Jin Dynasty. Multiple epidemics occurred in the 18th century simultaneously in
Asia, Africa and North America. The first confirmed case of dengue was reported in
1789 by Benjamin Rush who called it the break-bone fever.1

Dengue has emerged as one of the most important mosquito-borne viral diseases of the
humans. If not managed timely and properly, it can carry significant morbidity and
mortality. It is predominantly a disease of urban and semi urban areas in the tropics and
sub-tropics. Due to changing weather pattern associated with the global warming,
mosquito vector is likely to extend its range from the tropical regions, deeper into the
subtropical zones.

The global spread of the disease owes credit to mass transportation and warfare. Many
give major credit to the Second World War, though by 1959 only 2 countries were
known to be affected by dengue (WHO). Over the next 50 years the number of affected
countries rose to 60 and by another 10 years, to as many as 110 countries.
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World Health Organization estimates (2013) that around 390 million dengue infections
occur each year (95% credible interval 284–528 million), out of which 96 million (67–136
million) are clinical (with any severity of disease). As far as the global prevalence of
dengue is concerned, approximately 3.9 billion people residing in 128 countries are at
risk of dengue.2

Dengue has emerged in Pakistan over the last decade and has unfolded into an
epidemic as reported in different studies. It has become an important public health
problem and has attracted public and political opinion alike making it the most heavily
3.4
budgeted disease in the province of Punjab . In 2011, 21685 cases with 350 deaths
associated with the menace pushed the redundant public health into the lime light thus
attracting international and national expertise and development of a novel prevention
and control program.5

The first confirmed outbreak of DHF in Karachi Pakistan occurred in 1994 with 145
cases and one fatality was reported.4 The second outbreak was reported from southern
Baluchistan where 57 cases were detected. In 2003, 1000 cases with 7 deaths were
reported from Haripur district of KPK. During 2005-2006, more than 3,640 patients were
reported with 40 deaths, of which 37 were from the province of Sindh.6

Punjab has seen the disease for a decade now and will be passing on to
hyperendemicity by another 15 to 20 years. A major shift over this period will be that the
disease (especially the severe forms like DHF) will be more rampant in the younger age
groups rather than the middle age group.
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Total dengue cases reported from Punjab for last five years is shown in the table below;

     
Year Confirmed Probable Suspected

2013 2661 1577 9903

2014 1439 1048 2159

2015 4348 1738 3748

2016 5059 981 6267

2017 1034 509 7971

Total 14541 5853 30048

In Punjab dengue presented in all its forms including, DF, DHF and DSS. The diagnosis
over the period of last 5 years is summarized in the chart below:
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Week wise reported cases of dengue in Punjab from year 2013 to 2017 are shown in
Figure 1.

Figure 1. Week wise distribution of dengue cases for the years 2013 to 2017.

The data shows that the disease in Punjab peaks between the 31 to 48 weeks (mid-July
to mid-November) with minor drifts possibly dependent on factors like rainfall and drop
in temperature. Another small peak visible in the figure 2 below is the rise in number of
cases in the early summer season (April to mid-May).

Figure 2. Week wise distribution of total entries on PITB Dashboard from week 1 to 30 for the
years 2013 to 2017.
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Figure 3 shows the number of confirmed cases reported for the years 2013 to 2017.
Here the peaks are more closely approximated depicting lesser variation.

Figure 3. Week wise distribution of confirmed dengue cases for the years 2013 to 2017.

The overall case fatality rate (CFR) of Dengue in Punjab for the last five years is 1.86/
1000 confirmed cases. The year-wise CFR is plotted in figure 4.

Figure 4. Case Fatality Rate/ 1000 confirmed dengue cases in Punjab for the years 2013 to 2017
(red line shows the mean value)
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As is visible from the figure 5, the females are just 31.5% of the total entries on the
dashboard.

Figure 5. Age wise and sex wise distribution of dengue cases for Punjab during the period 2013
to 2017.

The pattern of age wise distribution of both males and females appears comparable as
is visible in Figure 6. Figure 7 shows that most of the entries are for the age group 20 to
30 years (32.0%) followed by 10 to 20 years (24.8%) and then 30 to 40 years (18.2%).
Figure 6 also shows that the age wise distribution has not modified much over the five
years period. The expected rise in the pediatric age group appears to be static at least
for the time being. Similar pattern is visible for confirmed, probable and suspected
cases.

Figure 7 shows district wise distribution of confirmed cases only. One can see that most
of the confirmed cases were reported from Rawalpindi district (24.7%) followed by
7 | P a g e  
 

Lahore district (19.7%). Islamabad has a prominent number of confirmed cases

(10.4%).

Figure 6. Age wise distribution of dengue cases for Punjab during the period 2013 to 2017.

Figure 7. District wise distribution of Confirmed dengue cases for Punjab during the period
2013 to 2017.
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2. VIROLOGY
Dengue infection is caused by dengue virus which is a mosquito-borne flavivirus. It is
transmitted by Aedes aegypti and Aedes albopictus.

Aedes Aegypti Aedes Albopictus

There are four distinct serotypes, DEN-1, 2, 3 and 4. Each episode of infection induces
a life-long protective immunity to the homologous serotype but confers only partial and
transient protection against subsequent infection by the other three serotypes.

Secondary infection (by another serotype) is a major risk factor for DHF, mainly due to
antibody induced enhancement (see section 3.3).
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Epidemiologic studies have identified young age, female sex, high body-mass index,
virus strain or virulence and genetics of the human host e.g. major histocompatibility
complex class I related sequence B and phospholipase C epsilon 1 genes as risk
factors for severe dengue. 8, 9 ,10

All four serotypes may be circulating in the population at any one time but from the
experience in the south-east Asia it appears that the predominant circulating dengue
virus will show a sinusoidal pattern – with a peak to peak interval of 6-7 years. It is likely
that this interval allows a buildup of immuno-naïve population of children.

 
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3. CLINICAL MANIFESTATIONS AND

PATHOPHYSIOLOGY
3.1 SPECTRUM OF DENGUE INFECTION
The incubation period (time between the viral invasion and onset of clinical disease) for
dengue infection is generally between 4-7 days (range 3-14).10 The spectrum of clinical
manifestations varies from totally asymptomatic disease to the severe disease, with or
without plasma leakage and organ impairment.

Clinically significant dengue infection is a systemic disorder where clinical and

hematological profiles may change by the hour or even minutes, particularly during the
critical phase while the plasma leakage is going on (refer to section 3.3).
Understanding the dynamic nature of this disorder is of paramount importance.

Realizing the systemic and dynamic nature of the pathophysiological changes during
each phase of the dengue disease, an attempt will be made to provide a rational
approach to the management of the disease.

3.2 CLINICAL COURSE OF DENGUE INFECTION

After the incubation period, the illness begins abruptly. Subsequent clinical course of
dengue disease can be highly variable but can be, broadly, divided in to three phases:
febrile, critical and convalescent phase (refer Figure 6). 11, 12

I. Febrile Phase

Typically, begins with sudden onset of high-grade fever. This acute febrile phase
generally lasts for 2-7 days and is often accompanied by facial flushing, skin erythema,
generalized body ache, myalgia, arthralgia and headache.11, 12

There is often associated anorexia, nausea and vomiting. Some patients may have sore
throat with congested pharynx and conjunctivae. These initial clinical features are
common to both the patients who have simple DF and those who would go on to
develop DHF subsequently.13

On physical examination: Mild hemorrhagic manifestations like mucosal bleeding,

petechial hemorrhages and positive tourniquet test are equally common – both in DF
11 | P a g e  
 

and DHF.13, 14 Vaginal bleeding is also seen frequently in the young adult females.
Uncommonly, however, massive vaginal or gastrointestinal bleeding may occur during
this phase.14, 15 Hepatomegaly is common but tender hepatomegaly is highly suggestive
of DHF.13

Investigations: The earliest hematological abnormality is a progressive decrease in total

white cell count. A precipitous drop in platelet count could be a heralding feature of
impending critical phase. This nonspecific viral response should alert the physician
about the possibility of dengue, particularly during the dengue epidemic. NS1 antigen
and PCR is generally positive during this early stage.

II. Critical Phase

Towards the end of febrile phase - around the time of defervescence (usually between
3rd to 5th day of illness but may up to 7th day) a few patients enter the phase of
increased capillary permeability. Unlike in other routine viral infections, where patient’s
condition tends to improves with defervescence, in DHF at this point, depending upon
the capillary leak, patient can go in two different clinical directions. Patients without
significant plasma leak would gradually convalesce but those who would develop
major plasma leak may actually deteriorate in the face of critical loss of volume.11,
12, 15, 16

The critical phase would typically last for about 24-48 hours. (Figure 6) During this
stage varying degree of circulatory disturbances (Table 1) can develop. In less severe
cases, these changes are minimal and transient. Many of these patients recover with
routine oral fluid and electrolytes or even with non-specific management at home. In
more severe forms of plasma leakage, significant volume depletion occurs. A
compensatory response in the form of increased sympathetic drive kicks in. Now the
patient becomes restless, with cold clammy skin, rapid thready pulse and prolonged
capillary refill time. As the diastolic blood pressure rises (increased sympathetic tone) in
the face of unchanged systolic pressure (due to vasoconstriction) the pulse pressure
narrows. Abdominal pain, persistent vomiting, restlessness, altered conscious level,
clinical fluid accumulation, mucosal bleed or tender enlarged liver are the clinical
warning signs of severe dengue with increased possibility of rapid progression to
shock.17, 18, 19 In this stage The patient can rapidly progress to profound and irreversible
shock, if fluid resuscitation is not instituted promptly and appropriately.

It is important to note that hemoconcentration (a rising trend of hematocrit from the

baseline value) and thrombocytopenia are usually detectable even before the
subsidence of fever and the onset of shock. It gives credence to the notion that low-
grade plasma leak has started before hemodynamic compromise has become clinically
apparent. Refer to 3.5.1 for further details. The HCT level correlates well with the
12 | P a g e  
 

amount of plasma volume loss and disease severity. Hematocrit may not, however, truly
represent the volume loss in case of frank hemorrhage, early and excessive fluid
replacement or when HCT determination is wrongly timed. Usually observed
biochemical abnormalities include leucopenia with relative lymphocytosis, prolonged
PT/APTT, elevated transaminases (typically AST > 3 x ALT), hypoproteinemia and
hypoalbuminemia.11, 12, 13

The HCT level correlates well with the amount of plasma volume loss and the
disease severity.
HCT may not, however, truly represent the volume loss in case of

 Significant obvious or concealed hemorrhage

 When HCT determination is wrongly timed

III. Convalescent Phase

Plasma leak stops within 24-48 hours from the time of onset, and is followed by
reabsorption of extravascular fluid. Patient’s general wellbeing improves, appetite
returns, gastrointestinal symptoms abate, hemodynamic status stabilizes and diuresis
ensues. Some patients may have a classical rash of “isles of white in the sea of red”.9
Some patients may experience generalized pruritus. Bradycardia and
electrocardiographic changes are not uncommon during this stage. It is important to
note that during this phase, HCT level may drop further due to resorption associated
hemodilution. The recovery of platelet count is typically preceded by recovery of white
cell count (WCC).

Signs of recovery – convalescent phase

 Improved appetite, generalized feeling of wellbeing, diuresis

 Development of rash - “White isles in the sea of red”

 Recovering platelet count followed by reversal of leucopenia

13 | P a g e  
 

Dengue related rash during

convalescence stage.

This maculo-papular rash is flat,

erythematous and blanch able
(disappears upon pressure): typically
described as isles of white in a sea of
red.

The rash in dengue is usually

centripetal.

This means that the rash starts on the

limbs before "moving" or spreading to the
trunk!

(Differential diagnosis would include

coxsackie virus infection, secondary
syphilis, and rocky mountain spotted
fever). 19

Figure 6: Clinical Course of DHF21

Note: Onset of defervescence usually occurs between day 3 to day 5 of illness

14 | P a g e  
 

 Critical phase is so named because during this stage, clinical deterioration

(due to the plasma leakage) can occur.

 It is therefore crucial to recognize the onset of this CRITICAL PHASE.

 Onset of critical phase often coincides with defervescence.

 Warning signs often precede the clinical evidence of plasma leak.

 Warning Signs (risk of plasma leak high):

Abdominal pain Persistent vomiting

Restlessness Altered conscious level

Enlarged tender hepatomegaly Extensive mucosal bleeding

 Evidence of plasma leakage includes: raised HCT (early marker), hemodynamic

instability, and fluid accumulation in extravascular space (rather late marker)
or hypoproteinemia.

 Non- Dengue cases: All those probable cases whose dengue confirmatory
tests (NS1/IgM) turn out to be negative and who have an alternative lab
confirmed diagnosis will be labelled as non-dengue. Moreover, all cases must
pass through series of entries as suspected probable and confirmed and the
status must be changed immediately after receiving of appropriate tests. No case
should be directly registered as a confirmed or non-dengue case.

3.3 PATHOPHYSIOLOGY OF PLASMA LEAK

The initial, febrile, phase of the Dengue disease mimics the picture of common acute
viral illnesses. Only towards the end of febrile illness, in a small subset of the patients,
features of increased capillary permeability and plasma leak are witnessed. Although it
might well be speculated that increased plasma permeability is present in all the case of
dengue disease – plasma leak remains small and clinically compensated in most of the
patients. Only in a small percentage of patients does this condition cross the critical
threshold of compensatory mechanisms to become clinically significant.
15 | P a g e  
 

This acute increase in vascular permeability beyond the critical limit of compensatory
responses - is the primary pathophysiological event that would differentiate DHF and
DSS from uncomplicated DF. This leak is responsible for the loss of plasma into the
extravascular compartment, giving rise to the hemoconcentration, hypovolemic state
and in extreme condition, to shock.11, 12, 22 In common with classical volume depleted
state, it leads to reflex tachycardia and generalized vasoconstriction as a result of
increased sympathetic activity.23, 24

This compensated stage of shock is characterized by the responses initiated by the

patient to overcome the stress of volume depletion. Physiological mechanisms - neural,
hormonal and bio-chemical – kick in to compensate for the stress of hypovolemia. The
baroreceptors in the arteries detect a drop in BP, and cause the release of adrenaline
and noradrenaline. These catecholamines cause vasoconstriction and tachycardia –
body’s attempt to increase the blood pressure. Vasoconstriction results in tissue
hypoxemia and anaerobic glycolysis which in turn gives rise to acidosis. Acidosis
mediated respiratory center stimulation causes hyperventilation (tachypnea). By
hyperventilating and washing out CO2, the body is, indirectly, trying to correct the
acidosis. Vasoconstriction can affect the kidneys, stimulating renin-angiotensin-
aldosterone axis to cause further vasoconstriction and conservation of fluid via
increased renal reabsorption. Vasoconstriction which started in the splanchnic
circulation can spread to kidneys, gastrointestinal tract, and other organs to divert blood
preferentially to the heart, lungs and brain. This reduction in renal circulation (GFR)
manifests itself in the form of reduced urine production.25

Severity of shock in the face of plasma leak - due to increased vascular permeability -
would depend upon:

 State of hydration at the time of the onset of the leak

 Cardiac reserve
 Severity of the vasculopathy (rate of plasma leak)
 Any existing co morbidity

Pathophysiological events that occur during DSS are exactly like those of “classical
hypovolemic shock” due to blood loss (or volume loss during gastroenteritis). The only
difference is that in DHF the volume lost to the serosal cavities is rich in proteins and is
available for reabsorption (through lymphatics) subsequently.
16 | P a g e  
 

Plasma Leakage Indicators:

 Right lateral decubitus CXR

 USG Chest & Abdomen

 Serum Albumin- <3.5 g%

 Serum Cholesterol- <100 mg%.

