proceedings - asia dengue summit

PROCEEDINGS

CURRENT ISSUES IN MANAGEMENT OF DENGUE

www.asiadenguesummit.org

Proceedings of the3RDASIA DENGUE SUMMITOn Evaluating the Preparedness of Countries for Dengue Vaccine Introduction in the Asia-Pacific Region


3RD ASIADENGUE SUMMIT

PROCEEDINGS

CURRENT ISSUES IN MANAGEMENT OF DENGUE


Introduction – Current Issues in Management of Dengue 1

2. Highlights

(A) WHO Dengue Case Classification 3

(B) Viral Evolution in the Epidemiology of Dengue Viruses 8

(C) Vector Control Strategies 13

(D) Addressing the Issue of Asymptomatic Dengue 16

(E) WHO SAGE Recommendation on Dengue Vaccination 19

3. Summary of Presentations

Session 1: Dengue Disease Burden and SurveillanceModerators: Duane Gubler, Rose Capeding

Plenary Lecture: Dengue Disease Burden in the Young and Old: Updates on Population-Based Disease Burden of DengueSpeaker: Prof. Donald S. Shepard

Plenary Lecture: Addressing the Issue of Asymptomatic Dengue:How Can We Bridge the Gap?Speaker: Dr. Anavaj Sakuntabhai

23

4. Symposium 1: Dengue SurveillanceModerators: Fadzilah Kamaludin, Sri Rezeki Hadinegoro

Dengue Surveillance: Where Do We Stand in Asia?Speaker: Dr. Hasitha Tissera

Can We Achieve an Integrated Surveillance System Across Asia?Speaker: Dr. In-Kyu Yoon

Digital Surveillance: Is it Feasible in Asia?Speaker: Dr. Syed Sharizman

Dengue Surveillance: Pakistan ExperienceSpeaker: Dr. Somia Iqtadar

26

5. Session 2: Diagnostics and Dengue Management

Plenary Lecture: The Role of Viral Evolution in the Epidemiology of Dengue VirusesModerators: ZulkifliIsmail,RoseCapedingSpeaker: Prof. Duane J Gubler

31

CONTENTS


CONTENTS

Page

6. Symposium 2: Diagnostics and Dengue ManagementModerators: Rahmat Bin Dapari, Daniel Goh

Dilemmas in Dengue DiagnosisSpeaker: Prof. Usa Thisyakorn

2009 WHO Dengue Case Classification: An updateSpeaker: Dr. Olaf Horstick

Proactive Management in the Dynamic Phase of DengueSpeaker: Prof. Lucy Lum

33

7. Symposium 3: Laboratory Diagnosis of DengueModerators: Yasmin Malik, Lulu Brovo

How Reliable are Laboratory Diagnosis Methods for Arboviral DiseasesSpeaker: Dr. Butsaya Thaisomboonsuk

Studies on Markers of Severe DengueSpeaker: Dr. Ravindran Thayan

Pre-Dengue Vaccination Testing: Reliability and PracticalitySpeaker: Assoc. Prof. Chukiat Sirivichayakul

37

8. Session 4: Overview of Dengue in AdultsModerators: ZulkifliIsmail,RoseCapeding

Plenary Lecture: Overview of Dengue in AdultsSpeaker: Prof. Terapong Tantawichien

40

9. Symposium 4: Critical Care Management of Dengue in AdultsModerators: Terapong Tantawichien, Mahiran Mustafa

Dengue in Adults: Experience in Thailand, Malaysia, Indonesia and VietnamSpeakers: Dr. Nattachai Srisawat, Dr. Shanthi Ratnam, Dr. Edsel Maurice T.

Salvana, Dr. Erni Juwita Nelwan

42

10. Session 5: Dengue Vector Control Strategies

Plenary Lecture: Vector Control Strategies - Strategies to Control Aedes: What Works?Moderator: Lee Han LimSpeaker: Dr. Olaf Horstick

44


Symposium 5: Dengue Vector Control StrategiesModerators: Duane Gubler, Syed Sharizman

New Initiatives in Managing Dengue VectorsSpeakers: Dr. Lee Han Lim, Dr. Chong Chee-Seng, Dato Dr. Fadzilah Kamaludin,

Dr. Adi Utarini Professor, Dr. Nazni Bt Wasi Ahmad

ADVA Lunch SymposiumCommunication and Advocacy: A Priority in a Dengue Vaccination ProgramModerators: Lucy Lum, Sally GatchalianSpeaker: Prof. Emeritus Lulu Bravo

How to Mobilize Resources and Political Support for Dengue Control – Lessons from MalariaSpeaker: Dr. Benjamin Rolfe

46

12. Session 6: Dengue Vaccines and Their Future

Plenary Lecture: Current Status of Dengue Vaccines – Challenges and OpportunitiesModerators: TikkiPangestu,ZulkifliIssmailSpeaker: Prof. Donald S. Shepard

49

13. Symposium 6: Dengue Vaccines and Their FutureModerators: TikkiPangestu,ZulkifliIssmail

Dengue Immunization in PhilippinesSpeaker: Prof. Juliet Sio Aguilar

Guideline for Dengue VaccinationSpeaker: Dr. Sri Rezeki Hadinegoro

Roadmap to Freedom from DengueSpeaker: Prof. Pratap Singhasivanon

51

14. Poster Abstracts 55

15. Call for Action on Dengue Prevention and Control 62

16. References 64

CONTENTS


1

CURRENT ISSUES INMANAGEMENT OF DENGUE


2

Introduction

The global burden of dengue continues to rise with an estimated 3.97 billion people in 128 countries at-risk of infection and 400 million people getting infected each year.1 (Ayukekbong et al, 2017) The WHO regions of South East Asia and the Western Pacific contribute to 75% of the total burden of dengue.2 (Shepard et al, 2013). The continued rise in dengue epidemic is a result of several factors; the major ones being uncontrolled urbanization, overcrowding, international travel and inadequate vector control strategies. Robust surveillance, successful implementation of vector control and vaccine advocacy are important aspects of consolidated efforts in fight against dengue.

The 3rd Asia Dengue Summit 2018 was held at Berjaya Times Square Hotel in Kuala Lumpur, Malaysia from 4 – 6 July 2018. The summit was co-organized by Asian Dengue Vaccination Advocacy (ADVA), Global Dengue and Aedes transmitted Diseases Consortium (GDAC), Southeast Asian Ministers of Education Tropical Medicine and Public Health Network (SEAMEO TROPMED), and Foundation Merieux (FMx). The Malaysian Society of Infectious Diseases and Chemotherapy and the Malaysian Paediatric Association supported the summit. The summit was preceded by two pre-summit workshops on immunology and economic evaluation of dengue vaccines. The 2-day summit highlighted the dengue disease burden and surveillance data in Asia, burden of asymptomatic infections, diagnostics and dengue management, dengue vector control strategies, and benefits, risks and future of dengue vaccination.

The summit provided an enriching opportunity for everyone in the dengue community (clinicians, researchers, government public health leaders and policymakers) to come together to exchange ideas, and share updates and achievements on dengue management strategies across the region. With participation of dengue experts from across the region and worldwide, current issues surrounding dengue disease management, new vector control measures and strategies for successful vaccine introduction across the region were discussed.