Clinical manifestations of vasoconstriction in various systems are as follows:

a. Skin–is cold, clammy skin, with pallor and delayed capillary refill time

b. Cardiovascular system–shows raised diastolic blood pressure and a narrowing

of pulse pressure – an effect of increased sympathetic outflow.

c. Renal system–As a result of reduced GFR, urinary output drops.

d. Gastrointestinal system–nausea, vomiting and abdominal pain

e. Central nervous system – As a function of reduced cerebral perfusion there

may be lethargy, restlessness, apprehension, impaired consciousness and
combative behavior.

f. Respiratory system – Tachypnea (respiratory rate >20/min in adults) – a feature

of shock

In patients where consciousness is not obtunded, intense thirst can also be a

significant symptom. As mentioned before, inadequate perfusion of the tissues, as a
17 | P a g e  
 

result of intense vasoconstriction and viscous hemoconcentrated blood, leads to

increased anaerobic glycolysis and lactic acidosis. If the loss of volume is not
corrected promptly, the patient will progress into the state of decompensated shock.
Once this stage of decompensation is reached, patient can rapidly progress to the stage
of refractory shock. In this state, any amount of volume replacement would not restore
the normal tissue perfusion or cardiac output and pressures, even if vasopressor agents
are used.

Primary reason for the irreversibility of shock at this point is that in the absence of O2, to
act as an electron receptor in the mitochondrial matrix, most of the cellular ATP gets
degraded into adenosine. Adenosine is a potent vasodilator. It readily diffuses out of
cellular membranes into extracellular fluid, further increasing the capillary vasodilation.
Because the cells have a very limited capacity to replenish adenosine (at the rate of
about 2% of the cell's total need per hour), restoring oxygen, at this point, is futile
because there is no adenosine to be phosphorylated into ATP.26

As mentioned before, lactic acidosis which often accompanies shock, has suppressant
effect on myocardium which in turn further worsens the hypotension.24 Intense
vasoconstriction and subsequent ischemic necrosis of the tissues can result in massive
bleeding, disseminated intravascular coagulopathy (DIC) and multi-organ failure - a
common late complications of prolonged shock.

  Key feature is PLASMA LEAK

 Rising HCT 20% or More OR even less but towards 20% if on IV fluids or on
excess oral fluids,

 Se Cholesterol <100mg/dl (or drop of 20mg/dl)

 Se Albumin <3.5 g/dl (or drop of 0.5g/dl)

Capillary Refill Time

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The following table is the summary of the continuum of various pathophysiological

changes in a patient who progresses from normal circulatory state to hypovolemic
shock.

Decompensated /
Normal Circulation Compensated Shock
Hypotensive Shock
Clear consciousness - shock Change of mental status
Clear consciousness can be missed if you do not - restless, apprehensive,
touch the patient combative or lethargic
Mottled skin, very
Brisk capillary refill time Prolonged capillary refill time
prolonged capillary refill
(<2 sec) (>2 sec)
time
Warm and pink Cold, Clammy
Cool extremities
extremities extremities
Good volume peripheral Weak & thready peripheral Feeble or absent
pulses pulses peripheral pulses
Normal heart rate for Severe tachycardia
Tachycardia
age bradycardia in late shock
Normal systolic pressure with
Normal blood pressure Hypotension / un-
raised diastolic pressure and
for age recordable BP
postural hypotension
Narrowing of pulse
pressure ≤20mmHg
Normal pulse pressure Narrowing pulse pressure
OR
for age (≤30 mmHg)
Pulse pressure not
recordable
Metabolic acidosis;
Normal respiratory rate
Tachypnea hyperpnoea Kussmaul’s
for age
breathing
Normal urine output Reduced urine output Oliguria or anuria

Table 1: A continuum of pathophysiological changes from normal circulation to

compensated and decompensated/ hypotensive shock

The molecular mechanism responsible for the increased vascular permeability seen
during DHF/DSS is still not well understood. This is partly due to the lack of animal
models that would accurately replicate the event of plasma leak as seen during DSS.
There is no evidence that the virus infects endothelial cells, and only minor nonspecific
changes have been detected in histopathological studies of the microvasculature27,
although some perivascular edema and loss of integrity of endothelial junctions with
endothelial dysfunction are found.28, 29
19 | P a g e  
 

It appears that immune hyper-drive results in massive over production of cytokines

(Cytokine Storm), due to aberrant activation of T-lymphocytes and disturbances of
homeostatic system involving Tregs. High concentrations of mediators of inflammation
including C3a, C5a, tumor necrosis factor-, interleukin 2, 6 and 10, interferon- and
histamine have also been noted.12, 30

Picture modified from ‐ Dengue: Review article: Simmons CP,  Jeremy J. Farrar JJ, Vinh Chau NV, 
Wills B, N Engl J Med: April, 2012: 366:pp‐1427 

There is still paucity of data to suggest a specific pathway that would link the
immunopathological event on one hand with event of increased vascular permeability
and disturbed thrombo-regulation on the other. However, there is some preliminary data
to suggest a transient dysfunction of the endothelial glycocalyx layer. 31, 32 This layer
functions as a molecular sieve, selectively restricting molecules from seeping out of the
vasculature, according to their size, charge, and shape.27 A crucial alteration in the
filtration characteristics of the glycocalyx occurs during dengue related plasma leak. It
would cause proteins - up to and including the size of albumin - to preferentially leak out
20 | P a g e  
 

of the vascular tree. This may explain hypoalbuminemia and proteinuria - observed
during dengue infection.33 Both the virus itself and dengue NS1 are known to adhere to
heparin sulfate, a key structural element of the glycocalyx, and increased urinary
heparan sulfate excretion has been detected in children with severe dengue infection.34,
35

It seems that increased capillary permeability is a non-specific event that happens in all
forms and phases of the Dengue Disease. It is just the extent and rapidity of the fluid
loss that defines the clinically crucial “critical phase”. Patients with minimal capillary leak
which occurs slowly, fall towards the benign end of the spectrum while those with rapid
& severe leak, which overwhelms the compensatory responses, constitute the “critical
end” comprising of DSS.

A second infection with a heterotypic dengue virus may impart increased risk of
developing DHF. Antibody-dependent enhancement of viral replication is believed to be
responsible for this phenomenon.36, 37, 38 Dengue virus is released from the host cells in
two forms. The immature form, unlike mature particles, is incapable of entering new
host cells. Sub-neutralizing concentration of the cross-reacting antibody from the
previous infection may opsonize these immature virus particles and allow the entry and
replication of immature virion in the macrophage or mononuclear cells.39 This is
mediated through Fc epitope recognizing domains on the macrophages. The T-cell
activation is also enhanced. Profound T-cell activation with cell death during acute
dengue infection may suppress or delay viral elimination, leading to the higher viral
loads and enhanced immunopathology found in patients with DHF.12, 30

 Dengue Disease exhibits a continuous spectrum of illness - from benign DF to

DSS - with escalating vascular permeability from minimum to severe.

 Increased vascular permeability - beyond the capacity of compensatory

mechanisms - leads to plasma leakage and results in hypovolemia & shock.

 Significant amount of volume is lost in the third space and it constitutes the
primary pathophysiological abnormality in DHF/ DSS.

3.4 TOURNIQUET TEST

In mild DHF, a positive tourniquet test may be the only indicator of hemorrhagic
tendency. The sensitivity of the test varies widely from low to very low. Depending upon
the phase of illness and how frequently the test was repeated it shows positivity in 0%
to 57%, of cases. A positive tourniquet test is quite non-specific. About 5-21% of
21 | P a g e  
 

patients with dengue like illness returned a positive tourniquet test but subsequently
turned out to have negative dengue serology.41

A recent study, however, asserts that presence of fever, leucopenia, thrombocytopenia,

hemoconcentration and positive tourniquet test had 95.3% positive predictive value for
dengue.42

How to perform tourniquet test

 Winthrop technique, involves raising the blood pressure to midway between

systolic and diastolic pressure for five minutes. Then release pressure and wait
about one minute or until the circulation comes back to normal. Read the result.
The positive test is ≥ 10 petechial/Inch42.

 The Daisy technique for tourniquet test is easier and can be used in children >
five years old and adults. In this technique, pressure is applied to 80 mmHg for
five minutes and then released and the result read as in the Winthrobe
technique42.

Recommendation

Although a positive tourniquet test alone has a poor predictive value but in the presence
of other supportive evidence may be helpful in differentiating dengue from other febrile
illnesses.
22 | P a g e  
 

3.5 WHO DENGUE CLASSIFICATION Based on current WHO dengue

classification scheme (refer Appendix 9), the key differentiating feature between DF
and DHF is the presence of plasma leakage in DHF. However, in the early febrile phase
of dengue infection, the symptoms do overlap and it is often impossible to differentiate
DF and DHF.

DHF is further sub-classified as mild (grades I and II) or severe (grades III and IV), the
presence of shock, due to volume leakage, being the main difference. Grades III and IV
are classified as Dengue Shock Syndrome (refer Appendix 9).

DF/DHF  Grade  Signs and Symptoms Laboratory 

DF    Fever with two of the   Leucopenia (WBC ≤5000 

following:   cells/mm). 
 Headache    Thrombocytopenia (Platelet 
 Retro‐orbital pain.  
count <150000 cells/mm). 
 Myalgia. 
 Arthralgia/bone pain.   Rising haematocrit (5%‐10%). 
 Rash.  
 No evidence of plasma loss. 
 Haemorrhagic 
Manifestations. 
 No evidence of 
plasma leakage. 
DHF  I  Fever and haemorrhagic  Thrombocytopenia 
manifestation (Positive 
3
tourniquet test) and evidence  <100,000 cells/mm ; HCT rise ≥ 20% 
of plasma leakage 

DHF  II  As in Grade I plus  Thrombocytopenia 

spontaneous bleeding 
<100,000 cells/mm3; HCT rise ≥ 20% 

DHF  III  As in Grade I or II plus  Thrombocytopenia 

circulatory failure  
<100,000 cells/mm3; HCT rise ≥ 20% 
(Weak pulse, narrow pulse 
pressure (≤20 mmHg), 
hypotension, restlessness). 

DHF  IV  As in Grade III plus profound  Thrombocytopenia 

shock with undetectable BP 
and pulse  <100,000 cells/mm3; HCT rise ≥ 20% 
23 | P a g e  
 

3.5.1 Limitations of WHO classification 41

With ever increasing spread of Dengue fever WHO recommendations were adopted
widely. But it has been observed that the existing WHO classification scheme has
several limitations and shortcomings. For example:

1. Dengue with shock without fulfilling all the 4 criteria for DHF (Fever,
Thrombocytopenia, Hemorrhage, Plasma Leak). There have been many case reports of
patients with severe dengue with shock who do not fulfill all the 4 criteria for DHF.
These patients would automatically get classified as dengue fever (DF) if the WHO
criteria were to be applied strictly.

2. Arguably; one of the major causes of morbidity and mortality in DHF is severe end-
organ impairment - hepatic, respiratory, cardiac and brain dysfunction – which is not
considered as a criterion for labeling it as DHF, based on the existing classification.

3. Plasma leakage in DHF: The requirement of 20% increase in HCT as one of the
evidence of plasma leakage is difficult to fulfill due to several issues:

a. Baseline HCT is often not available in most of the patients. Diagnosis of a

plasma leak can, therefore, be only be made retrospectively, using this
criterion.

b. Dilution due to early fluid administration may affect the level of HCT

c. Bleeding will have an impact upon patient’s HCT and may not rise despite
significant leak.

4. The existing WHO classification, sometimes, cannot be used prospectively in the

clinical management of the patient because the disease can only be classified
retrospectively.

Patients can present with severe dengue without fulfilling ALL the four criteria (refer
Appendix 9) for DHF/DSS.

3.5.2 WHO Classification 2009

Grading the disease according to severity is a very useful tool for clinical management
and algorithm driven decision making. It can help decide the course of action for the
clinician in a reproducible fashion as to where, when and how intensively the patient
should be observed and treated (i.e. triage) which is particularly useful in outbreaks.
 24 | P a g e  
 

Figure 7: Suggested Dengue Classification and Level of Severity

DENGUE ± WARNING SIGNS SEVERE DENGUE

   

1. Severe plasma leakage 
With warning 
Without  2. Severe hemorrhage  
signs 
 
3. Severe organ impairment
 
 
 
 
 
 
CRITERIA FOR DENGUE ± WARNING SIGNS CRITERIA FOR SEVERE DENGUE

Probable dengue Warning Signs Severe plasma leakage leading to:

Lives in / travel to dengue endemic  No clinical improvement /
area.
worsening clinical parameters  Shock (DSS)
Fever and 2 of the following criteria:  Fluid accumulation with respiratory
 Persistent vomiting
 Nausea distress
 Rash  Severe abdominal pain
 Aches and pains  Lethargy and or restlessness Severe bleeding
 Tourniquet test positive  Giddiness as evaluated by clinician
 Leukopenia  Pale cold clammy extremities
 Any warning sign  Bleeding: epistaxis, gum bleed, Severe organ involvement
bloody stolls, hematemesis, liver : AST or ALT> =1000
Laboratory - confirmed dengue hemoptysis, menorrhagia, CNS : Impaired consciousness
(Important when sign of plasma leakage) hematuria Heart and other organs
 Pulse pressure <25mmHg
 Less/no urine output for 4-6 hours.
 Falling trend in PLTs drop of
> 30,000 in 24 hours.

Source:  World  Health  Organization.  Dengue  Guidelines  for  Diagnosis,  Treatment,  Prevention  and  Control  ‐  New 
Edition 2009. WHO: Geneva; 2009  
25 | P a g e  
 

3.6 OTHER IMPORTANT MANIFESTATIONS

Severe bleeding or organ impairment might occur without plasma leakage. The
Following manifestations are important in dengue infection but are often under-
recognized or misdiagnosed:

1. Acute abdomen:

Acute abdominal pain - a common symptom in dengue infection - and occasionally

misdiagnosed as acute appendicitis; can have diverse etiology ranging from flavivirus
associated hepatitis, acalculous cholecystitis and shock.43, 44 When fever precedes
abdominal pain, along with laboratory findings of leucopenia, thrombocytopenia (instead
of leukocytosis, prolonged APTT) it help to differentiate acute abdominal pain due to
dengue infection from surgical causes of acute abdomen.41 Again subsidence of
abdominal pain with treatment of shock with appropriate fluids would characterize
dengue rather than surgical cause.

2. Liver Involvement in Dengue Infection:

As in other flaviviruses, mild to severe hepatitis is common in patients with DF/DHF

irrespective of the degree of plasma leakage. In some cases, liver failure may occur.37
Patients with liver failure have a high propensity to bleed, especially from
gastrointestinal tract. 45, 20

3. Neurological manifestation:

A few patients (<1%) with dengue infection may develop neurological manifestations,
mainly encephalitis, encephalopathy 46, 16 and rarely myelitis and Guillain-Barré
Syndrome 47. Some of these patients, at least, belong to MAS (Macrophage activation
syndrome) associated encephalopathy, therefore, dengue fever must be included in the
differential diagnosis in any patient diagnosed as viral encephalitis.

4. Kidneys Involvement in Dengue Infection:

Renal involvement has been reported in Dengue Hemorrhagic Fever (DHF). Mild
proteinuria is frequently seen. Acute Kidney injury (AKI), overt proteinria and, rarely, a
clinical picture of Acute Glomerulonepgritis are also the renal manifestations of DHF. In
a retrospective analysis of 304 patients with DHF, 10 patients (3.3%) were found to
have acute renal failure. In a similar study in pediatric population, 0.9% of 2893 Dengue
hospital admissions developed acute kidney injury (AKI). Dehydration and shock state
are the most likely causes for AKI in DHF; Rhabdomyolysis, ATN and immune mediated
glomerulonephritis are the other possible pathogenic mechanisms.40
26 | P a g e  
 

5. Hemophagocytic Histiolymphocytosis (HLH) syndrome

This is an uncommon syndrome and is often seen as sequel to overactive cytokine

productions. It is often associated with dysregulated T cell activation and macrophage
function, following dengue virus infection. The “cytokine storm” induced by massive
activation of T cells and the macrophages results in vascular injuries, followed by the
immense plasma leakage leading to cellular edema, cellular damage, necrosis and the
cell death. This syndrome should be looked for in patients with unusually low ESR,
progressive cytopenia and multi-organ complications. Serum triglycerides and serum
ferritin are often markedly elevated with very low fibrinogen levels. Definitive diagnosis
can be made by performing bone marrow biopsy which demonstrates hemophagocytic
activity.

3.7 DIAGNOSTIC CHALLENGES

It is easy to misdiagnose dengue in non-endemic setting because clinical features of
dengue infection are rather non-specific and mimic many other diseases. An early an
accurate diagnosis would need an astute physician with high index of suspicion.
Situation may get complicated further if a dengue patient carries an additional co-
infection with another pathogen.

Using a syndromic approach, Tables 2 and 3 provide quick and helpful references to the
differential diagnoses which vary at different stages of dengue disease.

FEBRILE PHASE

Clinical syndrome Differential diagnoses

Influenza; Measles; Chikungunya,
Flu - like syndrome Adenovirus; Infectious mononucleosis
Acute HIV seroconversion illness
Rubella; Measles; Scarlet fever,
Rash
Meningococcal Infection; Drugs
Diarrhea Rotavirus, Food poisoning
Meningo-encephalitis
Neurological manifestation
Febrile seizures

Table 2: Differential diagnoses for dengue illness during febrile phase

27 | P a g e  
 

CRITICAL PHASE

Clinical syndrome Differential diagnoses

Acute appendicitis; Acute cholecystitis
Acute abdomen Perforated viscus; Viral hepatitis
Diabetic ketoacidosis
Shock Septic shock; Cardiogenic shock
Respiratory distress Diabetic ketoacidosis; Renal failure
(Kussmaul’s breathing) Lactic acidosis
Acute leukemia; Aplastic anemia;
Immune thrombocytopenic purpura;
Leucopenia & Thrombotic thrombocytopenic purpura;
Thrombocytopenia/Bleeding Malaria / Leptospirosis / Typhoid / Typhus
Bacterial sepsis; SLE
Acute HIV seroconversion illness

Table 3: Differential diagnoses for dengue illness during critical phase

4. DISEASE NOTIFICATION
4.1 Case Reporting and Epidemiological Categorization
For the purpose of epidemiological disease notification, the prompt diagnosis and
reporting of all the dengue cases is essential.

In areas of the world where dengue disease is endemic, all the cases of PUO,
presenting with nonspecific features, would have DF included in the list of differential
diagnosis. The category of “SUSPECTED DENGUE” as defined by GCP guidelines will
be inclusive of all such cases (Appendix 5). The diagnostic yield in non-epidemic
situation, within this cohort, is often very small. (All the viral illnesses, malaria, typhoid
and PUOs would muddy up the data).

In our clinical practice, all the “suspected cases” have to have a CBC done. If Patient
has WBC count of less than 4000 and platelet count of less than 100,000, patient would
be categorized as “PROBABLE DENGUE”. Case reporting is then, mandatory.
(Section 5.1 & DEAG “Form R”, Appendix 4a)

Confirmatory tests in these patients in the form of viral isolation (PCR), documentation
of NS1, or four fold increases in the immunoglobulin titer on paired sample taken 5 days
apart would clinch the diagnosis as “CONFIRMED DENGUE” – albeit too late for
28 | P a g e  
 

epidemiological purpose. (Section 5.2 & Appendix 5) Filing of a detailed case report
form (Appendix 4b) is mandatory here.

Dengue fever diagnosis is divided into three categories for epidemiological

purposes (This is not a clinical staging)

 Suspected dengue:

 Probable dengue:

 Confirmed Dengue: (See Appendix 5 for detailed description)

All Probable dengue cases, admitted to the hospital or under the care of a GP, must be
notified to the EDO health who in turn will report to DG health within one hour – it is to
be followed by written notification within 24 hours using the standard notification format
(Ref to DEAG “Form R” on Appendix 4a).

In the state of epidemic, notification should be done as soon as a clinical

diagnosis of dengue is suspected; hematological/serological confirmation is not
necessary. All those health facilities (both public and private) who have been issued
login credentials for dengue dashboard must report all suspected, probable and
confirmed cases in real time. Other must notify CEO health of the all district of cases
presenting to that health care facility.

Failure to notify dengue is liable to be compounded under the Punjab prevention and
control of Dengue (temporary) regulations 2018 - NO.S.O. (PHP) 9-98/2002 (REG)48
(Appendix 7)

5. LABORATORY INVESTIGATIONS
5.1 Disease Monitoring Laboratory Tests
Full Blood Count (FBC)

1. White blood cell count (WBC):

In the beginning of the febrile phase WBC is usually normal but will decrease rapidly as
the disease progresses.13 WBC may show relative lymphocytosis, this non-specific
trend of leucopenia should raise the suspicion of possible dengue infection in
appropriate settings.
29 | P a g e  
 

2. Hematocrit (HCT):

Hemoconcentration as depicted by rising HCT is a marker of plasma leakage in dengue

infection and helps to differentiate between DF and DHF –A significant blood loss and
early fluid replacement may mask the trend.49 It is of paramount importance to get a
baseline HCT in the early febrile phase of disease. It would be easier later on to
recognize start of plasma leak – detection of rising HCT level.

Criteria for CBC

 All febrile patients at the first visit to get the baseline HCT, WBC and PLT

 All patients with warning signs

 All patients with fever >3 days

 All patients with circulatory disturbance/shock (+glucose check).

3. Thrombocytopenia:

Thrombocytopenia is perhaps the most common (and most maligned) laboratory

investigation in dengue infection.40 In the early febrile phase, platelet count is usually
within normal range but it will decrease rapidly as the disease progresses to the late
febrile phase or at defervescence and it may continue to remain low for the first few
days of recovery. There is a significant negative correlation between disease severity
and platelet count 11, 50 but it is not predictive of bleeding.51, 52, 53, 54, 55
30 | P a g e  
 

4. Liver Function Test

Abnormal LFTs in the form of elevated transaminases is common and is characterized

by greater elevation of the AST as compared to the ALT.56 The frequency and degree of
elevation of the liver enzymes are higher with DHF compared to DF.56, 57

 Leucopenia followed by progressive thrombocytopenia is suggestive of dengue

infection.
 A rising HCT with accompanying progressive thrombocytopenia is suggestive of
DHF.
 There is no local data available on the normal range of HCT in adults. In the
absence of a baseline HCT level, a HCT value of >40% in female adults and
>46% in male adults should raise the suspicion of plasma leakage.

Recommendations

 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)

Additional Investigations

 Serum electrolytes and BUN, creatinine

 Liver function tests.

 Cardiac enzymes or ECG if indicated, especially in adults.

 Serum amylase

5.2 Diagnostic Tests

Definitive diagnosis of dengue infection can only be made through laboratory
investigations. Interpretation of laboratory diagnostic results, however, should
only be done in the clinical context.
31 | P a g e  
 

Laboratory confirmatory tests include antibody detection (serology e.g.

Hemagglutination Inhibition Test), virus isolation, detection of virus genetic materials
(polymerase chain reaction -PCR) and detection of dengue virus protein (NS1 antigen).

5.2.1 Dengue Serology Tests

Hemagglutination Inhibition Test
The hemagglutination Inhibition (HI) test: HI test is considered a gold standard for
the serological diagnosis of dengue. It is non-mechanized labor intensive test which
requires paired samples for proper interpretation, therefore it is a test that is mainly
being used for research - to differentiate between primary and secondary dengue
infections.

Dengue IgM test: Dengue-IgM capture enzyme-linked immunosorbent assay (ELISA)

is the most widely used serological test, to diagnose dengue. The titer of IgM tends to
be significantly higher in primary infections (10) as compared to secondary (20)
infections.58 Once the IgM becomes detectable by day 5, it rises rapidly and peaks at
about 2 weeks after the onset of symptoms, it wanes slowly in the following months to
reach undetectable levels after a variable interval. Some fully recovered healthy people,
who had had an exposure to the dengue virus in the recent past, might well test positive
to the dengue IgM. Therefore, mere presence of IgM might not be diagnostic of a
current illness.59 A positive IgM result, in endemic situation, therefore, has to be
interpreted with care taking the clinical picture into consideration. If the dengue IgM test
is the only available diagnostic test in the hospital, a paired sample - one in early
febrile phase and other later, after day 5 of illness - will be essential for proper
interpretation of the results.59

Specific IgM was detected in all the cases with primary dengue virus infection on
disease day 9 or later.58 Anti-dengue IgM is, a sensitive test for detection of primary
infection of dengue after day seven – (IgM was detected in only 55% of patients with
primary dengue infections between day 4-7 of the onset of fever) - which become
positive in 100% of the patients after day seven to nine.

In secondary dengue infections, IgM was detected in only 78% of patients after day
seven.58 In another study, 28% of secondary dengue infections remained undiagnosed
when IgM was the only test performed.12, 61, 62 It can be assumed, therefore, that IgM is
not very reliable test for detection of secondary dengue infection.

Indirect IgG ELISA test: Both primary & secondary dengue infection, dengue IgG
becomes detectable in 100% of patients after day seven of onset of fever. A paired
dengue IgG is, therefore, a recommended test to see the seroconversion; if dengue IgM
stays negative after day seven and the disease is still suspected clinically.60, 61
32 | P a g e  
 

Recommendations

 Seroconversion for dengue IgM in a paired sample is conclusive evidence of

dengue fever. Therefore, dengue IgM should be taken as soon as the disease is
suspected.

 Dengue IgM is usually becomes positive after day 5-7 of illness. Therefore, a
negative IgM taken before day 5-7 of illness does not exclude dengue infection.

 If dengue IgM is negative before day seven, a repeat sample must be taken in
recovery phase.

 If dengue IgM is still negative after day seven with negative IgG test reported at less
than seven days, a fourfold rise in reciprocal IgG antibody titre between acute and
convalescent sera is needed for diagnostic confirmation. Appendix 4b

Immune-Chromatography Test- (strip assays)

Simple rapid tests such as the strip assays (immune-chromatography test) are available
for qualitative detection of dengue IgM and IgG. These rapid tests have moderate
sensitivity and specificity when the samples are collected in the late convalescent
phase. These can be used when ELISA test are not available65 But these strip test
have to be interpreted within the clinical context with clear understanding that they have
significantly reduced sensitivity and specificity.64, 65, 62, 66 It is recommended that the
dengue IgM ELISA test be done after a rapid test.64

Note: False positive dengue serology:

Serological tests for dengue have been shown to cross-react with:

• Other flavivirides – Japanese Encephalitis.67, 62

• Non-flavivirus infections– malaria, leptospirosis, toxoplasmosis, syphilis.68, 65

Connective tissue diseases – i.e. rheumatoid arthritis.65

5.2.2 Virus Isolation

The definitive test for dengue infection is the virus isolation. However, this test can only
be performed in specialized labs equipped with tissue culture and virus isolation
33 | P a g e  
 

facilities. It is useful only at the early viremic phase of the illness. Generally, virus can
be detected in the blood until day five of illness; i.e. before the formation of neutralizing
antibodies.

During the febrile illness, dengue virus can be isolated from serum, plasma and
leucocytes. It can also be isolated from post mortem specimens. The monoclonal
antibody immunofluorescence test is the method of choice for identification of dengue
virus. This costly test may take up to two weeks to complete.

Note: Virus isolation has a poorer yield as compared to PCR. It is most probably due to
poor viability of the virus and the poor quality of the samples.69

Investigations for Complications-ABCS

 Acidosis –ABGs

 Bleeding – G/C, PT, APTT

 Calcium

 Sugar

5.2.3 Polymerase Chain Reaction– (DENV-RNA by RT-PCR)

In the early phase (< 5 days of illness), molecular tests such as the reverse
transcriptase – polymerase chain reaction (RT- PCR) can be very useful for the
diagnosis of dengue infection. It was shown to have a sensitivity of 100% in the first 5
days of disease, but is reduced to about 70% by the day six, as expected with declining

viraemia.70, 71, 72 An additional advantage of RT-PCR is the ability to determine dengue

serotypes 72, 71, 74, 69, 75

Limitations of RT- PCR are:

a) This test is only available in a few centers with facilities and trained personnel.

b) The test is costly.

c) The specimen requires special handling for storage and transport, between the time
of collection and extraction (Appendix 10). In view of these limitations, the use of RT-
PCR should only be considered in-patients who present with diagnostic challenges in
the early phase of illness.
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5.2.4 Non-Structural Protein-1 (NS1 Antigen)

NS1 antigen is a highly conserved glycoprotein that seems to be essential for virus
viability. Secretion of the NS1 protein is a hallmark of flavivirus infecting mammalian
cells and can be found in dengue infection as well as in yellow fever and West Nile
virus infection. This antigen is present in high concentrations in the sera of dengue
infected patients during the early phase of the disease.76, 77 The detection rate is much
better in acute sera of primary infection (75%- 97.3%) when compared to the acute sera
of secondary infection (60% - 70%).77, 79, 80, 81

The sensitivity of NS1 antigen detection starts to drop off from the day 4-5 of illness
and is usually undetectable in the convalescence phase.72, 81, 79, 80 It is recommended to
carry out Dengue NS1 testing by ELISA technique. Simple rapid tests such as strip
assays (Immune chromatography technique ECT) have significantly reduced sensitivity
and specificity and must be interpreted in clinical context.

Recommendations

 DENV-RNA by RT-PCR can be used as a diagnostic tool in early dengue

infection. It is not recommended as a routine diagnostic test due to limited
availability and cost.

 NS1 Ag is a good diagnostic tool that is very useful in the early phase of dengue
infection. It is not useful in the convalescence phase.

Please refer to Appendix 10 for methods of sample collection for diagnostic tests
35 | P a g e  
 

6. INVESTIGATION OF POST MORTEM CASE

Suitable samples for viral isolation and PCR should be obtained from the liver, lung,
thymus, spleen, lymph nodes, CSF, pleural fluid and brain tissues in a patient
suspected to have died of DF/DHF.11, 83 However PCR is a more sensitive method.83, 84,
85

For serological confirmation of dengue illness, a seroconversion of dengue IgM needs

to be demonstrated. In a patient who has died suspected of dengue, a repeat dengue
serology together with the samples mentioned above should be obtained.

Caution: Massive blood transfusion may affect the test results mentioned above.

Recommendations

 A repeat dengue serology should be obtained at the time of death.

 Suitable specimens for virus isolation and/ or RT-PCR and/ or antigen detection
are recommended for confirmation of diagnosis.

Please refer to Appendix 10 for methods of sample collection.

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7. MANAGEMENT OF DENGUE INFECTION

7.1 Introduction
Currently there is no specific anti-viral medication available against the dengue virus.
The mainstay of dengue infection management stays symptomatic and supportive. A
stepwise approach as suggested in Table 4 can be useful. Dengue is a dynamic
disease and management issues vary according to the three phases of the clinical
course (section 7.4). It is crucial to recognize plasma leakage & shock at an early
stage, to guard against severe organ impairment. This can only be achieved through
frequent clinical and laboratory monitoring.

Dengue patients who are managed in the outpatient setting should be provided with an
OPD form (DEAG Form O, Appendix 3a) to ensure that all relevant information stays
available to all the concerned health care providers.

Table 4: Stepwise approach to a Patient with Dengue Infection

Step 1. Overall assessment it is important to evaluate every patient in a stepwise
manner as follows.