The Organizing Chairperson Datuk Prof. Zulkifli Ismail, and Chairperson of Asian Dengue Vaccination Advocacy, Dr. Maria Rosario Capeding welcomed the participants to the 3rd Asia Dengue Summit. Dr. Lee Boon Chye, Honorable Deputy Minister of Health, Malaysia presented the opening address and officially launched the 3rd Asian Dengue Summit. 300 registered participants from 15 countries attended the 2-day summit, which culminated with the celebration of ASEAN Dengue Day on 7 July 2018.


3

HIGHLIGHTS

(A) WHO DENGUE CASE CLASSIFICATION


4

1997 Dengue Case Classification

The WHO 1997 dengue case classification that included dengue fever (DF), dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) was developed by an expert consensus in 1975.3 (Horstick et al, 2014) According to the 1997 classification, DF is a non-specific febrile illness with classical constitutional signs and symptoms, while DHF is classified in four grades of severity characterized by increased vascular permeability and may progress to dengue shock syndrome DSS (DHF grade III and IV). 4 (Bandopadhyay et al, 2006) However, the role of 1997 classification has been questioned because it was based only on pediatric cases in Southeast Asia. Moreover, over time dengue has spread to different geographical locations, affects older individuals and is characterized by variable clinical manifestations. In addition, several limitations of the original case classification were identified such as difficulty in applying case classification due to rigid definitions, low sensitivity, and clinician assumption that DF is a mild disease.4 (Bandopadhyay et al, 2006) (Table 1)

Table 1: Drawbacks of WHO 1997 Dengue Case Classification3-4

Poorly related to disease severity3,4

• Overlap of clinical manifestations in the different dengue entities• Severity of thrombocytopenia, plasma leakage and hemorrhagic

manifestations are highly variable in DHF • Many severe DSS cases do not have platelet counts less than 100 x 109/L • Some DHF I/II patients may need hospitalization

Misdirects clinicians identifying severe disease3,4

• Dengue with shock without fulfilling the four DHF criteria would be classified as DF

• Dengue with unusual severe hemorrhage without increased vascular permeability may require blood transfusion

• Organ dysfunction out of proportion to the degree of plasma leakage can occur

Difficult to use due to the tests required3

• Difficulty in application and interpretation of tourniquet test• The positive tourniquet test does not differentiate between DF and DHF• Variability in frequency and/or method of the platelet count

Low sensitivity in classifying DHF is due to• Failure to repeat the tests or physical examinations at the appropriate time• Early intravenous fluid therapy• Lack of adequate resources in an epidemic

Does not help for triage in outbreaks3

Generates different reports globally due to difficulties faced by clinicians in using the classifications(Bandopadhyay et al. 2006 and Horstick et al 2014)


5

Step-by-step Approach: Revising Dengue Case Classification

In order to overcome the difficulties associated with the 1997 classification, and allow physicians to identify and manage cases of severe dengue and save resources, the revised dengue case classification was developed. The methods used for developing the revised case classification included a prospective cohort study, comparative analyses of existing data, systematic literature reviews, focus group discussions and expert consensus groups. The step-by-step approach used for revising dengue case classification is illustrated in table 2. (Horstick et al, 2012)

Table 2: Developing Revised Dengue Case Classification5

Step 1: Systematic literature review that highlighted the difficulties with the DF/DHF/DSS classification

Step 2: Review of dengue clinical guidelines and their use in Asia and Latin America

Step 3: A prospective cohort study in seven countries confirmed that:• Application of DF/DHF/DSS classification is difficult in tertiary care• DF/DHF/DSS does not represent levels of disease severity

Step 4: Three regional expert consensus groups on the use of DF/DHS/DSS classification (Cuba, Malaysia and Germany) concluded that• ‘Dengue is one disease entity with different clinical presentations

and often with unpredictable clinical evolution and outcome’

Step 5: Global expert consensus meeting in Geneva, Switzerland 2008• Revised dengue case classification was developed: dengue with or

without warning signs and severe dengue.

Step 6: Revised dengue classification was validated in 18 countries• Usefulness and applicability of revised classification was confirmed

Step 7: Upcoming study on predictive value of warning signs for severe dengue


6

2009 WHO Dengue Case Classification

In 2009, WHO Tropical Disease Research (TDR) recommended a new classification of dengue, which classified dengue into dengue (D), dengue with warning signs (DW) and severe dengue (SD) (Figure 1).

(Source: Dengue Guidelines for diagnosis, treatment, prevention and control, New edn. Geneva: WHO; 2009)(SlidefromProf.OlafHorstick’spresentationtitled:2009WHOdenguecaseclassification:Anupdate)

The usefulness and applicability of the revised dengue case classification was evaluated in a multi-centre study in 18 countries. 13.7% of dengue cases could not be classified using the DF/DHF/DSS classification, compared to only 1.6% with the revised classification. The revised classification allowed timely recognition of severe disease with 51.9% of the DF cases classified as dengue plus warning signs and 5.7% as severe dengue.7 The acceptance and perceived user friendliness was high with the revised classification as it was considered simple, practical and easy to use, further improving management, referral and triage.7 (Barniol et al, 2011)

A 2-day expert consensus meeting in Cuba, 2013 that presented the experience of Pan American Health Organization (PAHO) member states when applying D/SD, recommends to update International Disease Classification 10 (ICD-10) to include the new classification of dengue (D/SD), include D/SD in country epidemiological reports, and implement studies improving sensitivity/specificity of the dengue case definition.8 (Horstick et al, 2015)

Figure 1: The revised dengue case classification6


7

Though the revised classification has potential to improve surveillance and triage and facilitate research, concerns over increased hospitalization rates if the warning signs are not defined clearly and higher costs with higher patient admissions have been raised.7 It is also understood that algorithms in the dengue case definition may vary from region to region or from country to country, and local adaptation of dengue clinical guidelines may be necessary.7 (Barniol et al, 2011)


8

HIGHLIGHTS

(B) VIRAL EVOLUTION IN THEEPIDEMIOLOGY OF DENGUE VIRUSES


9

Geographical Spread of the Dengue Virus

Dengue viruses (DENV 1-4) have been hyperendemic in many Asian countries following World War II. The first reported epidemics of DHF occurred in Philippines (1953–1954) and Thailand (1958) followed by Singapore, Malaysia and Vietnam (1960) and Indonesia and Burma (Myanmar) (1970).9 (Gubler 2011) DHF was the major cause of hospitalization and death in South East Asian children in 1980s. Similarly, in Americas, though epidemic dengue was well controlled in 1950-1960, rapid urbanization saw re-introduction of dengue viruses in 1970s followed by hypernedemicity and epidemic DHF.9 (Gubler 2011)

Dengue has spread dramatically to over 128 countries over the past 40 years with expanding geographical distribution, increased epidemic activity, hyperendemicity and emergence of severe disease. Increased incidence and geographical spread of dengue is due to a variety of reasons, however the most important factors include changing life styles, unplanned urbanization, overcrowding and globalization, international travel and lack of effective mosquito control.9 (Table 3) (Gubler 2011)

Table 3: Factors affecting geographical spread of dengue9

• Unplanned urbanization- Over-crowding- Lack of water and sewage management - Increased population densities

• Changing lifestyle increasing larval habitats- Overuse of plastic containers providing ideal sites for larval habitat- Truck tires provide ideal oviposition sites - Lack of water supply resulting in water storage in containers

• Globalization- Increasing number of people using air travel allowing transfer of dengue

viruses to other cities via infected individuals- Allowing development of viruses with better resilience and epidemic

potential

• Failure to control mosquito vector- Lack of political will and resources- Replacement of successful mosquito control programs with emergency

space spraying, which only targets adult mosquitoes and not larval habitats(Gubler 2011)


10

Evolution of the Dengue Virus

There are 4 distinct types of dengue viruses ((DENV-1, DENV-2, DENV-3, and DENV-4). A complex interaction of viral, host and environmental factors is responsible for differences in epidemic potential, disease severity and pathogenesis. Different strains of viruses have variable fitness and epidemic potential.