1. History
• Date of onset of fever/ illness • Oral intake of fluids (estimated)
• Assess for warning signs (refer to Table 5) • Diarrhea
• Bleeding • Change in mental state/seizure/dizziness
• Urine output (frequency, volume and time of last voiding)
• Other important relevant history of:
- Contact with Dengue fever patient
- Visit to outdoor parks, gardens and swimming pools etc.
- Recent travel to dengue endemic zones
-- Any co-morbidity
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2. Physical examination
Assess for:
i. Mental status and record Glasgow Coma Scale (GCS)
ii. Hydration status
iii. Hemodynamic status
-Skin color -Cold/ warm extremities
-Capillary refill time (normal <2 seconds) -Pulse rate & volume
-Blood pressure/Pulse pressure
iv. Tachypnea/ acidotic breathing/ pleural effusion
v. Abdominal tenderness/ hepatomegaly/ ascites
vi. Bleeding (occult/overt)
vii. Tourniquet test
2. Investigations
1. CBC (including platelet counts & HCT)
2. Dengue serology

OPD form (Appendix 3a – DEAG Form O) is useful for screening febrile patients with
suspected and probable dengue. Elucidating details in history and examination as
above will be required in admitted patients (Appendix 3b – Form I)
After establishing the diagnosis, it is important to recognize stage of the disease and
presence of any warning sign. Further management will depend on preceding
information.
Step 2. Diagnosis, disease staging and severity assessment

Based on evaluations from history, physical examination +/- CBC and HCT, the
clinicians should be able to determine:

1. Diagnosis of Dengue Fever (suspected, probable or confirmed)

2. The phase of illness (febrile/critical/convalescent or recovery)
3. The hydration and hemodynamic status of patient
4. Whether the patient requires admission
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Step 3. Plan of management

1. Notification of disease:

Uploading of all suspected, probable and confirmed cases on dengue dashboard

by filling DEAG-Form O & R (Appendix 3a & 4a).

2. Admission is indicated in:

 Suspected cases with one or more warning signs

 All probable and confirmed cases
3. Manage the patient according to phase of illness and disease severity (Fluid
Management in Dengue Shock - page 50)

4. If admission is not indicated:

• Daily or more frequent follow up with CBC is necessary especially from day 3 of
illness onwards until the patient becomes afebrile for at least 24 hours without
antipyretics
• Refer to Home Care Advice Leaflet for Dengue Patients (Appendix 12)

Table 5: Warning signs (one or more)

Signs & Symptoms Laboratory Findings

No clinical improvement / worsening clinical Bleeding: epistaxis, gum bleed,

parameters bloody stolls, hematemesis,
hemoptysis, menorrhagia, hematuria

Persistent vomiting Free fluid in pleura or peritoneum on

ultrasonography 

Severe abdominal pain HCT <30% or ≥ 55%

Lethargy and or restlessness Increasing HCT with falling platelets

Giddiness Pale cold clammy extremities

Less/no urine output for 4-6 hours. Falling trend in PLTs drop of >
30,000 in 24. Hours

Pulse Pressure < 25mmHg

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Patients who are not in critical phase and hemodynamically stable can be treated at
home with close follow-up as required

Table 6: Clinical and Laboratory Criteria for Patients Who can be Treated at Home

1. Tolerating orally, adequate urine output

2. Absence of significant manifest bleed
3. Absence of clinical alarm signals (refer Table 5)
Physical examination defining hemodynamic stability.

Pink, Warm extremities Normal capillary refill time (normal <2

seconds)

Good pulse volume Stable blood pressure

Normal pulse pressure (> 30mmHg) Absence of disproportionate tachycardia

No tachypnea or acidotic breathing Absent hepatomegaly or abdominal

tenderness

No bleeding manifestation No sign of pleural effusion / ascites

No alterations in mental state and full GCS score

Investigation during Hematological Stability

7.2 TRIAGING THE PATIENT AT ACCIDENT & EMERGENCY /

OUTPATIENT DEPARTMENT
The purpose of triaging patients in A&E department is to identify those patients who
would require urgent medical attention. This is to avoid critically ill patients being
ignored while less critical patients are being attended to.89, 88, 90, 91

Triage the patient according to warning signs already given (Table 5)

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7.3 CRITERIA FOR HOSPITAL REFERRAL / ADMISSION

7.3.1 Referral from primary care providers to hospital
The decision for referral and admission must not be based on a single clinical
parameter but should depend upon the overall assessment of the patient, taking history,
physical examination and labs into consideration.

Referral from primary care providers to hospital

1. Symptoms

 Presence of warning signals (Table 5)

 Inability to tolerate oral fluids

 Inadequate urine output (less than 25ml/hour or 0.5ml/kg/hour in children)

 Seizure
2. Signs

 Clinical signs of dehydration

 Shock (Table 1)

 End organ failure

3. Special Situations for early referral to the hospital

 Patients with co-morbidity e.g. Diabetes, Hypertension, Ischemic Heart Disease,

Coagulopathies, Morbid Obesity, Renal Failure, Chronic Liver disease, COPD

 Infants < 1 year of age and elderly > 65 years of age

 Pregnancy

 Social factors that limit follow-up e.g. living far from health facility, no transport,
patient living alone, etc

4. Laboratory Criteria

 Rising HCT accompanied by reducing platelet count

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7.3.2 Referral from basic health units / hospitals without specialist to

the hospitals with requisite expertise
All the doctors are encouraged to talk to the DEAG expert for on-line advice. Early
consultation with the nearest expert should be initiated for all DHF patients, irrespective
of the complications, end organ dysfunction or bleeding.

Prerequisites for transfer

1. All efforts must be made to optimize the patient’s condition before and during
transfer.

2. The Emergency Department and/or Medical Department of the receiving hospital

must be informed prior to transfer.

3. Adequate and essential information must be sent together with the patients that
includes fluid chart, monitoring chart and investigation results.

7.4 DISEASE MONITORING

7.4.1 Principles of Disease Monitoring
1. As discussed previously, dengue is a systemic and dynamic disease. Therefore,
disease monitoring would vary dynamically in different phases of the disease.

2. During the critical phase (plasma leakage) which may last for 24-48 hours, monitoring
needs to be intensified and frequent adjustments in the fluid regime may be required.

3. Recognition of onset of convalescent phase is also important because intravenous

fluid regime needs to be progressively reduced/ discontinued at this stage.

7.4.2 Outpatient Disease Monitoring

Every patient, who presents in outpatient or A & E department and is suspected to be
suffering from dengue, should be assessed in stepwise manner as recommended in
Table 4.

Daily or more frequent follow up is necessary especially from day 3 of illness, until the
patient becomes afebrile for at least 24- 48 hours without antipyretics. An outpatient
assessment and advice form is recommended for use for outpatient care (Appendix
3a).
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7.4.3 Inpatient Disease Monitoring

Once admitted, every patient with suspected dengue should be reviewed thoroughly in
the shortest possible time (Form I, Appendix 3b).

In addition to the routine history, physical examination a stepwise approach (Table 4)

should be employed to record the relevant data. The plan of management and
monitoring cannot be static and should be based on the phase of the disease and the
hemodynamic status of the patient. Different phases of the dengue illness are
summarized in table 7.

Table 7: Key points in different phases of Dengue Fever

Phase of Illness Key Points

- Differentiation of dengue illness from other febrile illness

Febrile
- Not possible to differentiate DF from DHF
- Plasma leakage occurs as patient progress to late febrile
phase or as temperature begins to defervesce (T < 38.0 oC)
- Clinical deterioration occurs during this phase due to
plasma leakage
- Plasma leakage results in hemoconcentration and
hypovolemic / shock.
Critical
- Excessive intravenous fluids may increase plasma leakage
in pleural space and contribute to respiratory distress
- Bleeding can be precipitated by prolonged shock and shock
can be perpetuated by bleeding.
- May mimic acute abdomen of other causes
- May be confused with septic shock or other forms of shock.
- Cessation of plasma leakage
- Reabsorption of fluid from extravascular compartment
Reabsorption - Hemodiluation occurs following fluid reabsorption.
- Hypervolemia and pulmonary edema if intravenous fluid
therapy is continued

Table 8. summarizes the recommendations regarding the parameters and

frequency of monitoring according to the different phases of the illness.
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Frequency of monitoring
Parameters of monitoring Convalescent
Febrile phase Critical phase
Phase
Use “Monitoring Use “Monitoring Chart   Use “Monitoring
Chart ” DEAG DF DEAG DF Form – 2” Chart”  DEAG DF
Monitoring charts to use
Form – 1 Appendix 2b” Form – 1
Appendix 2a” Appendix 2a”
Clinical parameters
General well-being, appetite /
oral intake, warning signs & Hourly 4-6 hourly
4 – 6 hourly
symptoms, neurological /
mental state
Signs of bleeding, Daily or more At least twice a day and Daily or more
abdominal tenderness, frequently towards more frequently as frequently as
ascites and pleural effusion late febrile phase indicated indicated
Hemodynamic status:
 Pink/ cyanosis
 Extremities(cold/warm) Hourly
 Capillary refill time 4 – 6 hourly
 Pulse Rate & volume, depending on During Shock:
 BP, Pulse pressure clinical status Every 15 minutes till 4 – 6 hourly
Respiratory status: stable then 1 – 2 hourly
 Respiratory Rate
 SpO2
Hourly 4 – 6 hourly
Urine output 4 – 6 hourly During shock:
Every 15 minutes
4 – 12 hourly depending
on clinical status
Daily or more During shock:
WBC + HCT frequently if Repeated before and after
indicated each bolus of fluid during Daily
resuscitation and as
indicated
At least daily or more
B.Urea/S.Creatinine
frequently as indicated
LFTs
During shock: As indicated
RBS As indicated
It is crucial to monitor
Coagulation profile
acid-base balance / ABG
HCO3/Lactate/ABGs
closely
Table 8: Parameters and frequency of monitoring according to different phases of
dengue Illness.
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7.5 FLUID MANAGEMENT

7.5.1 Dengue with Warning Signs (Table 5)
Presence of warning signs usually heralds the onset of plasma leak in critical phase. All
such patients should be admitted and monitored in a health care facility.

Common pitfalls in fluid therapy:

1. Treating patient with unnecessary fluid bolus basing decision solely on HCT

2. Excessive and prolonged fixed fluid regime in stable patients. Failure to adjust
rate of fluid administration in accordance with the rate of plasma leak which can
be assessed with appropriate monitoring

3. Continuation of intravenous fluid during the convalescent phase

At least some of patients exhibiting warning signs of dengue would recover with early
intravenous rehydration without ever going into shock. However, some cases would
deteriorate to severe dengue shock syndrome. If the patient has dengue fever with
warning signs, the recommended action plan is depicted in Table 9a.

Table 9a: Action Plan for Patient who has Dengue Fever with Warning Signs (without
shock)

Recommendations

 Admit the patient. If stable may be given fluid quota (7.5.5) orally

 IV fluid is indicated in patients who are vomiting or unable to tolerate oral

fluids. 9b: section 7.5.2

 IV fluid is also indicated in patients with increasing HCT (indicating on-going

plasma leakage) despite increased oral intake.

 Crystalloid (0.9% Saline) is the fluid of choice

As mentioned above, if patient is unable or is non-tolerant of oral fluids; IV fluids may be

started according to table 9b: section 7.5.2
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7.5.2 Patients in Critical Phase without Shock

There are no studies that have looked at fluid therapy in non-shock dengue patients.
Appropriate (as per quota) oral fluid intake may be sufficient in some patients who are
hemodynamically stable and not vomiting. However, IV fluid (0.9% saline is
recommended) is indicated in patients with serially increasing HCT (indicating on-going
plasma leakage) despite appropriate oral intake. Intravenous fluid therapy should also
be considered in patients who are vomiting and not tolerating orally.91, 87

The normal maintenance requirement for IV fluid therapy in such patients could be
calculated based on the formula (M+5% - 7.5.5). Frequent adjustment of maintenance
fluid regime is often needed during the critical phase. Often 1.2-1.5 times the normal
maintenance will be required during the critical phase. Fluid infusion rate should be
reviewed regularly to match the rate of infusion with estimated rate of plasma leak.

A rising HCT AND/ OR hemodynamic instability indicates on-going plasma leakage and
will require an increase in the IV fluid infusion rate. If patients deteriorate and progress
to shock, a more aggressive fluid resuscitation is indicated (section 7.5.3).91, 87

Reduce or consider discontinuation of IV fluid therapy when patients begin to show

signs of recovery (usually after 24-48 hours of beginning of critical phase) or the HCT
drops in a hemodynamically stable patient.

Table 9b - IV Fluid management during critical phase without shock

 Obtain a baseline HCT before fluid therapy

 Use crystalloids solution (such as 0.9% saline).

 Start with 1.5 - 7 ml/kg/hour for 1 hour. Subsequent rate should be adjusted
according to the pulse pressure (≥30 mm) and urine output (≥ 0.5 ml/kg/hr or
25ml/hr in adults).

 If the clinical parameters are worsening and HCT is rising, increase the rate
of infusion.

 Reassess the clinical status, repeat the HCT and review fluid infusion rates
accordingly.
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7.5.3 Dengue Shock Syndrome (DSS) (Compensated and

Decompensated - Refer to Fluid Management in Dengue Shock Syndrome)
Dengue shock syndrome is a medical emergency. Recognition of shock in its early
(compensated) stage and prompt fluid resuscitation will ensure a good clinical
outcome.91 (Refer to Table 1 for details). Consequences of failure to recognize the
compensated shock phase may be drastic. As the compensated phase leads to
decompensated phase the disease outcome becomes less certain with increasing
chance of a more complicated course. Pulse pressure of < 20 mmHg and severe
oliguria are late signs of shock

All patients with dengue shock should be managed in high dependency intensive care
units. Fluid resuscitation, however, must be initiated promptly and should not be
delayed while waiting for admission to ICU or high dependency unit.

In spite of successful initial resuscitation the patient may experience recurrent episodes
of shock because of continuing capillary leakage which can last for 24-48 hours.

Intravenous fluid therapy is the mainstay of treatment for dengue shock. 11, 92, 93 These
studies showed no clear advantage of using any of the colloids over crystalloids in
terms of the overall outcome. However, colloids may be preferable as the fluid of choice
in patients with intractable shock after crystalloid resuscitation. Colloids seem to restore
the cardiac index and reduce the level of HCT faster than crystalloids in patients with
intractable shock. 93 The choice of colloids includes dextran 40 and hetastarch solution.

Principles for fluid resuscitation

The volume of initial and subsequent fluid resuscitation depends on the degree of
shock. Initial fluid bolus can be 10 or 20 ml/kg ideal body weight in compensated and
decompensated shock respectively. The volume and rate of fluid replacement should be
carefully titrated to the clinical response to maintain an effective circulation while
avoiding an over replacement.
47 | P a g e  
 

Improvement in the following parameters indicates adequate fluid resuscitation:

Clinical parameters indicating adequacy of fluid resuscitation:

 Improvement in general well-  Improving pulse pressure

being

 Good orientation &mental state  Reduction in tachycardia or

normalization of heart rate

 Warm peripheries  Increase in urine output

 Capillary refill time ≤ 2sec  Reducing tachypnea or

normalization of respiratory rate

 Stable BP

Laboratory parameters indicating adequacy of fluid resuscitation:

 Decrease in HCT (in face of hemodynamic stability)

 Improvement in metabolic acidosis

If the initial cycles of fluid resuscitation with crystalloids (30 ml/ kg in total - refer to
Algorithms for Dengue Shock Syndrome) fail to establish a stable hemodynamic state
and HCT remains high, colloids should be considered 11, 87

If the repeat HCT drops after fluid resuscitation and the patient remains in shock, one
should suspect significant bleed (often occult) and blood transfusion should be instituted
as soon as possible (refer to Algorithm for fluid management for DSS).

7.5.4 Persistent Shock (Refer to Fluid Management in Dengue Shock Syndrome)

Consider persistent shock in patients who fail to improve with adequate fluid
resuscitation
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Following causes of persistent shock must be considered and managed:

Significant bleeding: (Often occult).

 Treat with Packed cells (5ml/kg) or whole blood (10ml/kg) may be used. This is
expected to increase the HCT by 5%. If HCT is >45% it must be decreased by
giving iv fluids before using blood; even if bleeding is likely

Hypocalcemia:

Treat with IV (10%) calcium gluconate @ 1 ml/kg (max 10mls diluted in equal volume of
saline) as slow bolus over 10 minutes with cardiac monitoring (may be repeated 6
hourly). Empiric treatment with calcium may be given if patient fails to improve or
deteriorates despite fluid resuscitation. 91

Acidosis:

If the arterial blood bicarbonate (HCO3) falls below 15 meq/l in the patients with
decompensated shock, treat with NaHCO3 (8.4%) with an empiric dose of 1ml/kg,
diluted in equal volume of saline in a slow infusion. (A bolus of not more than 10 ml
/dose – maximum up to 5 doses). Shift the patient to HDU under expert supervision 91

Hypoglycemia:

Treat with intravenous dextrose after bed side glucose measurement

If patient’s is still in state of persistent shock despite all the above measures consider
sepsis and cardiogenic shock

 Treat with I/V antibiotics: Use intravenous antibiotics as oral administration may
worsen vomiting and result in erratic absorption. Choice of antibiotics should be
sufficiently broad to provide cover for Gram+, Gram- and anaerobic organisms in
keeping with the prevailing culture sensitivity pattern. Choice may later be
reviewed in light of blood C/S result of the patient.

Cardiogenic Shock:

 Consider inotropic support

Fluid therapy has to be judiciously controlled to avoid fluid overload which could result in
massive pleural effusion, pulmonary edema or ascites. 11, 87
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7.5.5 Calculation of Fluid Quota for Adults

Fluid quota in adults is based on the maximum lean mass of 50kg in adults. Irrespective
of the real weight of an adult - (even if he weighs more than 50 kg) - he still would have
the same amount of circulatory volume as that in a 50 kg adult. For adults weighing less
than 50 kgs, the actual weight may be used for calculating fluid quota (Section 11). The
following discussion explains fluid calculation for adults weighing ≥ 50 kgs. The formula
is referred to as M+5%. This refers to a sum of maintenance fluids PLUS 5% losses.
The entire fluid quota is given over 48 hours (the duration of the critical phase). For
patients presenting in shock the quota may be given over 24 hours. Such a patient may
have been leaking for a considerable length of time and may well be in the latter half of
the critical phase.

Calculation of total fluids during critical phase in adult (50 kg)

M (Maintenance) 100ml/kg for 1st 10 kg 1000

+50 ml/kg for next 10 kg + 500
+20 ml/kg for balance wt + 600
Total Maintenance 2100

5% of body weight = 50ml x body wt. (kg) 50 kg x 50 mls = 2500 mls

M + 5% = 4600 mls

It is important to note that if the patient is taking oral fluids, this oral intake should also
be included in the total fluid quota which also would include any fluid given in the form of
boluses.
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IV fluids
Crystalloids

 Normal Saline

 <6m age may use half Normal Saline

Colloids

Dextran 40 (Dextran 40 in Saline)

 Hyper-oncotic osmolarity of 310 mOsm/L. Oncotic pressure 1693 mmHg.

 High oncotic pressure - volume expender

 Molecular wt 10,000- 100,000(average 40,000) when given as a bolus all

molecules tend to stay together

6% Hetastarch (voluvan)

osmolality -308mosm/ mol wt 100,000 – leaking less; volume expansion –less

*** about 60% of pts with dengue shock could be managed only with crystalloids

Crystalloids Colloids

 0.9% Saline
 Dextran 40
 5%Dextrose 0.9%
 Hetastarch 6%
Saline
 5% Dextrose ½ saline
 Ringer lactate

When to give colloids

 Crystalloids also leak through leaky capillaries during leaking phase and will not
hold on volume and PCV for long (not more that 1-2 hrs)

 Colloids will not leak easily and will hold on to volume and maintain PCV for
longer period (4-5 hrs)
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7.6 MANAGEMENT OF BLEEDING/HAEMOSTASIS

7.6.1 Hemostatic Abnormalities in Dengue Infection
The hemostatic changes that occur in dengue infection are considered to be the result
of endothelial activation.96, 97 This process may aggravate thrombocytopenia in addition
to the activation of coagulation pathways which are an inherent part of the disease.96, 97,
98
However, thrombocytopenia and coagulation abnormalities would not reliably predict
bleeding in dengue infection. 51, 52

Markers of endothelial activation such as elevated levels of thrombomodulin, tissue

factor and Von Willebrand factor are more often seen in severe dengue fever.99, 100
Increased levels of these proteins may indicate microvascular thrombosis and end-
organ damage.100

7.6.2 How to Recognize Significant Occult Bleeding?

Bleeding is considered significant when it results in hemodynamic instability. Bleeding
from the gums or per vagina, epistaxis and petechiae are common but will usually
cease spontaneously and are often not significant.11 Significant bleeding can a
consequence of disseminated intravascular coagulation which usually occurs following
prolonged shock and acidosis.50

Suspect significant occult bleeding in the following situations:

1. Hematocrit not as high as expected, for the degree of shock to be explained by

plasma leakage alone. 50

2. A drop in hematocrit, without clinical improvement, despite adequate fluid

replacement 50, 85

3. Severe metabolic acidosis and end-organ dysfunction despite adequate fluid

replacement.50
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Patients at risk of major bleeding are those who:

• prolonged/refractory shock;

• hypotensive shock and renal or liver failure and/or severe and persistent
metabolic acidosis

• given non-steroidal anti-inflammatory agents

• pre-existing peptic ulcer disease

• anticoagulant therapy

• any form of trauma

• Blood transfusion is life-saving and should be given as soon as severe bleeding

is suspected or recognized

• Do not wait for the haematocrit to drop too low before deciding on blood
transfusion

7.6.3 Management of Bleeding in Dengue

Mild bleeding such as from the gums, per vagina, epistaxis or petechiae, usually cease
spontaneously and do not require blood transfusion.3 Transfusion of blood and blood
components in dengue is indicated when there is evidence of significant bleeding.50

Transfusion of blood in patients with significant bleeding

• Transfuse 5 ml/kg of fresh-packed red cells or 10 ml/kg of fresh whole blood at an

appropriate rate and observe the clinical response.

• Repeat blood transfusion if there is further blood loss or HCT fails to rise appropriately
after blood transfusion.
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Recommendations

 Patients with mild bleeding such as from the gums or per vagina, epistaxis and
petechiae do not require blood transfusion.

 Blood transfusion with whole blood or packed cell (preferably less than 1 week) is
indicated in significant bleeding.

7.6.4 Management of Upper Gastrointestinal Bleeding

There is no study to our knowledge that has looked at the use of proton pump inhibitor
in upper GIT bleeding in dengue setting. Endoscopy and endoscopic injection therapy in
upper GIT hemorrhage increases the risk of bleeding and must be avoided.101

Generally, most of the GIT bleed will improve after 48-72 hours of the defervescence.
Any bleed that persists beyond this time will require further investigation.

Recommendations

 Endoscopy and endoscopic injection therapy in upper GIT hemorrhage should be

avoided.

 Blood transfusion with whole blood or packed cell (as fresh as is available,
preferably less than one week old) is indicated in significant bleeding.

7.6.5 Management of Cardiac Complications in Dengue

Infection
Cardiac dysfunction is increasingly recognized as a component of shock in dengue
infection and manifest as arrhythmias, functional myocardial impairment and
myocarditis.102, 103, 104 Functional myocardial impairment can be caused by subclinical
myocarditis, myocardial edema or circulating myocardial depressant factors.105 Possible
mechanisms include regional vulnerability to coronary hypoperfusion, cytokine storm,
direct myocardial inflammation and altered calcium homeostasis.

Cardiac complications of dengue should be suspected in those with fluid refractory

shock or haemodynamic compromise disproportionate to capillary leakage/HCT
increase (refer to Fluid Management in Dengue Shock Syndrome). In such patients,
it is recommended to do ECG, cardiac biomarkers and echocardiography.
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a. Investigations:

Cardiac biomarkers:

Cardiac biomarkers (CK/CKMB or Troponin) have limited --sensitivity and could be

normal.105

ECG:

ECG alterations reported in dengue infection are often transient. --ECG changes might
be the only sign of cardiac involvement with normal biomarker levels and
echocardiograms. Common ECG changes reported are:

 Sinus bradycardia

 Atrioventricular block

 Atrial fibrillation

 T-wave and ST-segment abnormalities

b. Echocardiography

The available data on role of echocardiography in assessing cardiac function of dengue

infected patients is limited.103, 106, 107 There is evidence of significantly low ejection
fraction during the critical stage of severe dengue infection.106, 107, 108

Measurement of ejection fraction is difficult to interpret as it is influenced by changes in

preload and afterload. In severe dengue infection, there may be evidence of systolic
and diastolic dysfunction with possible segmental wall abnormalities of the septum as
well as right ventricular wall.103, 108

Echocardiography is indicated in refractory shock despite adequate fluid resuscitation

and suspected myocardial dysfunction.

c. Treatment:

Management of dengue infection in such patients should primarily be focused on

cautious fluid resuscitation, aiming to give just sufficient IV fluid therapy to maintain
adequate tissue perfusion.

There has been no evidence to support the use of antiviral and immunomodulatory
treatments such as beta interferon, corticosteroids and IV immunoglobulins for dengue
myocarditis.105
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7.6.6 The Role of Prophylactic Transfusions in Dengue

Prophylactic transfusion with platelets and fresh frozen plasma does not produce
sustained changes in the coagulation status and platelet count in patients with
DHF/DSS.110, 111 Prophylactic transfusion with platelets and fresh frozen plasma does
not change or reduce the bleeding outcome in DHF. 54, 110, 111

Inappropriate transfusion of blood components increases the risk of pulmonary edema

and respiratory embarrassment.110

Recommendation

There is no role for prophylactic transfusion with platelets and fresh frozen plasma to
prevent bleeding in the dengue patients.

7.6.7 The Role of Adjunctive Therapy in Dengue

There is insufficient evidence to support the use of recombinant activated factor VII in
dengue patients with significant bleeding.112, 113 The coagulation system seems to be
over-activated in dengue and infusion of activated factor concentrates may increase the
risk of thrombosis.114

There is insufficient evidence to support the use of intravenous immunoglobulin115 and

steroids117 in the management of dengue patients. Likewise, there appears to be no role
for the use of Vitamin K and tranexamic acid. However there are anecdotal reports, 117
that demonstrated a dramatic response when pulse methylprednisolone and high dose
immunoglobulin G (lgG) was used in the early phase of haemophagocytic syndrome.

7.7 MANAGEMENT IN HIGH DEPENDENCY UNIT (HDU)

The management DSS in high dependency unit (HDU) follows the general principles of
management of any critically ill patient in the HDU. However, there are certain aspects
which are of particular relevance to the management of DSS. There are several
indications for referring these patients for care in HDU. These are listed in the box
below. 18, 118, 119
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Indications for referral to HDU:

1. Any patient with significant plasma leak – (Patients falling in Algorithms for Dengue
Shock Syndrome)

 Pulse Pressure < 30 mm of Hg, Urine output of < 25ml/hour

2. Requirement for respiratory support (non-invasive and invasive ventilation)

3. Significant bleeding

4. Encephalopathy or other complications

7.7.1 Indications for respiratory support (non-invasive and

invasive ventilation)
The main objectives of respiratory support are to support pulmonary gas exchange and
to reduce the metabolic cost of breathing. There is some evidence that respiratory
support should be considered early in a patient’s course of illness and should not be
delayed unnecessarily.120

In patients with metabolic acidosis, respiratory support may be considered early despite
the preservation of relatively normal arterial blood pH. When PaCO2 is higher than what
is expected to compensate for the acidosis, the patient should be promptly intubated.

Formula to calculate the expected PaCO2 = 1.5 x [HCO3-] + 8±2 mmHg

In patients with encephalopathy and GCS of < 9, intubation is often required to protect
the airway.121, 122

Indications for mechanical ventilation:

• Respiratory failure

• Severe metabolic acidosis

• Encephalopathy with GCS < 9

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7.7.2 Indications for Hemodynamic Support

In dengue, hypotension is usually due to plasma leakage or internal bleeding. Fluid
resuscitation is crucial and should be initiated first. However, vasopressor (e.g.
dopamine, noradrenaline) may be considered when a mean arterial pressure is
persistently <60 mmHg despite adequate fluid resuscitation. 123

CAUTION: While vasopressors increase the blood pressure, tissue hypoxia may
be further compromised by the vasoconstriction. Instituting inotropic support
without fluid repletion may be detrimental.

Formula: MAP (Mean Arterial Pressure) = DBP + 1/3 (SBP - DBP)

DBP = diastolic blood pressure; SBP = systolic blood pressure

Volume overload, seen towards the end of the critical phase and subsequently,
provokes an important patho-physiological consideration.

It can be argued that in the face of normal cardiac & renal function, it is difficult to
overhydrate a person to an extent that pulmonary edema results. Kidneys are very
efficient in getting rid of extra volume. Volume over load in the recovery phase of
dengue theoretically may be explained by the following:

 Renal status in dengue related volume overload is akin to that of post-surgery

patient with poor volume handling.

 Extravasated fluid is protein rich and exerts its own colloidal osmotic pressure
thereby retaining fluid in the third space, only to be resorbed through lymphatics.
Balance between extravasation and reabsorption may be critical in determining
the circulatory volume.

7.7.3 Safety and risk – a guideline for invasive procedures

a. Central venous catheter (CVC) insertion

Volume resuscitation alone would not be a justification for CVC if adequate peripheral
intravenous access can be obtained (e.g. 14 – or 16-gauge intravenous catheters).
Assuming that the diameter stays equal, peripheral intravenous catheter may provide a
better flow rate because of a shorter length.124

There are no studies that would, specifically, address the (bleeding) risks of invasive
procedures in dengue patients. In general, thrombocytopenia and other bleeding
diathesis are relative contraindications for placement of CVC. A high femoral, low
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internal jugular and subclavian venous punctures are difficult to compress and thereby,
confer an increased risk of uncontrolled bleeding. However, studies have shown that
there are significant variations (0 - 15.5%) in the risk of bleeding in patients with
different coagulopathy.125, 126, 127, 128, 129

When CVC is indicated in dengue patients (e.g. poor peripheral venous access,
requirement of vasopressors, monitoring of CVP in critically ill and surgical patients) it
should be inserted by an experienced operator and under ultrasound guidance if
available.130, 131

There are multiple insertion sites to choose from: femoral 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 for a patient with a bleeding diathesis132, 133

Recommendation

 Volume resuscitation does not require a central venous catherization (CVC) if

sufficient peripheral intravenous access can be obtained.

 When CVC is indicated, it should be inserted by a skilled operator, preferably

under ultrasound guidance if available.

 Subclavian vein cannulation should be avoided as far as possible.

b. Arterial catheter insertion

Intra-arterial cannulation provides additional advantage of continuous arterial pressure

monitoring and repeated arterial blood gas sampling. It has a very low incidence of
bleeding (1.8 – 2.6%) 134

Recommendation

An arterial catheter should be inserted in DSS patients who require intensive monitoring
and frequent blood taking for investigations.

c. Gastric tube

It is hard to imagine a reason for NG tube in dengue; but if a NG tube is required, the
nasogastric route should be avoided. Consider orogastric tube as this is less traumatic.
60 | P a g e  
 

d. Pleural tap and chest drain

Intercostal drainage of pleural effusions should be avoided as it can lead to severe

hemorrhage and sudden circulatory collapse.135

Recommendation

Intercostal drainage for pleural effusion is not indicated to relieve respiratory distress.
Mechanical ventilation should be considered.

e. Metabolic acidosis:
 

Patient could be in shock even with normal blood pressure as the leakage happens
slowly over hours and body compensates well by peripheral vasoconstriction to
maintain the mean arterial pressure. Thus, compensated metabolic acidosis is an
early sign of shock due to leakage or bleeding. Lactic acidosis due to tissue hypoxia
and hypoperfusion is the most common cause of metabolic acidosis in dengue shock.
 

Monitoring of blood lactate levels is commonly carried out in patients with severe
dengue. A lactate level of <2 mmol/L in a critically ill patient generally implies that the
patient has adequate tissue perfusion, although higher levels are not necessarily the
result of tissue hypoxia.
 