It is hypothesized that during the process of replication in humans and mosquitoes, the dengue virus undergoes genetic changes, and these small genetic changes are responsible for variable phenotypic expression. The phenotypic changes include increased virus replication and viremia, severity of disease, and epidemic potential.10 (Gubler, 1998). It is suggested that dengue virus evolution by natural selection and/or genetic drift is responsible for the emergence of fitter viruses that play a role in the epidemiology and pathogenesis of severe dengue disease.

During the 1974 DENV 2 outbreak in the Pacific island Kingdom of Tonga mild clinical disease was seen with few hemorrhagic manifestations, low attack rate and low viremia levels.11 On the other hand, a severe disease with frequent hemorrhagic manifestations and a high attack rate characterized the outbreak of DENV 1 in 1975. The difference in clinical presentation with the two epidemics in Pacific islands was attributed to the difference in viral virulence.11 (Gubler, 1978)

(Slide from Prof. Duane Gubler’s presentation titled: The Role of Viral Evolution in the Epidemiology of Dengue Viruses)

Figure 2: Dengue epidemics in Puerto Rico


11

Puerto Rico is a perfect example to explain the viral evolutionary change during dengue epidemics. (Figure 2) The first DENV-4 epidemic in Puerto Rico occurred in 1981-1982, followed by another DENV-4 outbreak in 1986. During the 1986 outbreak there was simultaneous transmission of three dengue virus serotypes. (DENV-1, DENV-2 and DENV-4), with many cases of severe and fatal hemorrhagic disease.12 (Dietz et al, 1996) During the next epidemic in 1994, the PR-2B DENV-2 replaced an endemic PR-1 DENV-2. The PR-2B DENV-2 produced increased levels of subgenomic flavivirus RNA (sfRNA) relative to genomic RNA during replication, thus down-regulating the type I interferon immune response further increasing the epidemiological fitness.13 (Manokaran et al, 2015) During the 1998 DENV-4 epidemic three amino acid replacements in the nonstructural gene 2A (NS2A) protein were detected highlighting the role of viral genetic turnover within a focal population.14 (Bennett SN et al, 2003) Three major DENV-4 lineages evolved in Puerto Rico due to amino acid substitutions in NS2A, polymerase (NS5) and non-translated regions (NTR) with group III as the dominant DENV-4 strain until 2010.15 (Martin et al, 2016)

Figure 3: Dengue epidemics in Sri Lanka

Though all 4 serotypes have been prevalent in Sri Lanka, DHF was rare. However, over the past decades DENV 3 has been responsible for unusual epidemics of DHF. (Figure 3) The first DHF epidemic in Sri Lanka in 1989 was associated with emergence of a new DENV-3, subtype III variant. Analysis of DENV-3 isolates from Sri Lanka before and after emergence of DHF revealed that there were separate groups within

(Slide from Prof. Duane Gubler’s presentation titled: The Role of Viral Evolution in the Epidemiology of Dengue Viruses)


12

subtype III, thus suggesting that a genetic shift in DENV-3 might be responsible for emergence of DHF.16 (Messer et al, 2003)

Epidemiologic data from dengue serotypes DENV-2, 3 and 4 from three different geographical regions thus highlights that small genetic changes manifest as increased clinical severity. Furthermore, it is understood that virus evolution via drift and positive selection results in the emergence of new viral lineages of the same genotype, which result in severe dengue disease.


13

HIGHLIGHTS

(C) VECTOR CONTROL STRATEGIES


14

WHO Position on Vector Management

Vector control strategies play an important role in reducing the burden of vector-borne disease by reducing or interrupting the disease transmission. However, cost-effectiveness, technical and administrative difficulties and lack of involvement of local communities are common obstacles in successful implementation of most vector control strategies. Therefore, the concept of integrated vector management (IVM) was introduced with the aim to prevent and control vector-borne diseases. IVM is “a rational decision-making process for the optimal use of resources for vector control”. 17 The WHO position on IVM outlines its important attributes that include legislation, regulatory frameworks, intra and intersectoral collaboration (linking vector control with sanitation, clean water supply, development projects), along with decision-making criteria, capacity building, cost-effectiveness and mobilization of local communities.17 (WHO Position Statement on Integrated Vector Management, 2008)

(Slide from Prof. Olaf Horstick’s presentation titled: Vector control strategies - Strategies to control Aedes- What works?)

Figure 4: Integrated Vector Management


15

Effectiveness of Vector Control Strategies

Although vector control can be beneficial, the efficacy is highly variable according to the type of intervention, implementation is difficult and data on the optimal delivery structures of vector control services is lacking.18 (Horstick et al, 2017) A systematic review evaluating the effectiveness of peridomestic space spraying with insecticide on dengue transmission shows that there is no clear evidence to recommend it as a single intervention, but may be useful as a part of integrated vector management.19 (Esu E et al, 2010). Similarly, though indoor residual spraying (IRS) is an effective adulticidal intervention against Aedes mosquitoes, there is inadequate evidence to demonstrate its effectiveness as a larvicidal intervention.20 (Samuel M et al, 2017). Another systematic review on success of pyriproxyfen as a dengue vector control method reveals that though pyridoxine can be effective in controlling the immature stages of dengue transmitting mosquitoes, there is limited evidence on reduction of human dengue cases.21 (Maoz D et al, 2017). Evidence on the role of application of organophosphate larvicide temephos to water storage containers, and usefulness of Bacillus thuringiensis israelensis in reducing dengue transmission is also limited.22-23 (George L et al, 2015) (Boyce R et al, 2013). In addition, there is a lack of strong evidence on role of copepods and larvivorous fish in dengue vector control.24-25 (Lazaro A et al, 2015) (Han W et al, 2015)

It is therefore clear that single vector control interventions are not successful, efficacy is highly variable and sustained community effectiveness has not been demonstrated.18 Furthermore, combinations of interventions have shown mixed results. To add to it, studies show that interventions are usually applied in outbreaks rather than to routine vector control.18 (Horstick et al, 2017). To be efficacious and community-effective, rigorous implementation of vector control measures is more important than the actual choice of combinations of vector control methods. There is an urgent need for standards to guide the design and reporting of vector control studies. Combinations of vaccines and vector control will be useful in reducing or interrupting the disease transmission.