Correction of shock and adequate fluid replacement will correct the metabolic acidosis.
If metabolic acidosis remains uncorrected by this strategy, one should suspect severe
bleeding, liver failure, acute kidney injury, sepsis, cardiac dysfunction, drugs (e.g. beta2
agonists, metformin) and hyperchloraemic metabolic acidosis.
Hyperchloraemia, caused by the administration of large volumes of 0.9% sodium
chloride solution (chloride concentration of 154 mmol/L), may cause metabolic acidosis
with normal lactate levels and present as a normal anion gap metabolic acidosis. If
serum chloride levels increase, change the fluid to balanced solution such as
sterofundin or Hartmann’s. This improves chloride-related acidosis. Sodium bicarbonate
for metabolic acidosis caused by tissue hypoxia is not recommended for pH >7.1.
Bicarbonate therapy is associated with sodium and fluid overload, an increase in lactate
and pCO2 and a decrease in serum ionised calcium.
 

A delay in lactate clearance or persistent lactate elevation is associated with poor

outcome. Persistent lactic acidosis contributes to myocardial depression, arrhythmias,
vasodilatation, increase in respiratory muscle workload, reduced oxygen delivery,
decreased ATP production and multi-organ failure.
 
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A likely more useful parameter for guiding therapy is lactate clearance. Lactate
clearance is calculated as follows: 136

Lactate initial - lactate subsequent X 100%

 
Lactate initial

A 20% clearance in two hours improves survival.

 

f. Arterial blood gases:

 

Arterial blood gas (ABG) analysis is frequently done (2-4 hourly) in patients with shock
mainly for detection of worsening acidosis by looking at base excess, bicarbonate, CO2
and lactate. Mixed respiratory alkalosis with metabolic acidosis (CO2 lower than
expected) commonly seen in liver failure, dengue encephalitis and sepsis. This is seen
in patients with pleural effusion and moderate ascites as they are tachypnoeic.
Hypoxaemia is a guide to warn us of fluid overload, pleural effusion and interstitial
oedema.
 

8. DISCHARGE CRITERIA
The following criteria are to be taken into account while contemplating a discharge of a
dengue patient.87, 85

Discharge criteria (Appendix 6b):

 Afebrile for 48 hours (without antipyretics)

 Stable general condition and vital signs. (Pulse < 90/m, PP >30mmHg)

 No or minimal visible bleeding in last 24 hours

 No dyspnea or respiratory distress attributable to pleural effusion or ascites

 Fully recovered organ dysfunction

(ALT, AST < 2 times normal S. Creatinine < 1.5mg/dl)
 Stable hematocrit for at least 24 hours

 Rising trend in platelet count (PLTs > 40,000)

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9. PREVENTION OF DENGUE TRANSMISSION IN

HOSPITALS
Patients are viraemic and hence potentially infectious during the febrile phase.137, 138

There are a few small studies that demonstrate higher 139, 140 levels and prolonged
duration of viraemia in patients with DHF. There are no scientific studies that address
the efficacy of mosquito repellents or mosquito netting in reducing dengue transmission
in hospitalized patients. However several community studies have shown that the use of
mosquito netting/screening was efficacious in preventing transmission of dengue in the
community.140, 142

Generally, repellent products with higher concentrations of DEET (N,N,diethyl-m-

toluamide) were found to have longer repellence times.143

A consensus dengue guideline advised the use of mosquito netting or repellent day and
night for hospitalized dengue patients to reduce nosocomial infection.85
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10. VACCINATION
Dengue is the world's fastest-growing infectious disease, afflicting up to 100 million
people worldwide, causing half a million life-threatening infections and killing up to
25,000 people, mostly children, each year. There are four distinct types of dengue. First
infection with any one of them can increase the chances of severe disease in secondary
infection when exposed to a different serotype. With no specific antiviral treatment,
vaccination seems to the only effective measure to control dengue.155

For a vaccine to be effective for its treatment, it must protect against all four types at
once. A weak response to one of them could act like a first infection and leave a person
vulnerable to severe disease when exposed second time.156

In December 2015, Dengvaxia, the world’s first vaccine against dengue virus developed
by French pharmaceutical company Sanofi Pasteur, was licensed and approved for use
in 19 dengue endemic countries for individuals 9 years of age and older. Vaccine
recipients with evidence of prior dengue infection benefited from vaccination, exhibiting
a substantial cumulative decrease in hospitalized and severe dengue. However, vaccine
recipients without such infection were shown to have an increased risk of hospitalized
and severe dengue specially in third year after vaccination. This was very serious
concern and led to withdrawal of this vaccine from market from many countries. 156, 157

Immunity conferred by vaccine is also variable in different serotypes, ranging from

47.1% for serotype 2 to 83.2% for serotype 4. In addition, it is not approved for use in
less than 9 years of age. Owing to its non-convincing data on efficacy, long term safety
and increased risk of sever dengue in naïve population it is not recommended by
DEAG.156

The other two vaccine trials in pipeline are by Takeda and NIH with results expected
end of this year.158
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11. DENGUE FEVER IN PEDIATRIC POPULATION

The pathogenesis of Dengue Fever and the principles of management apply equally to
both children and adults. In the pediatric population, special consideration has to be
given to the weight of patients because of its wide variation. Fluid quota, therefore, has
to be carefully calculated keeping in mind the weight of the patient. In the dehydrated
child the measured weight may not be true representation of the actual weight of the
child. Additionally, the ideal body weight of a child may not be the same as the actual
weight.

11.1.1 Calculation of Ideal Body Weight

Estimation of the ideal body weight may be made by any of the following ways:
 Weight for height using a growth chart (50th centile) - Best Method
 Weight for age using a growth chart (50th centile)
 In an emergency situation use the following formulae:

<1 year Age (in Months)+ 9

2
< 7 years (Age x 2)+ 8
> 7 years Age x 3
APLS (Age + 4) x 2

The weight chosen for calculation should be the current weight or ideal body weight,
whichever is lower.

Following illustrates calculation of fluids for critical period in a Child:

Calculation of total fluids for critical period
M (Maintenance) 100 ml/kg for 1st 10 kg
+50 ml/kg for next 10 kg
+20 ml/kg for balance wt
Deficit
(5% of body weight) +50 ml x body wt (kg)
Example
Fluid requirements for a child with a weight of 25 kg will be as under:
(This is the ideal or actual body weight, whichever is smaller)

Maintenance =100 x 10 + 50 x 10 + 20 x 5 = 1600 ml

Deficit 5% = 50 x 25 = 1250 ml
M + 5% = 1600 + 1250 = 2850 ml
This is the total fluids for the entire critical period irrespective of its length.

The maximum weight for which fluid is calculated in any patient should not exceed 50
kg. Accordingly, M+5% should not exceed 4600 ml in any patient (adult or pediatric).
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11.1.2 Choice of fluids

Use half normal saline (N/2) in 5% dextrose in infants less than 6 months of age
because of poor sodium handling by immature kidneys.

For children above 6 months of age, when the patient is not taking orally for prolonged
periods, it is useful to give normal saline in 5% dextrose to avoid hypoglycemia.

11.1.3 Rate of administration of IV fluids in critical phase –

without shock

 Upon entering the critical phase shift to HDU and start IV fluids.
 Initial fluid requirement (oral + IV) is 1.5 ml/kg/hr. Those who can drink well may
be given IV fluids at the minimal rate 0.5ml/kg/hr and the balance as oral.
 Calculation of fluid quota (M+ 5%) is for entire critical phase. If the patient has
been in the critical phase for some time, calculate the remaining volume of fluid
keeping in mind the duration of critical phase elapsed and the amount of fluid
already given.
 Rate of infusion depends on the rate of leak judged by pulse, BP, pulse pressure,
capillary refill time, HCT and urine output.
 Urine output should be maintained between 0.5 -1 ml/ kg/hour during the critical
period. 

Hourly urine output is the best guide to decide the rate of infusion. If UOP is above one
ml/kg/hour itsuggests that infusion rates are too high. If the UOP is<0.5ml/kg/hr it may
suggest inadequate fluids. Catheterization may be required for accurate UOP
measurement.

* There is wide variation in the rate of leak from patient to patient and within the same
patient over period of time.
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(Chart below may be used as a guide for patients with shock while remembering that
there is wide variation in rate of leak from patient to patient)

Courtesy of WHO Collaborating Centre for Case Management of Dengue/DHF/DSS,

Queen Sirikit National Institute of Child Health, Bangkok, Thailand (Fluids for
adolescents are mentioned with-in brackets.)

11.1.4 Intravenous fluid replacement – during shock (refer to

Algorithms for Dengue Shock Syndrome)
 Patient who is in significant shock might well be in a stage of plasma leak for
considerable length of time, therefore he might stop leaking much earlier than 48
hours.

 Individual patient's fluid rates administered will depend on his/her rate of leak –
as judged by the pulse pressure and urine output.
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 Remember that total fluid quota (M+5%) would not only include the IV fluids but
also the bolus fluids given during resuscitation and any administered orally.

(Chart below may be used as a guide for patients with shock while remembering that
there is wide variation in rate of leak from patient to patient)

Courtesy of WHO Collaborating Centre for Case Management of Dengue/DHF/DSS,

Queen Sirikit National Institute of Child Health, Bangkok, Thailand

11.2 Special Considerations for Infants

 DHF/DSS is less common in infancy but mortality is higher than in older children.

 There are very few published studies on fluid management in DHF in infant.

 Physiologically speaking, fluids account for a greater proportion of body weight

in infants than in children and minimum daily requirements are correspondingly
higher.

 Infants have lower intracellular fluid reserves and the capillary beds are
intrinsically more permeable than in older children and adults.
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 Early cardiovascular compromise and significant fluid overload are more likely to
occur if capillary leak occur in this age group.
 Babies born to mothers who have dengue fever near delivery will have circulating
antibodies due to trans-placental passage. In such babies DHF may develop
even during first infection due to antibody-dependent enhancement of viral
replication mediated by the antibodies of maternal origin.

 Like in adults, primary dengue infection in infants often presents as simple fever,
indistinguishable from other viral infections. Maculopapular rashes may
accompany the fever or may appear during defervescence. Upper respiratory
and gastrointestinal symptoms (gastroenteritis) may be seen. Unusually, infants
may present with seizures.

 Splenomegaly has been observed in young infants (especially under six months)
clinically or by radiological examination (USS).

 Leucopenia may not be present; instead the total white cell count may be high -
reaching up to 18-19 x 103.

 Infants are more likely to have liver involvement with AST in the range of 200 –
500 (may occasionally rise to > 1000).

 They are also more prone to electrolyte Imbalance due to poor renal handling of
Na+.
As compared to older age group, infants experience plasma leakage for shorter duration
and respond quickly to fluid resuscitation. The volume actually required may be less
than the calculated quota of M + 5%. Fluid administration in infants should be evaluated
meticulously and oral intake (i.e. breast feeding) taken into account 135. Intravenous
fluids should be stopped as soon as the leaking phase is over – in order to avoid the
risk of fluid overload. All infants with dengue fever must be treated as high-risk patients
in HDU and they all would require early intervention with colloids, as compared with the
older children with severe disease. 

 
Dengue in infants: Difference from the adult presentation
 
Fits are more common URT, or GI features predominate

Leucocytosis rather than leucopenia More prone to plasma leak

More prone to electrolyte imbalance Hepatomegaly and deranged LFTs are

(particularly sodium) more common
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12. DENGUE FEVER IN PREGNANCY

There are very few studies addressing the management of dengue in pregnancy.
Generally the presentation and clinical course of dengue in pregnant women is similar
to that in non-pregnant individuals. 150, 151
However, the signs and symptoms may be confused with other complications of
pregnancy such as toxemia, Hemolysis, Elevated Liver Enzymes, Low Platelets
(HELLP) syndrome.96 There are some reports of an increased incidence of prematurity,
in-utero death and abruptio placenta in these women.151, 152 The following physiological
changes in pregnancy may make the diagnosis and assessment of plasma leakage
challenging:

• Elevation of HCT in dengue is masked by hemodilution due to increase in plasma

volume especially in the 2nd and 3rd trimester. Serial HCT measurement is crucial for
disease monitoring in pregnancy.

• The detection of third space fluid accumulation is difficult due to the presence of gravid
uterus.

• Baseline blood pressure is often lower and pulse pressure wider

• Baseline heart rate may be higher

Management of infected pregnant patients close to delivery:

Risk of bleeding is at its highest during the period of plasma leakage (critical phase). If
possible, avoid Lower Segment Caesarean Section (LSCS) or induction of labor during
critical phase (plasma leakage).96 Procedures/maneuvers that may provoke or augment
labor should be avoided during this critical phase.
Care for the mother should be provided in a multidisciplinary way in an area of the
hospital where there are trained personnel available to handle labor and its
complications.
The baby should be observed for vertical transmission of dengue after delivery.93

Recommendation

All pregnant women with suspected dengue infection must be admitted.

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13. DENGUE FEVER IN IMMUNOCOMPROMISED

PATIENTS
Despite the high prevalence of dengue fever in endemic regions, it is infrequently
reported in immunocompromised patients. It is possible that there is under reporting in
these populations due to overlapping sign and symptoms, such as skin rash, cytopenia,
and fever, are commonly attributed to others related co-morbidities159
A working definition of immunocompromised states would be:

1. Patients on cancer chemotherapy

2. Solid organ transplant patients undergoing anti-rejection therapy
3. Bone marrow transplant patients undergoing anti-rejection therapy
4. Primary/congenital immunodeficiency disorders
5. Chronic steroid therapy (≥ 7.5 mg prednisolone per day for ≥ 3 weeks or
equivalent doses of other steroid).
6. Auto-immune diseases undergoing treatment with immunomodulator/immune
suppressive medicines
7. HIV/AIDS with CD4 count < 200 (severe immune deficiency), between 200-500
(mild to moderate immune deficiency)
8. The following conditions may not be considered to have significant
immunosuppression
a. Use of corticosteroids (< 2 weeks) or when corticosteroids were stopped
more than one month prior
b. HIV patients with CD4 count > 500
c. Patients with leukemias/lymphomas/lymphoreticular diseases whose
disease is in remission and last chemotherapy was more than 3 months
prior
d. Patients with bone marrow transplant done > 2 years prior and not taking
any immunosuppressive medications AND without graft versus host
disease

13.1. Management guidelines

1. Clinical presentation of dengue in immunocompromised patients seems to be similar

to that in immunocompetent individuals, except for a few differences:

 Except for fever, other typical symptoms of dengue such as abdominal pain,
myalgias, and headaches may be absent161
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 Viremia is prolonged as a result NS1 and PCR stays positive for a longer
period of time: IgM response may be absent with consequent diagnostic
confusion
 Neutropenia and thrombocytopenia may be more marked and platelet
recovery can be delayed.159

2. Unusual presentations of dengue infection do occur but does not seem to be as

common as in other infections
3. Diagnosis of dengue poses a major challenge in neutropenic patients with fever
because of similar clinical presentations.161 Hence laboratory confirmation of dengue
is important in these patients.159 A high index of suspicion should be maintained in
all immunocompromised patients living in endemic areas, who develop fever,
unexplained volume loss, anuria and hypotension or other related symptoms.
4. Limited data suggest similar sensitivity and specificity of diagnostic tests as in
immunocompetent individuals. PCR can be used in immunocompromised
populations even after 1st week because of the prolonged viremia.160
5. Principles of treatment and prevention remains the same as in immunocompetent
individuals
6. Individuals with severe neutropenia (absolute neutrophil count below 500) and fever
(above 38.3C) may be given empiric antimicrobial cover with an antibiotic, as per
standard guidelines for such patients (e.g. IDSA guidelines for febrile neutropenic
patients)
7. Because no prospective study of dengue has been conducted in these populations,
the actual morbidity and mortality of dengue is unknown in this patient population.
13.2. Potential immunocompromised state in dengue fever patients

1. This may be due to neutropenia as a result of Dengue

i. Management principles of treatment would be as per standard

guidelines, PLUS

ii. Empiric use of antibiotics may be considered, (after blood has been
drawn for culture and sensitivity in individuals with severe
neutropenia - absolute neutrophil count below 500 – PLUS fever of
more than 38.3oC.
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14. ANTIHYPERTENSIVE TREATMENT IN DENGUE

FEVER:
1. Patients with uncomplicated hypertension, once diagnosed to have Dengue
Fever (irrespective of plasma leak) should stop taking diuretics as soon as the
diagnosis is suspected. Patients taking diuretics for other reasons (Chronic heart
failure, valvular lesions, etc.) should be evaluated individually.