New Initiatives in Dengue Vector Control

Sterile insect technique is an emerging, environmentally friendly dengue vector control technique that involves release of large numbers of sterile male mosquitoes in the field. Mating of sterile males with native female mosquitoes results in reduction of female reproductive potential.26 Reduction in target population can be achieved if sufficient number of sterile males can be released over sufficient period of time.26 (Alphey, L et al, 2010) The World Mosquito Program (WMP) (formerly Eliminate Dengue Program) uses introduction of Wolbachia infection in Aedes aegypti mosquitoes to make them resistant to dengue, Zika, chikungunya and yellow fever viruses, in turn reducing their ability to transmit these viruses to people.27 The WMP is currently operating in 12 countries across Asia, the Americas, the Pacific Islands and Australia.27


16

HIGHLIGHTS

(D) ADDRESSING THE ISSUE OFASYMPTOMATIC DENGUE


17

Asymptomatic Dengue

Though the clinical presentation of dengue varies from mild febrile illness to severe dengue hemorrhagic fever, there are a large proportion of patients who have a sub-clinical infection and are therefore asymptomatic. It is estimated that about 290 million people of the total 390 million DENV infections per year are clinically inapparent or mildly symptomatic.28 (Bhatt S et al, 2013) Though these people are infected with dengue virus, they are asymptomatic without any change in their daily lives, and thus have a potential to contribute to virus transmission by infecting mosquitoes.

It is well understood that disease severity correlates with viremia and patients with a high early viremia have a greater time-window of infectiousness.29 (Carrington et al, 2014) Therefore it was believed that asymptomatic individuals with not very high levels of viremia are dead-end hosts for transmission, and thus cannot transmit the virus to mosquitoes.30 (Duong et al, 2015) However, a recent study shows that asymptomatic individuals can transmit the virus to mosquitoes and are remarkably more infectious to mosquitoes than clinically symptomatic patients. To add to this asymptomatic individuals are shown to have a higher transmission potential with ~100-fold lower 50% mosquito infectious dose.30 (Duong et al, 2015)

(Slide from Dr. Anavaj Sakuntabhai’s presentation titled: Addressing the Issue of Asymptomatic Dengue: How Can We Bridge the Gap?)

Figure 5


18

Moreover, since asymptomatic individuals move around doing their daily activities, they have a higher chance of being bitten by more mosquitoes than sick patients resting at home or hospital, and therefore have a significant potential to transmit infection to more mosquitoes.30 (Duong et al, 2015) Asymptomatic dengue with the potential to contribute to the transmission of infection has greater public health implications with respect to the need for early and rapid response to outbreak, development of preventive strategies, and innovations in antivirals and vaccines to prevent human to mosquito transmission.30 (Duong et al, 2015)

A study in Cambodian population of clinical dengue patients versus strictly asymptomatic viremic individuals revealed that asymptomatic cases have increased antigen presentation, T cell activation, and T cell apoptosis with reduced plasmablast differentiation and anti-dengue antibodies.31 The study highlights that increased activation of adaptive immune response and proper feedback regulation eliminates the virus without excessive immune activation and clinical symptoms.31 (Simon-Lorière E et al, 2017). During DENV infection among asymptomatic individuals there is a down-regulation of host defense response (innate, adaptive, cytokines and matrix metalloproteasel) genes and up-regulation of genes offering protection against clinical DENV infection.32 (Yeo et al, 2014). In order to close the gap on issue of asymptomatic dengue infection, more research on immuno-protective mechanism, cellular immunity, systems biology and human to mosquito transmission is warranted.


19

HIGHLIGHTS

(E) WHO SAGE RECOMMENDATIONON DENGUE VACCINATION


20

Dengue Vaccination

As per global strategy for dengue prevention and control, 2012-2020, WHO objectives include reduction in dengue mortality by at least 50% by 2020 and reduction in dengue morbidity by at least 25% by 2020.33 (WHO Global strategy for dengue prevention and control 2012-2020) The Strategic Advisory Group of Experts (SAGE) on immunization acknowledges that an integrated approach for dengue prevention and control should include sustained vector control, best evidence-based clinical care and vaccination.34 (WHO Weekly epidemiological record, 2018)

The first dengue vaccine, CYD-TDV (Dengvaxia®) has been licensed in 20 countries. Clinical efficacy and safety of tetravalent dengue vaccine has been tested in three phase III trials in Asia Pacific and Latin America. Following CYD-TDV there was a 65.6% reduction in symptomatic dengue, 80.8% decrease in hospitalized dengue and 92.9% decrease in severe dengue.35 (Hadinegoro et al, 2015). Efficacy of dengue vaccine has been demonstrated in Asian children aged 2-14 years when given as three injections at months 0, 6, and 12.36 (Capeding et al, 2014)

(Slide from Dr. Alain Bouckenooghe’s presentation titled: Comprehensive CYD-TDV Clinical Development Plan)

Figure 6


21

Findings from the dengue anti–nonstructural protein (NS1) case-cohort study showed that though the vaccine had a favorable effect on public health, seropositive and seronegative individuals reacted differently. Overall population benefit was seen in seropositive individuals aged 9 years or older; however, there was an increased risk in seronegative individuals.34 (WHO. Weekly epidemiological record, 2018) The NS1 study demonstrated that CYD-TDV confers protection against virologically confirmed dengue and hospitalization for ≥5 years in seropositive individuals. Vaccine efficacy was 76% in seropositive individuals compared to 38.8% in seronegative individuals in 25 months after first dose. Risk of hospitalized dengue and of severe dengue reduced by ~80% in seropositive individuals aged ≥9 years. However, increased risk of hospitalized dengue and severe dengue was seen in seronegative individuals.37 (Sridhar et al, 2018)

In November 2017, after the vaccine manufacturer warned that the dengue vaccine could increase the risk of severe dengue in seronegative recipients of all ages, there was a climate of fear and loss of public confidence and trust. Following which, WHO SAGE issued revised recommendations on use of dengue vaccine in April 2018.34 WHO/SAGE acknowledges the strong protective benefit of CYD-TDV in seropositive individuals; and in order to maximize the public health benefit and minimize the impact on seronegative individuals, SAGE has recommended two main approaches.34 (WHO. Weekly epidemiological record, 2018) (Table 4)

Figure 7

(Slide from Dr. Alain Bouckenooghe’s presentation titled: Comprehensive CYD-TDV Clinical Development Plan)


22

Table 4: SAGE Recommendation on use of Dengue Vaccine34

Pre-vaccination screening Population seroprevalence

• Pre-vaccination screening is the preferred strategy

• Screening to be done prior to vaccination and only seropositive individuals to be vaccinated

• Dengue IgG ELISA could be used but does not provide point-of- care information

• Rapid diagnostic tests (RDT) to detect previous dengue infection are not currently validated

• Alternate strategy is vaccination according to population seroprevalence

• Vaccination in high seroprevalence areas without pre-vaccination screening

• Vaccine to be used in populations with a seroprevalence of >80%

• Population seroprevalence studies to identify target population for vaccination

SAGE has stressed the need for more research on development of RDT with high specificity and high sensitivity, simplified immunization schedules and need for booster doses.34


23

SUMMARY OF PRESENTATIONS

SESSION 1:DENGUE DISEASE BURDEN AND

SURVEILLANCE

Moderators: Duane Gubler, Rose Capeding


24

Plenary Lecture: Dengue Disease Burden in the Young and Old: Updates on Population-Based Disease Burden of Dengue

Prof. Donald S. ShepardProfessor at Heller School for Social Policy and ManagementBrandeis University, USA

The global disease and economic burden of dengue continues to rise. Assessment of dengue burden provides vital information to evaluate and compare dengue with other illnesses, monitor trends, provide a tool to evaluate effectiveness and cost-effectiveness of interventions, and inform priorities in health sector. Commonly used measures to estimate disease burden are Disability Adjusted Life Year (DALY), which is the number of years of healthy life lost due to a disease or risk and Quality-Adjusted Life Year (QALYs), which is years of good health experienced. Improved methods of data collection are generating substantially higher estimates of the disease and economic burden of dengue than originally estimated.

2013 data that assessed the economic burden of dengue from symptomatic cases in the 141 countries and territories with active dengue transmission showed that there were 58.40 million symptomatic dengue virus infections with 13586 fatal cases. The total annual global cost of dengue illness was US$8.9 billion. Global distribution of dengue cases was 18% admitted to hospital, 48% ambulatory, and 34% non-medical.38 (Shepard et al, 2016). From 2005 to 2015, dengue deaths over the world increased by 48.7% resulting in 18,400 deaths in 2015.39 Economic and disease burden of dengue in 12 countries in South East Asia was estimated at an annual average of 2.9 million dengue episodes with 5,906 deaths, annual economic burden of US$950 million and annual 372 million disability-adjusted life-years.2 (Shepard et al, 2013) Dengue cost per capita in South East Asia was 68% of that in Americas; however, DALYs per million in South East Asia were 4.6 times higher than in the Americas. This is attributed to the higher incidence of dengue hemorrhagic fever and dengue shock syndrome in South East Asia.2 (Shepard et al, 2013) The dengue burden in South East Asia is higher than that of 17 other conditions, including Japanese encephalitis, upper respiratory infections, and hepatitis B.2 (Shepard et al, 2013) The ever-increasing economic burden of dengue in South East Asia warrants aggressive efforts towards dengue prevention and control.


25

Plenary Lecture: Addressing the Issue of Asymptomatic Dengue: How Can We Bridge the Gap?

Dr. Anavaj SakuntabhaiDepartment of Genome and GeneticsFunctional Genetics of Infectious Diseases UnitInstitut Pasteur, Paris

Majority of primary dengue infections are asymptomatic or subclinical, where the individual does not feel the need to consult a physician. It is estimated that about 300 million people of the total 390 million DENV infections per year are clinically inapparent or mildly symptomatic.28 (Bhatt S et al, 2013) Though these people are infected with dengue virus, they are asymptomatic without any change in their daily lives, and thus have a potential to contribute to virus transmission by infecting mosquitoes. A comparative study in Cambodian population of clinical dengue patients versus strictly asymptomatic viremic individuals revealed that asymptomatic cases have increased antigen presentation, T cell activation, and T cell apoptosis with reduced plasmablast differentiation and anti-dengue antibodies.31 The study highlights that increased activation of adaptive immune response and proper feedback regulation eliminates the virus without excessive immune activation and clinical symptoms.31 (Simon-Lorière E et al, 2017)

Due to not very high levels of viremia it was believed that asymptomatic dengue viremic individuals are dead-end hosts for transmission, and thus cannot transmit the virus to mosquitoes.30 (Duong et al, 2015) However, recent study shows that asymptomatic people can transmit the virus to mosquitoes and are remarkably more infectious to mosquitoes than clinically symptomatic patients with ~100-fold lower 50% mosquito infectious dose.30 In addition, since asymptomatic people move around doing their daily activities, there are high chances of them being bitten by more mosquitoes than sick patients resting at home or hospital and therefore have a significant potential to transmit infection to more mosquitoes.30 In order to close the gap on issue of asymptomatic dengue infection, more research on immuno-protective mechanism, cellular immunity, systems biology and human to mosquito transmission is needed.


26


SYMPOSIUM 1:DENGUE SURVEILLANCE

Moderators: Fadzilah Kamaludin, Sri Rezeki Hadinegoro


27

Dengue Surveillance: Where Do We Stand in Asia?

Dr. Hasitha TisseraNational Dengue Control ProgrammeMinistry of Health Sri Lanka

Though dengue is a notifiable disease in many countries, there is substantial underreporting of dengue to national surveillance systems. The objectives of dengue disease surveillance are to monitor disease incidence, estimate disease trends, report circulating serotypes and geographical distribution, detect outbreaks early to allow timely application of control measures, confirm disease outbreaks on the basis of serological evidence, and monitor the cost and effectiveness of control-measures.40-41 (Sarti et al, 2016) (WHO, Dengue control/Disease Surveillance)

Important aspects of dengue disease surveillance include surveillance of human cases, laboratory based surveillance (serological and virological diagnosis), vector surveillance and monitoring of environmental and social risks.42 (WHO Dengue: Guidelines for Diagnosis, Treatment, Prevention and Control: New Edition, 2009) Passive surveillance, which uses standardized reporting forms is less costly compared to other methods and does not put a burden on healthcare providers. The drawbacks of passive surveillance include underreporting and lack of standardized case classification.43 On the other hand active surveillance is costlier and involves extra efforts to report cases through visits to laboratories, hospitals and providers. Sentinel surveillance, is a type of active surveillance, which extrapolates sample data from a smaller population to a larger population, and is therefore is less expensive and provides high quality data.43 (Runge–Ranzinger et al, 2008) Some methods of entomological surveillance include sampling larvae and pupae, pupal demographic surveys, passive collection of larvae and pupae, sampling of adult mosquito population, and sampling the ovipositing population.42 (WHO Dengue: Guidelines for Diagnosis, Treatment, Prevention and Control: New Edition, 2009)

Expert recommendations on best practices in dengue surveillance include mandatory reporting of dengue in endemic countries, application of WHO regional case definitions, use of electronic reporting systems and use of standardized laboratory methods. Dengue fever, dengue hemorrhagic fever and dengue shock syndrome, dengue deaths, hospitalization and mortality rates need to be reported as per age group. Periodic studies should be conducted to detect under-detection and under-reporting.44 (Beatty et al, 2010)


28

Can We Achieve an Integrated Surveillance System Across Asia?

Dr. In-Kyu YoonDirector of Global Dengue & Aedes-Transmitted Diseases ConsortiumInternational Vaccine Institute

A robust surveillance system is essential in order to effectively prevent and control dengue. However, dengue surveillance is challenging due to lack of standardization of classification of dengue, limited resources and infrastructure, ineffective vector surveillance, limited access to good clinical care and lack of advanced entomological tools.45 (Ng et al, 2011) Strategic framework comprising of WHO, SEARO & WPRO and SEAN, and regional operational networks supporting surveillance, research and training already exist in Asia. However, lack of unified coordination of regional initiatives due to complexity of regional networks and their respective roles, and non-sustained political will and non-sustained resourcing add to the challenges in developing an integrated dengue surveillance system across Asia. In order to establish integrated surveillance system across Asia, continuous advocacy with strong supportive evidence base is necessary; which can be generated through epidemiological and operational research to provide justification for allocation of resources. New technologies and tools such as real-time dengue transmission mapping, climate mapping, social media, point-of-care diagnostics and reporting are being used to improve evidence base, which will be useful in achieving an integrated surveillance in Asia.