2. Other antihypertensive agents (beta blockers, Calcium channel blockers, ACE

inhibitors) may be continued with frequent monitoring of blood and pulse
pressure at home - (at least 6 hourly). For in hospital management refer to
Appendix 2

3. A declining trend in blood pressure or pulse pressure on two consecutive

occasions should be taken as warning sign for the patient at home or the GP to
refer to a better equipped health facility.

4. Dengue related hospital admissions, taking antihypertensive treatment, should

be monitored regularly as per monitoring charts. Appendix 2

5. Fall in pulse pressure ≤30 mm Hg indicates that patient may be developing

hemodynamic instability. If blood pressure measured on 3 successive occasions
at hourly intervals reveal PP to be ≤30 mm Hg; Stop All antihypertensive
treatment - patient monitored as per Appendix 2b.

6. Once the pulse pressure starts rising above 30mm Hg, depending upon the
clinical judgment, antihypertensive medication may be carefully reintroduced.
One may like to choose shortest acting agent, from within the class of
antihypertensives, patient was already taking; avoiding diuretics.

7. Once the patient is stable and in convalescent phase regular anti hypertensives
may be reintroduced one by one according to the clinical status.

 Diuretics should be stopped as soon as the probable diagnosis of dengue is

made.

 Other anti-hypertensive treatment may be continued if the Pulse Pressure

stays above 30 mm of Hg.

 In case the Pulse Pressure drops, ≤30 mm Hg, stop all anti-hypertensive
treatment and introduce monitoring –Appendix 2b.
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15. DENGUE FEVER IN PATIENTS ON

ANTITHROMBOTIC THERAPY 152
A significant number of patients with cardiac ailments would be on long term anti-
coagulants/antithrombotic treatment. Management of these patients, in case of dengue
virus infection, needs careful considerations. Risk of significant bleed during DF may be
compounded by anticoagulation/antithrombotic treatment. While hemoconcentration and
rising HCT can be prothrombotic.

From the perspective of clinical management, the need of anti-coagulation /

antithrombotic treatment could be obligatory in high risk group and non-obligatory in the
low risk group.

As a general rule acetyl salicylic acid should be avoided in patients with DF

because of worsening of complications from thrombocytopenia and bleeding –
unless patient is at a high risk of thromboembolism. 

High risk patients - need of anti-coagulation obligatory:

Following group of patients have high risk for thrombotic complications:

1. Patients with recent coronary angioplasty with stent placement (one month for
bare-metal stents and three to six months for drug-eluting stents)
2. Patients with mechanical valve prostheses, particularly in the mitral or tricuspid
positions,
3. Patients with chronic atrial fibrillation (CAF), previous history of thromboembolism
or with more than one mechanical valve.
4. CAF patients with multiple risk factors for thrombo-embolism (ventricular
dysfunction, increased age, hypertension, diabetes, valvopathy, previous stroke,
or intra-cavity thrombus).

For this high-risk group, the antiplatelet treatment may be continued.

High Risk patients already taking anti-platelet therapy:

 For patients who are at a high risk of thrombo-embolic event and are
already using clopidogrel and asprin these drugs should be continued.
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 Stop in case of significant bleeding.

High Risk patients needing obligatory anti-coagulation:

 In patients using warfarin, the current recommendation is to withhold it and

perform serial platelet and coagulation monitoring.
 As soon as the INR is below the therapeutic range introduce heparin to
keep INR within the desired range - continue serial platelet and
coagulation monitoring.

Even in these High Risk patients –

All anti- coagulants should be withheld if:

 Platelet count falls below 50,000/mm3

 There is clinical or laboratory evidence of bleeding
 Patient is in shock.

Low risk patients - need of anti-coagulation non-obligatory:

These patients exhibit minimal short-term risk for thrombo-embolic event:

1. Stable coronary artery disease patients

2. Patients with coronary angioplasty with a stent emplacement more than six
months previously
3. Chronic Atrial Fibrillation patients without additional risk factors (or with a single
risk factor) for thromboembolic event;
4. Patients with biological valve prosthesis

Current recommendation for the low risk group is to withhold asprin and consider
withholding clopidogrel and warfarin for one week.
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16. DENGUE IN PATIENTS WITH RENAL DISEASE

Dengue infection manifests in more severe form in patients with pre-existing renal
dysfunction and the outcome is also poor. Various case reports and a retrospective
review have found a higher possibility of DHF/DSS when infection occurs in patients
who already have chronic Kidney disease. The mortality is also much higher. In a study
the CKD patients with Dengue infection had higher (28.6%) death rate than non CKD
group (1.2%).163

Fluid management will be more cautious in these patients to avoid volume overload.
This aspect has not been studied in trials. It is recommended that the maintenance fluid
should be equal to daily insensible losses (~700 ml) and 5% quota should be made 50%
initially. Further adjustment may be made according to hemodynamic status and urine
output of the patient.

Acute Kidney Injury (AKI) is found in more than 10% of patients with Dengue
Hemorrhagic fever and Dengue Shock Syndrome. The usual etiology is dehydration and
hypovolemia caused by capillary leak and, in some cases, rhabdomyolysis resulting in
Acute Tubular Necrosis (ATN). Glomerular involvement is also now well described in
animal models and human beings. Immune complex deposition and direct entry of virus
particles in renal tissue, both have been found on histopathology. Presence of
proteinuria and /or hematuria differentiate acute glomerulonephritis from ATN.
Treatment of renal involvement in Dengue fever is supportive. 164
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17. SURGERY IN DENGUE

Algorithm for Surgical Management in Dengue Patients 
Defer all elective procedures until platelet count is within normal limits 
Emergency surgery

Get urgent CBC, HCT, platelet count, blood glucose, serum calcium, blood for grouping and cross matching, ultrasound 
chest and abdomen  

Dengue Fever (no evidence of leak)  Dengue Fever in critical phase  Dengue Shock 

(plasma leak but no shock) 

Platelet management  
Fluid management   Resuscitate the patient (Algorithms for 
*Start with maintenance     Dengue Shock Syndrome) to achieve 
fluids Monitor   heamodynamic stability.  Perform only 
Platelet count more  Platelet count less than   UOP (keep between    damage control surgery if utmost 
than 50,000  50,000  0.5 to 1ml/kg/hr)   necessary. 
 MAP>60mmHg 
 HCT(measure 3 hrly) 
Transfuse 1 bag of single donor   CVP(measure ¼ hrly) 
platelet 

Proceed with surgery  Urine output 
(One bag of single donor platelets on standby)  < 0.5ml/kg/hr‐ increase rate of maintenance fluids > 1ml/kg/hr 
‐ consider decreasing rate of maintenance fluids   
Complications: (Consider when no improvement) 
Pulse Pressure ≤ 30‐ follow Algorithms for Dengue Shock 
A: Acidosis If the arterial blood bicarbonate 
(HCO3)  falls  below  15  meq/l 
Syndrome as appropriate 
give  NaHCO3  (8.4%)  1ml/kg, 
diluted in equal volume of saline  HCT– Falling HCT consider whole blood transfusion 20ml/kg 
as  slow  bolus  (10  ml  /dose–  
maximum upto 5 doses)           ‐ Volume overload with falling HCT 10 ml/kg PCV 

B: Bleeding Consider  Whole  blood  (10 

ml/kg) or packed cell (5 ml/kg)  CVP (maintain between 10 – 14 cm of water) 
 Rising trend – consider decreasing rate of i.v fluids &    
C: Hypocalcemia  Check serum calcium and QT  furosemide 0.5mg/kg if BP is normal 
intervals Give 10% calcium   Falling trend – consider increasing rate of i.v fluids 
gluconate. Dose 1ml/kg/min, 
–consider whole blood transfusion if HCT 
max 10ml at one time, repeat 6 
hourly if needed.  falls ≥ 10 points                                                    
S: Sugar Levels Monitor  Blood  Sugar  levels  and  from base line 
manage accordingly.
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18. CRITICAL TECHNOLOGICAL INTERVENTIONS IN

DENGUE CONTROL PROGRAM
The episodes of dengue outbreak present a general wellbeing challenge, particularly in
developing countries like Pakistan. The recurrence of such outbreaks increased over
the last several years calling for the need to reinforce the notifiable diseases
observation and reporting framework. Any good reporting framework is practical only if it
has the ability to process, consolidate, and present all the reporting variables timely and
accurately.

PITB brought IT expertise to anti-dengue campaign and laid down the basis for
modernization of data consolidation and reporting methodologies with special emphasis
on user-friendliness for the people who work to prevent and contain dengue infections.
The four portals developed by PITB are Dengue Tracking System, Health CMS, Vector
Surveillance System and Dengue Patient Portal. These systems help in the following
ways

18.1. Larvae detection and geo-tagging of surveillance activities

The scope of the monitoring and surveillance activities has increased over the last
several years with their work becoming useful in keeping a tab on Aedes Aegypti (the
mosquito that can carry dengue virus among others) population having special focus on
sites likely to provide favorable breeding conditions and habitat.

Dengue monitoring and surveillance staff across Punjab is registered on Dengue

Tracking system in which the work carried out is reflected in pre-defined sections and
reports. The monitoring teams have been equipped with Android phones. These mobile
phones are used to tag, map and upload activities digitally in real time. The team that
performs the activities takes before and after-the-activity pictures with android handsets;
these pictures are then geo-tagged on the particular location (latitude and longitude)
and uploaded on the portal. This mechanism limits fake reporting. These users have to
conduct at least 30 activities for every working day as per established SOPs. The user
wise activities report enables identification of resources who fall short of their targets.
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The activities report and maps are essential features of discussion at various anti-
dengue platforms aimed at optimizing and enhancing the work efficiency.

A Hotspot regime was introduced to further strengthen the surveillance and monitoring
system. The high-risk areas or sites which are known to provide conducive environment
for Aedes Aegypti mosquito were termed hotspots and it was agreed that these
hotspots should be visited at least once a week to ensure timely reporting and
eradication of Aedes Aegypti larvae population.

Indoor Surveillance teams are tasked with door to door surveillance. The teams visit
random houses in their respective domains where each one of them inspects water
bodies such as bathtubs, water buckets, bathrooms, fridge trays, water coolers, AC
water outlets, lawns, stores and any other site likely to host favorable habitat for dengue
mosquito population. All these surveillance activities are photographed and geo-tagged
on Dengue Tracking System. The respective house owners/ keepers are also cautioned
to ensure cleanliness in their homes and surroundings to prevent disease occurrence.

The component is extremely important even in winters when mosquitoes tend to stay
indoors in the environment normally made conducive due to domestic climate control.
PITB’s system pinpoints polygons with minimal to no indoor surveillance and outlines
geographical regions needing attention. In addition to micro plans developed by
districts, the geographical regions identified by this information system identify
additional areas requiring attention.
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The screenshots above depict the indoor larvae reporting mechanism.

Sample Polygons for district Rawalpindi with activity count

The monitoring and evaluation teams are also regularly monitored and supervised by
inspectors and entomologists ensuring quality of the reported work utilizing different
type of reports based on district activities, department activities, town activities and case
evidence reports. The geo-tagging and mapping of anti-dengue activities enable
identification of areas, regions which are overlooked or where surveillance is not
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conducted in line with agreed SOPs. The missing area reports being a key reporting
indicator are a regular feature of discussion at various anti-dengue campaign platforms.

18.2. Satscan Alert –the prediction of a possible outbreak

Satscan alert is formulated on the basis of parameters that help in identification of the
particular area from where a possible outbreak can occur. The parameters that are used
are weather data and the density of positive larvae in a particular area.

The alert is sent to all the concerned authorities so that preventive measures can be
taken in that particular area.

The below snapshot illustrates one such case, a few positive larvae were detected from
an area and after a few days, on 12thof September the satscan alert was auto generated
from this area. On 17thof September of that year, a confirmed patient was reported.

Sep 1 to Sep 7 Larvae Incidence: Sep 12 Confirmed Patient: 17 Sep 

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18.3. Patient reporting, tagging and case evidence

PITB has also developed a patient portal. The access to this patient portal is provided to
all the hospitals of Punjab. The portal contains the information about the patients’
demographics, clinical information, laboratory information, diagnoses and a unique id.

The field officers geo-tag the residence and workplace locations of confirmed patients.
This tagging is depicted on the maps provided in the dengue portal. With the help of
these geo-tagging IRS (the insecticide sprays) are carried out and this spraying activity
is in turn geo-tagged to monitor this case response. This exercise enabled by
technology prevents further infections in the vicinity of confirmed patients.

The following pictures show this workflow of patient location and subsequent IRS geo-
tagging.

Third party validation (TPV) through Dengue android application is an essential step to
monitor if confirmed patient or positive larvae case response has been carried out as
per SOPs or not. The system allows TPV users to mark if the carried-out activity is
according to SOPs and record their findings.
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18.4. Vector Surveillance System and Breteau Index report

Prevention of dengue infections is possible with a proactive approach to eliminate the

conditions conducive to the presence and breeding of Aedes Aegypti mosquito
population. It requires extensive monitoring and surveillance. A large number of
monitoring and surveillance teams are deputed. They are required to furnish details of
the sites / spots / houses inspected for presence of larvae.

The data uploaded on Vector Surveillance System is available in the form of reports
based on date and time and/or districts, towns and all the way down to union councils.
In addition, Breteau Index Report is also available in this system indicating areas which
need immediate attention.

18.5. Monitoring the anti-dengue activities through Complaint Management

System

Health helpline (0800-99000) has evolved into Health Complaint Management System
(CMS) which serves as a platform where citizen complaints are logged, categorized and
reflected on the basis of districts, towns, responsible agencies, departments, elapsed
time etc. The Health CMS is available to all allied departments as an additional tool for
dengue prevention and control.

To assess the performance of various departments in anti-dengue campaign, Dengue

Virus Report (DVR) app was introduced. This app allows logging of complaints as an
alternative to helpline. In addition, this system also manages the lifecycle of complaint
from logging to resolution. The Special Branch of Police Department uses this app for
logging complaints about the areas that are conducive to larvae breeding yet not visited
by responsible department. The app features pictorial evidence, real time tracking and
mapping of activities pertaining to resolution of any reported instance. The automation
has enabled resolution of most of the complaints within 24 hours from the time of the
complaint being initially lodged.

 
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USE OF APPENDICES 1 TO 5: 
Appendix  1a:  Dengue  Fever  Proforma  after  Admission  –  To  be  used  in  admitted  patients  for 
summarizing investigations in conjunction with patient case notes 

Appendix  1b:  Radiology  Request Form  –  To  be used  for  requesting  and  reporting evidence  of 
plasma leak in patients in critical phase 

Appendix 2: Dengue Monitoring Charts – To be used for monitoring admitted patients  

                 2a: DEAG DF Form – 1 to be used in admitted patients during Febrile Phase 

                 2b: DEAG DF Form – 2 to be used in admitted patients during Critical Phase/Shock  

Please note that monitoring parameters remain the same as in previous charts but monitoring 
is required at 15 minutes intervals. 
 
Appendix 3a OPD Form: To be used in patients presenting in the out‐patient department.  Text 
boxes may be appropriately ticked to arrive at the diagnosis of suspected, probable or 
confirmed dengue fever. 

Appendix 3b Form I: To be used for history taking, examination and documenting relevant 
investigations in admitted patients with dengue fever.   