29

Digital Surveillance: Is it Feasible in Asia?

Dr. Syed SharizmanDivision of Disease ControlMinistry of Health Malaysia

Digital surveillance provides real-time, customizable, web based information accessible at all levels, providing effective tools for planning and decision making, reducing under-reporting while stimulating public interaction and participation. The various digital surveillance systems used in Malaysia include eNotifikasi, eDengue, dengue epidemic management system (SPWD) and iDengue. eDengue is a real time web based system accessible from district, state or headquarters; or any place with internet capabilities. It is a smart system that can alert outbreak through automated calculation of the effectiveness of control activities. It provides comprehensive data on number of cases, deaths, laboratory result, control activities, vector index, outbreak localities, health education activities, enforcement activities, and insecticide stock. The Dengue Outbreak Management System (SPWD) is a collaborative project between Remote Sensing Malaysia Agency (MRSA) and Ministry of Health Malaysia (MOH). It provides real-time supervision through monitoring of cases and outbreaks distribution daily and helps to improve efficacy of control activity by accurately identifying borders through high- resolution satellite. SPWD manages outbreak control by determining work force, identifying available resources, estimating time for coverage, identifying route for vehicle, fuel estimation, insecticide usage estimation and estimating operational costs. iDengue is a system that empowers the community by providing information on latest cases and outbreaks, monthly cases by district, current dengue indexes, and outbreak area maps and provides a channel for complaints and feedback for the public. www.asiadenguesummit.org

30

Dengue Surveillance: Pakistan Experience

Dr. Somia IqtadarMaster Trainer on Clinical Management of Dengue FeverWHO and Government of PunjabAssociate Secretary Dengue Expert Advisory Group

Punjab faced the worst-ever reported dengue epidemic in the world in 2011, with approximately 0.6 million suspected cases, 22,000 confirmed cases and 375 deaths in a span of 73 days. Punjab had no previous experience of coping with the outbreak of dengue where all efforts were based on simple mosquito control. However, since then tremendous efforts were put in to develop and implement several initiatives and activities to combat dengue. Advocacy and political commitment resulted in establishment of Central Emergency Response Committee with daily meetings chaired by chief minister. The Town Emergency Response Committee and Prevention and Control Program of Epidemics in Punjab were launched. Aggressive social mobilization, communication and public awareness campaigns were held and vector surveillance system, dengue tracking system, patient reporting system and health helplines were set up. Vector surveillance system was put in place followed by dengue tracking system, online patient reporting system and system alerts. (Vector-based alerts, GIS based alerts and WHO based alerts)


31


SESSION 2:DIAGNOSTICS AND DENGUE MANAGEMENT


32

Plenary Lecture: The Role of Viral Evolution in theEpidemiology of Dengue VirusesModerators: Zulkifli Ismail, Rose Capeding

Prof. Duane J GublerEmeritus ProfessorProgram in Emerging Infectious DiseasesDuke-NUS Medical School, SingaporeChairman, Global Dengue & Aedes-Transmitted Diseases Consortium

There are 4 distinct types of dengue viruses (DENV-1, DENV-2, DENV-3, and DENV-4). A complex interaction of viral, host and environmental factors is responsible for differences in epidemic potential, disease severity and pathogenesis. Different strains of viruses have variable fitness and epidemic potential. Dengue has spread dramatically to over 128 countries over the past 40 years. Increased incidence and geographical spread of dengue is due to a variety of reasons, however the most important factors include lack of effective mosquito control, changing life styles, unplanned urbanization, overcrowding and globalization and international travel.9

(Gubler, 2011) It is hypothesized that during the process of replication in humans and mosquitoes, the dengue virus undergoes genetic changes, and these small genetic changes are responsible for variable phenotypic expression. The phenotypic changes include increased virus replication and viremia, severity of disease (virulence), and epidemic potential.10 (Gubler, 1998)

Epidemiologic data from dengue serotypes DENV-2, 3 and 4 from three different geographical regions (Pacific island Kingdom of Tonga, Puerto Rico, and Sri Lanka) highlights that small genetic changes manifest as increased clinical severity. Though all 4 serotypes have been prevalent in Sri Lanka, DHF was rare. The first DHF epidemic in Sri Lanka in 1989 was associated with emergence of a new DENV-3, subtype III variant. Analysis of DENV-3 isolates revealed separate groups within subtype III, thus suggesting that a genetic shift i n DENV-3 might be responsible for emergence of DHF.16 (Messer et al, 2003) Three major DENV-4 lineages have evolved in Puerto Rico due to amino acid substitutions in NS2A, NS5 and NTR with group III as the dominant DENV-4 strain until 2010.15 (Martin et al, 2016) It is understood that virus evolution via drift and positive selection results in the emergence of new viral lineages of the same genotype, which result in severe dengue disease.


33


SYMPOSIUM 2:DIAGNOSTICS AND DENGUE MANAGEMENT

Moderators: Rahmat bin Dapari, Daniel Goh


34

Dilemmas in Dengue Diagnosis

Prof. Usa ThisyakornChulalongkorn University, Thailand

Clinical manifestations of dengue vary with age. The severity of DF manifestations increases with age, and dengue shock syndrome (DSS) is more common in children than in adults, while adult co-morbidities results in increased risk of mortality.47 (Thisyakorn, 2015) Adults have a higher prevalence of underlying diseases, such as coronary artery disease, peptic ulcer, hypertension, diabetes mellitus and chronic kidney diseases, which should be considered in dengue management. Pre-existing liver diseases such as chronic hepatitis, alcoholic cirrhosis, and hemoglobinopathies may aggravate the liver impairment in dengue infection.48 (Thisyakorn, 2016)

Successful treatment of DHF depends on early recognition and careful monitoring of development of shock. Decrease in preload along with decreased left ventricular performance and a subnormal heart rate response results in decreased cardiac output during toxic stage of DHF.49 (Khongphatthanayothin et al, 2003) Transient myocardial depression is common in patients with DSS. Cardiac dysfunction in children may be responsible for increased clinical severity and degree of fluid overload in children.50 (Khongphatthanayothin et al, 2007) There is no standard recommendation of fluid resuscitation in dengue hemorrhagic fever (DHF)/dengue shock syndrome (DSS). For initial fluid resuscitation in DSS, there is no difference between crystalloids and colloids; and there is no significant evidence to support colloids as the fluids in severe DSS. One type of colloid is not significantly different from other. The decision in choosing appropriate type of fluid depends on the physician’s judgment.51 (Permpalung et al, 2009)www.asiadenguesummit.org

35

2009 WHO Dengue Case Classification: an update

Dr. Olaf HorstickDirector of the Teaching Unit at the Institute of Public HealthUniversity of Heidelberg, Germany

The WHO 1997 dengue case classification that included dengue fever (DF), dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) was developed by an expert consensus in 1975.3 (Horstick et al, 2014) According to the 1997 classification, DF is a non-specific febrile illness with classical constitutional signs and symptoms, while DHF is classified in four grades of severity characterized by increased vascular permeability and may progress to dengue shock syndrome DSS (DHF grade III and IV).4 (Bandopadhyay et al, 2006) However, the role of 1997 classification has been questioned because it was based only on pediatric cases in Southeast Asia. Moreover, over time dengue has spread to different geographical locations, affects older individuals and is characterized by variable clinical manifestations. In addition, several limitations of the original case classification were identified such as difficulty in applying case classification due to rigid definitions, low sensitivity, and clinician assumption that DF is a mild disease.4 (Bandopadhyay et al, 2006) In 2009, WHO Tropical Disease Research (TDR) recommended a new classification of dengue, which classified dengue into dengue (D), dengue with warning signs (DW) and severe dengue (SD). The usefulness and applicability of the revised dengue case classification was evaluated in a multi-centre study in 18 countries. The revised classification allowed timely recognition of severe disease with 51.9% of the DF cases classified as dengue plus warning signs and 5.7% as severe dengue.7 The acceptance and perceived user friendliness was high with the revised classification as it was considered simple, practical and easy to use further improving management, referral and triage.7 (Barniol et al, 2011) www.asiadenguesummit.org

36

Proactive Management in the Dynamic Phase of Dengue

Prof. Lucy LumDepartment of PediatricsUniversity of Malaya

The 2011 revised World Health Organization (WHO) guidelines emphasize early diagnosis and intervention to reduce the case fatality rate due to dengue fever.52 (Pothapregada et al 2016) Maintaining hydration is associated with reduced risk of hospitalization in dengue cases. Evidence indicates that at least 5 glasses of fluid per day reduces hospitalization rates and this simple measure has protective effect against severity of dengue.53 (Harris et al, 2003) Fluid charts in outpatient clinics have also been shown to also reduce hospitalization rates and requirement of intravenous fluids.54 (Nasir et al, 2017) According to the 2009 WHO guidelines, fluid intake of 5 glasses or more is essential in adults suspected to have dengue fever. Fluids including milk, fruit juice, oral rehydration solution, and barley, rice water or coconut water are helpful in maintaining adequate hydration.54 (Nasir et al, 2017) In addition; management of co-morbid conditions is essential during dengue illness.

Fluid overload is common and associated with increased morbidity and mortality. 55-56 (Alobaidi et al, 2018; Payen et al, 2008) Proactive management of fluid therapy is essential to prevent fluid overload. Clinical assessment, hematological, biochemical and radiological monitoring of hemodynamic responses to fluid therapy is critical. Minute-to-minute evaluation and decision-making is essential in DSS to achieve and maintain hemodynamic equilibrium. Team training and rehearsal from triage to ICU team in recognition, fluid therapy and monitoring is crucial for successful outcome.

The stages of fluid resuscitation include rescue, optimization, stabilization and de-escalation.57 The goal of rescue phase is to correct shock (macro-circulation) and goal of optimization phase is to optimize and maintain tissue perfusion (microcirculation). The goal of stabilization phase is to aim for zero or negative fluid balance, which takes several days. The goal of last phase, de-escalation, is to mobilize accumulated fluid, which takes days to weeks.57 (Hoste et al, 2014)


37


SYMPOSIUM 3:LABORATORY DIAGNOSIS OF DENGUE

Moderators: Yasmin Malik, Lulu Brovo


38

How Reliable are Laboratory Diagnosis Methods for Arboviral Diseases

Dr. Butsaya ThaisomboonsukMedical Research Scientist at Department of VirologyUSAMD-AFRIMS

The presentation provided an overview of medically important arbovirus diseases, dengue immune response and its biological biomarkers, conventional laboratory dengue diagnosis, kinetics of dengue viremia IgM IgG and NS1 antigenemia, and evaluation of conventional dengue Diagnosis VS Rapid Test.

Studies on Markers of Severe Dengue

Dr. Ravindran ThayanHead of Virology Unit at Institute for Medical Research, Malaysia

The mechanism by which only a few DENV infected individuals progress to severe dengue disease (SDD) is poorly understood. Circulating immune-modulating proteins have brought new possibilities as prognostic markers of severe dengue; and viral factors, HLA, host protein, blood group and clinical signs act as further prognostic markers. The objectives of identifying markers for severe dengue in patients include triage of those at risk of developing severe dengue, reduction in cost of managing severe dengue patients (when intervention instituted earlier), prevention of unnecessary hospitalization and reduction of diseases burden. Identification of predictors of severe disease is crucial for reducing morbidity and mortality with dengue.58 (Jain et al, 2017) Extensive studies have been carried out to search for severe dengue diagnosis markers. Some of the methods used to identify severe dengue include ELISA, FACS, immunoarray, real time PCR, sequencing, microarray and meta-analysis. Certain biomarkers have been discovered with potentials as severe dengue markers, and these proteins are differently expressed among dengue, severe dengue and healthy individuals and other febrile illness. Alpha tubulin and thioredoxin peroxidase, and Alpha1-antitrypsin and NS1 protein can be used as early indicators of DHF risk and have the potential to be utilized as biomarkers for DHF.59-60 (Thayan et al, 2009) Clinical markers can also be used to predict SDD. Bleeding (hematemesis/melena), vomiting/nausea, abdominal pain, skin rashes, and hepatomegaly may predict the development of SDD.61 (Zhang et al, 2014)


39

Pre-Dengue Vaccination Testing: Reliability and Practicality

Assoc. Prof. Chukiat Sirivichayakul Department of Tropical PediatricsMahidol University, Thailand

Efficacy of CYD-TDV dengue vaccine has been demonstrated across three studies in Asian–Pacific and Latin America. Pooled vaccine efficacy from CYD14 and CYD15 in subjects aged >9 years was 81.9% in those who were seropositive at baseline compared to 52.5% in those who were seronegative at baseline. In the subjects aged <9 years, the corresponding vaccine efficacies were 70.1% and 14.4% respectively.35 (Hadinegoro et al, 2015) WHO-SAGE acknowledges the strong protective benefit of CYD-TDV in seropositive individuals; and in order to maximize the public health and minimize the impact on seronegative individuals, SAGE has recommended two main approaches; pre-vaccination screening and population seroprevalence.34 (WHO. Weekly epidemiological record, 2018) As per SAGE recommendations, the preferred option is a pre-vaccine screening strategy where only seropositive individuals are vaccinated. People with previous dengue infection can be identified through screening tests. Serological assays such as dengue IgG ELISA, and rapid diagnostic tests (RDT) can be considered. The ELISA assays do not provide point-of-care information, while currently available RDTs have not yet been validated for the purpose of screening for previous dengue infection.34 Sensitivity and specificity of the screening test, hospitalization rates and affordability of both CYD-TDV and screening tests will need to be considered at individual country level.34


40


SESSION 4:OVERVIEW OF DENGUE IN ADULTS

Moderators: Zulkifli Ismail, Rose Capeding


41

Plenary Lecture: Overview of Dengue in Adults

Prof. Terapong TantawichienChairman of Department of MedicineChulalongkorn University, Thailand