Appendix 4: Reporting forms to be used for reporting dengue fever patients to the EDO/office 
of the Director General Health 

                  4a: Reporting Form (R) to be used in patients who have suspected or probable 
disease based on the criteria given on the form but without confirmatory evidence 

                   4b: Reporting Form to be used in patients who have confirmatory evidence of 
dengue fever. Criteria for confirmation are as given in the form. For each confirmed case 
detailed information must be documented as given in the form. 

                  4c:  SOP for Reporting Dengue Patients – Gives steps to be taken from diagnosis of 
dengue fever to electronic reporting of cases in hospital setting. 

Appendix 5:  Dengue Diagnostic Criteria – To be used during none epidemic phase and epidemic 
phase . Please note that diagnostic criteria may need revision from time to time and may be 
different during an epidemic.
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APPENDICES  
APPENDIX 1a Dengue Fever Proforma after Admission
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APPENDIX 1b Radiology Request Form

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APPENDIX 2 Dengue Monitoring Charts

2a. DEAG DF Form -1 (to be filled 4 days data)
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2b. DEAG DF Form – 2 (To be filled 48 hours data)

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APPENDIX 3a OPD Form

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APPENDIX 3b Inpatient Form

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APPENDIX 4a Reporting for Dengue Patients (Suspected & Probable)

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APPENDIX 4b Reporting Form for Dengue Patients (Confirmed)

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APPENDIX 4c
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APPENDIX 5 Diagnostic Criteria – Non Epidemic Setting

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APPENDIX 5 Diagnostic Criteria – Epidemic Setting

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APPENDIX 6a
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APPENDIX 6b
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APPENDIX 9

 
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APPENDIX 8a
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APPENDIX 8b
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APPENDIX 9
World Health Organization Classification of DF and DHF (1997) 9

CASE DEFINITION FOR DENGUE FEVER

Given the variability in the clinical illness associated with dengue infection, it is not
appropriate to adopt a detailed clinical definition of dengue fever. Rather, the need for
laboratory confirmation is emphasized.

The following classifications are proposed:

• Probable

– An acute febrile illness with two or more of the following manifestations:

- Headache - retro-orbital pain

- Myalgia - arthralgia

-Rash - hemorrhagic manifestations

- Leucopenia

AND

- Supportive serology (a reciprocal haemagglutination-inhibition antibody titre = 1280, a

comparable IgG enzyme-linked immunosorbent assay (ELISA) titre or a positive IgM
antibody test on a late acute or convalescent-phase serum specimen)

OR

- Occurrence at the same location and time as other confirmed cases of dengue fever

• Confirmed – a case confirmed by laboratory criteria (see below).

• Reportable – any probable or confirmed case should be reported.

Laboratory criteria for confirmation of dengue fever are

• Isolation of the dengue virus from serum or autopsy samples: or

• Demonstration of a fourfold or greater change in reciprocal IgG or IgM antibody titres

to one or more dengue virus antigens in paired serum samples; or

•Demonstration of dengue virus antigen in autopsy tissue, serum or cerebrospinal fluid

samples by immunohistochemistry, immunofluorescence or ELISA;
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OR

• Detection of dengue virus genomic sequences in autopsy tissue serum or

cerebrospinal fluid samples by polymerase chain reaction (PCR).

CASE DEFINITION FOR DENGUE HEMORRHAGIC FEVER

The following must ALL be present:

1. Fever, or history of acute fever, lasting 2–7 days, occasionally biphasic.

2. Hemorrhagic tendencies, evidenced by at least one of the following:

a. A positive tourniquet test

b. Petechiae, ecchymoses or purpura

c. Bleeding from the mucosa, gastrointestinal tract, injection sites or other

locations

d. Hematemesis or melena.

3. Thrombocytopenia (100,000 cells per mm3 or less).

4. Evidence of plasma leakage due to increased vascular permeability,

manifested by at least one of the following:

a. A rise in the HCT equal to or greater than 20% above average for age, sex
and population;

b. A drop in the HCT following volume-replacement treatment equal to or

greater than 20% or baseline;

c. Signs of plasma leakage such as pleural effusion, ascites and

hypoproteinaemia.
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CASE DEFINITION FOR DENGUE SHOCK SYNDROME

All of the above four criteria for DHF must be present, plus evidence of circulatory
failure manifested by:

• Rapid and weak pulse, and

• Narrow pulse pressure [<20mmHg (2.7 kPa)]

Or manifested by:

• Hypotension for age, and

• Cold, clammy skin and restlessness.

Grade l: Fever accompanied by non-specific constitutional symptoms; the only

hemorrhagic manifestation is a positive tourniquet test and / or easy bruising.

Grade ll: Spontaneous bleeding, in addition to the manifestations of Grade l patients,

usually in the form of skin or other hemorrhages.

*Grade lll: Circulatory Failure manifested by a rapid, weak pulse and narrowing of pulse
pressure or hypotension with the presence of cold, clammy skin and restlessness.

*Grade lV: Profound shock with undetectable blood pressure or pulse.

Note: *

i. Grades III and IV are classified as Dengue Shock Syndrome

ii. The WHO classification is being reviewed and revised.

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APPENDIX 10
Methods of Sample Collection
1. Dengue Serology (ELISA)

i. Draw 3-5 ml of blood into a plain tube without anti-coagulants.

ii. Clot at ambient temperature

iii. Dispatch to the laboratory within 4 hours of collection for serum separation by
centrifugation.

Note: Hemolysed or icteric or lipaemic specimens invalidate certain test. If such

specimens are received, the samples will be rejected to assure results are of clinical
value.

2. Viral Particles Detection (PCR)

Blood

i. Collect 3-5 ml of blood into plain tube.

ii. Send directly to virology lab within 2 hours of sampling. If this is delayed, centrifuge
and aliquot serum into sterile tube. Keep the sample in a freezer at -70ºC and put in ice
when sending to virology lab the next day.

Cerebrospinal fluid (CSF)

i. Collect a minimum of 0.5 ml (5 drops) of CSF into s sterile bijoux bottle.

ii. Pack in ice for transport

iii. Send directly to virology lab within 2 hours after being taken.

iv. Send together with serum sample

Post-mortem tissue sample

Tissue specimens should be placed in a sterile container and sent immediately to the
lab. The specimens should be “snap” frozen in liquid nitrogen or in a -70 ºC bath such
as dry ice/alcohol as quickly as possible after collection. Once frozen, the tissue
specimen can be stored at -70ºC until detection by PCR.
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3. Viral Isolation
Blood

i. Draw 3-5 ml of blood into a plain tube without anti-coagulants

CSF

i. Collect at least 1 ml of CSF specimen in a sterile plain screw capped container

(universal or Bijou Bottle). Do not add in VTM or freeze.

ii. Pack the specimen individually in biohazard plastic bag and keep in 4ºC or in cold box
with ice.

iii. Send to the lab within 24 hours after collection.

Tissue or post mortem tissue

i. Put the tissue in sterile container screw capped tight to avoid drying of tissue. Do not
add in VTM

ii. Packed the specimen individually in biohazard plastic bag and keep in 4ºC or in cold
box with ice.

iii. Send to the lab within 24 hours after collection

• Inform the laboratory processing the samples that the case was fatal

• Obtain a blood sample to attempt virus isolation and serology

• Obtain tissue samples for separate tests of virus isolation and

immunohistochemistry
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APPENDIX 11 - Clinical Case Classification

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APPENDIX 12
Home Care Advice Leaflet for Dengue Patients
Front View

HOME CARE ADVICE FOR DENGUE PATIENTS

What should be done?
 Adequate bed rest
 Adequate fluid intake (more than 5 glasses for an average person)
- Milk, fruit juice (caution with diabetes patients) and isotonic electrolyte
solution (ORS) and barley water
- Plain water alone is not sufficient and may cause electrolyte imbalance.
(Nicaragua 2003, Level 8)
 Take Paracetamol (not more than 4 gram per day)
 Tepid sponging
 If possible, use mosquito repellent or rest under a mosquito net even
during day time to prevent mosquito bites
 Look for mosquito breeding places in and around the home and eliminate
them
What should be avoided?
 Do not take non-steroidal anti-inflammatory (NSAIDs) e.g. aspirin /
Mefenamic acid (Ponstan) or steroids. If you are already taking these
medications please consult your doctor.
 Antibiotics are not required.
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THE DANGER SIGNS OF DENGUE INFECTION

(IF ANY OF THESE ARE OBSERVED, PLEASE GO IMMEDIATELY TO THE NEAREST HOSPITAL)
1. Bleeding
for example:
 Extensive red spots or patches on the skin
 Excessive bleeding from nose or gums
 Black tarry stools
 Heavy menstruation / vaginal bleeding
2. Frequent vomiting
3. Severe abdominal pain
4. Drowsiness or irritability
5. Pale, cold and clammy skin
6. Difficulty in breathing
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APPENDIX 13
Patient Information Brochure in Urdu
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APPENDIX 14
List of Abbreviations
BP Blood Pressure
BU SE C Blood urea, Serum Electrolytes, Creatinine
CRT Capillary Refill Time
CVC Central Venous Catheter
CBC Complete Blood Count
DBP Diastolic Blood Pressure
DF Dengue Fever
DSS Dengue Shock Syndrome
FBC Full Blood Count
GCS Glasgow Coma Scale
GXM Group Cross Match
HCT Hematocrit
HCO3 Bicarbonate
HELLP Hemolysis, Elevated Liver Enzymes , Low Platelets
HI Hemagglutination inhibition
ICU Intensive care unit
IgG Immunoglobulin G
IgM immunoglobulin M
LFT Liver function Test
NG Tube Naso-Gastric Tube
NSI Ag Non-structural protein – 1 antigen
PCR Polymerase chain reaction
PP Pulse pressure
PR Pulse rate
RBS Random blood sugar
RR Respiratory rate
RT-PCR Reverse transcriptase Polymerase chain reaction
RTI Respiratory Tract Infection
UTI Urinary Tract Infection
URT Upper Respiratory Tract Infection
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U/S Ultrasonography
SBP Systolic blood pressure
TCO2 Total CO2
WCC White cell count

APPENDIX 15
Acknowledgement
The development group of this guideline would like to express their gratitude

and appreciation to the following for their contributions:

 Panel of external reviewers who reviewed the draft

 Technical Advisory Committee for Clinical Practice Guidelines for their valuable
input and feedback.

APPENDIX 16
Disclosure Statement
None of the primary authors holds shares in pharmaceutical firms or acts as consultants
to such firms.

APPENDIX 17
Sources of Funding
The development of the CPG on Management of Dengue Infection in Adults was
supported financially in its entirety by the Government of the Punjab Pakistan and was
developed without any involvement of the pharmaceutical industry.
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APPENDIX 18
Outcome and Management Indicators
Primary Indicators:

i. Case fatality rate (DF & DHF)

Numerator: No of adult DF & DHF/DSS death

Denominator: No of adult DF & DHF cases (clinically diagnosed)

National target = ? < 0.2%

ii. DHF fatality rate

Numerator: No of adult DHF/ DSS death

Denominator: No of adult DHF/ DSS cases (clinically diagnosed)

National target = ? <1.0%

SECONDARY INDICATORS (Adults)

1. Appropriateness of usage of blood and blood components

(a)

Numerator: No of DF/DHF cases received platelet concentrates

Denominator: No of DF/DHF cases with significant bleeding

(b)

Numerator: No of DF/DHF cases received Fresh Frozen Plasma

Denominator: No of DF/DHF cases with significant bleeding

(c)

Numerator: No of DF/DHF cases received Whole blood/ Packed cells

Denominator: No of DF/DHF cases with significant bleeding

Denominator: No of DF/DHF cases with no or insignificant bleeding

Note: All dengue deaths should be audited at individual hospitals/state/national level

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APPENDIX 19
Self-Evaluation - Review
1. What is the epidemiological data for dengue? (Section 1, P1)

2. How to diagnose dengue? (Section 3.7, P10, Appendix 5)

a. Clinical

i. Latest definition of DF, DHF, DSS, Non-Dengue cases (Section 3.1, P10)

ii. Stages of disease and pitfalls of WHO Classification (Section 3.5, P22)

iii. Differential diagnosis (Section 3.7, P26)

iv. Unusual presentation (hepatitis, liver failure, acute abdomen, encephalitis,

myocarditis) (Section 3.6, P25)

v. Co-infection – Typhoid, septicemia, malaria (Section 3.7, P26)

b. Laboratory diagnosis and its pitfalls (Section 5, P 29, Appendix 5)

i. When should IgM and IgG be taken? Role of rapid test kit. (Section 5.2.1, P31)

ii. What is the role of PCR / NS1 in the diagnosis? (Section 5.2.2, P33)

3. How to manage the patients with dengue infection as outpatients and in the
emergency facility? (Appendix 3a – Form O)

i. OPD and A/E triaging-fast tracking during outbreak (Section 7.2, P39)

ii. Who can be treated at home? Clinical and laboratory criteria – risk
stratification at first contact (Table 6, P40,)

iii. When should the GP refer the suspected dengue case to OPD or
hospital? (Section 7.3.1, P40)

iv. What should be the home care advice (Appendix 3a, Form O)

v. Specific out patient management and follow-up (Appendix 3a, Form O)

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4. When to hospitalize?

i. Clinical and laboratory criteria including social assessment (Section 7.3.1, P40)

ii. Co-morbidities (which need hospital admission)? (Section 7.3.1, P40)

iii. Communication and notification protocol (government / inter-departmental/

inter-hospital and inter healthcare facilities) (Appendix 4a, 4b, 4c)

iv. Role of bed netting and/or mosquito repellent in the hospital setting-place
under general issues (Section 9, P63)

5. How to monitor the patient in the ward?

i. What to monitor - parameter (Table 8, P 43, Appendix 2a, 2b, 3b)

ii. Pitfalls of management (Section 7.5.1, P44)

iii. Alarm triggers - Aid chart /alert card /refer algorithm (Table 5, P39)

6. When to refer patient from district hospital without specialist to general

hospital? (Section 7.3.2, P41)

i. Clinical and laboratory criteria

ii. Risk stratification protocol,

iii. When to obtain early specialist advice for those at higher risk

7. When to refer the patient for high dependency management? How to manage
the critically ill dengue patient?

i. What are the clinical criteria for referral to HDU. (Section 7.7 P56 )

ii. Criteria for respiratory and hemodynamic support. (Section 7.7.1, 7.7.2, P 57, 58)

iii. Guide on safety and risk of invasive procedures (Section 7.7.3, P58 )

8. What should be the fluid management in DF/ DHF /DSS? (Section 7.5, P44, Algorithms
for Dengue Shock Syndrome, P50)

9. DHF/DSS

i. Definition based on WHO classification (Section 3.5, P22 )

ii. Management of shock (Algorithms for Dengue Shock Syndrome) (P50)

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10. How do we manage hematological and hemostatic abnormalities?

i. Interpreting laboratory results (particularly HCT) (Section 5.1, P29 )

ii. Is there a role of prophylactic transfusion? (Section 7.6.5, P54)

iii. Is there any role of prophylactic platelet transfusion? (Section 7.6.5, P54)

11. How to management bleeding in dengue patient?

i. What is considered to be significant bleeding? (Section 7.6.2, P 52)

ii. GIT Bleed - role of OGDS/ PPI and other treatment (Section 7.6.4, P54)

iii. Use of blood and blood products (Section 7.5.4, P 47 , Algorithms for Dengue Shock
Syndrome, P 50)

iv. Role of vitamin K and Tranexamic acid (Section 7.6.6, P56)

v. Recognizing occult bleed (Section 7.6.2, P52)

12. Is there a role of drug therapy in DHF/DSS?

i. Role of recombinant Factor VII (Section 7.6.6, P56)

ii. Role of IV- Immunoglobulin G (Section 7.6.6, P56)

iii. Role of steroid (Section 7.6.6, P56)

13. What are the discharge criteria? (Section 8, P 62)

14. What is the guidance for follow-up for those patients where

i. Dengue serology returns negative (Section 5.2.1, P31)

ii. Complications develop (patients with complications should remain

admitted…common sense!!)