The WHO 2009 guideline emphasized that dengue is one disease entity with different clinical presentations and often with unpredictable clinical evolution and outcome. Older adults usually have clinical manifestation as DF; on the other hand, in adolescents and younger adults dengue commonly manifests as DHF. The challenges in adult patients include delayed diagnosis of DF and DHF, co-morbidities and higher incidence of internal bleeding with age. WHO guidelines highlight the diagnostic criteria for DF and DHF with clinical presentation and laboratory findings. Confirmatory diagnosis involves detection of viral antigen, NS1, PCR (polymerase chain reaction) and/or antibodies in serum. The Royal College Physician of Thailand practical guideline for management of dengue in adults states the indications for hospitalization in adults: one of the following criteria: significant bleeding, dengue shock syndrome (DSS), hematocrit > 50 %, platelet < 20,000/ mm3, AST or ALT > 500 IU/mL, acute renal failure, hepatic failure, heart failure, alteration of consciousness, severe hypoxemia, pregnant woman, morbid obesity or patients cannot follow up in an out-patient setting.62 (Tantawichien, 2015) Bleeding complications such as gastrointestinal bleeding and uterine bleeding are common in adult patients. The indications for platelet transfusions are bleeding associated with active peptic ulcer, trauma, liver failure, receiving antiplatelet, or platelets <10,000/mm62. Hormonal therapy might be needed in uterine bleeding. Close monitoring of vital signs, peripheral perfusion, and clinical assessment is recommended every 15-30 minutes until resolution of shock, and every 1-4 hours beyond.62 The Royal College Physician of Thailand indicates that hematocrit should be monitored 1-4 times per day; and fluid intake and output should be assessed every 1 to 4 hours.62


42


SYMPOSIUM 4:CRITICAL CARE MANAGEMENT OF

DENGUE IN ADULTS

Moderators: Terapong Tantawichien, Mahiran Mustafa


43

Dengue in Adults: Experience in Thailand, Malaysia, Indonesia and Vietnam

Dr. Nattachai Srisawat from Division of Nephrology, Department of Medicine, Chulalongkorn University, Thailand talked about the role of balanced solution in high-risk acute kidney injury patients and role of early organ support, and also touched upon dengue-induced hemophagocytic lymphohistiocytosis (HLH), which is a rare but serious condition where early recognition and treatment is essential.63 HLH is diagnosed either with molecular diagnosis or diagnostic criteria. Five of the total 8 criteria need to be fulfilled to establish the diagnosis of HLH. These include fever, splenomegaly, cytopenias, hypertriglyceridemia or hyperfibrinogenamia, hemophagocytosis in bone marrow/spleen/lymph nodes, and no evidence of malignancy, low or absent NK cell activity and high ferritin levels>500 μg/L.63 (Ray et al, 2017)

Dr. Shanthi Ratnam, Consultant Physician and Intensivist from Malaysia, highlighted that as per Clinical Practice Guidelines (CPG) recommendations in Malaysia all cases of severe dengue in shock should have echocardiography to look for evidence of cardiac dysfunction and to guide in fluid management. Adequate fluid resuscitation is a pre-requisite before myocardial dysfunction can be diagnosed and cautious volume resuscitation is required in those with myocardial dysfunction to avoid risk of iatrogenic fluid overload. Intravenous fluid therapy is the mainstay of treatment for dengue shock.64 (CPG Management of Dengue Infection in Adults (3rd Edition), Malaysia) Renal replacement therapy (RRT) should be provided early in the course of acute kidney injury. Hemodiafiltration, albumin dialysis, and plasma exchange are available options to provide artificial liver support.

Dr. Edsel Maurice T. Salvana from the University of The Philippines National Institutes of Health indicated that local Philippine Dengue Guidelines are based on WHO Guidelines from 2009.65 Group A patients receive same treatment per WHO with oral rehydration solution following specific targets for fluid hydration, with specific admonition against high osmolarity drinks such as sports drinks. For group B patients there is specific advice for added oral hydration in those without warning signs. For group C patients, with compensated and hypotensive shock, over-hydration should be avoided and fluids should not exceed 3 L/day, with no hard stop at 48 hours similar to WHO guidelines.65

Dr. Erni Juwita Nelwan, Division of Tropical and Infectious Disease, Faculty of Medicine Universitas Indonesia, reiterated that treatment of dengue in adults broadly includes intensive care admission, oxygenation, fluid balance and symptomatic drug treatment.


44


SESSION 5:DENGUE VECTOR CONTROL STRATEGIES


45

Plenary Lecture: Vector Control Strategies - Strategies to Control Aedes:What Works?Moderator: Lee Han Lim

Dr. Olaf HorstickDirector of Teaching at Institute of Public HealthUniversity of Heidelberg

Vector control strategies play an important role in reducing the burden of vector-borne disease by reducing or interrupting the disease transmission. However, cost-effectiveness, technical and administrative difficulties and lack of involvement of local communities are common obstacles in successful implementation of most vector control strategies. Therefore, the concept of integrated vector management (IVM) was introduced with the aim to prevent and control vector-borne diseases. IVM is “a rational decision-making process for the optimal use of resources for vector control”. The WHO position on IVM outlines its important attributes that include legislation, regulatory frameworks, intra and intersectoral collaboration (linking vector control with sanitation, clean water supply, development projects), along with decision-making criteria, capacity building, cost-effectiveness and mobilization of local communities.17 (WHO Position Statement on Integrated Vector Management, 2008) Although vector control can be beneficial, the efficacy is highly variable according to the type of intervention, implementation is difficult and data on the optimal delivery structures of vector control services is lacking.18 (Horstick et al, 2017)

Several vector control strategies such as peridomestic space spraying, indoor residual spraying, pyriproxyfen, organophosphate larvicide temephos, and use of Bacillus thuringiensis israelensis have been studied. Single vector control interventions are not successful, efficacy is highly variable and sustained community effectiveness has not been demonstrated. Furthermore, combinations of interventions have shown mixed results. To add to it, studies show that interventions are usually applied in outbreaks rather than to routine vector control.18 (Horstick et al, 2017). To be efficacious and community-effective, rigorous implementation of vector control measures is more important than the actual choice of combinations of vector control methods. There is an urgent need for standards to guide the design and reporting of vector control studies. Combinations of vaccines and vector control will be useful in reducing or interrupting the disease transmission.


46


SYMPOSIUM 5:DENGUE VECTOR CONTROL STRATEGIES

Moderators: Duane Gubler, Syed Sharizman


47

New Initiatives in Managing Dengue Vectors

Dr. Lee Han Lim from Medical Entomology Unit, WHO Collaborating CentreInstitute for Medical Research, Kuala Lumpur explained that Sterile Insect Technique (SIT) is a technique widely used in agricultural practice in order to control population of insects. SIT is an environmentally benign method of insect control in which large numbers of sterile males are released in the field. Mating of sterile males with native female insects results in reduction of female reproductive potential.26 (Alphey et al, 2010) SIT is cost-effective and can lead to suppression or elimination of target pest population. Several successful SIT programs have been documented such as screwworm fly Cochliomyia hominivorax Coquerel from the United States, Mexico, and Central America and fruit flies in the United States, Central and South America, South Africa, Europe, and Asia. SIT uses various technologies such as recombinant DNA technology, irradiation, aerial release, and Wolbachia.26

Evidence shows that the strategy of releasing genetically modified male mosquitoes can reduce the mosquito populations. However, in order to maintain the effect, continuous release of genetically modified male mosquitoes is required to compensate for migration of unmodified mosquitoes from neighboring areas.66 (Dorigatti et al, 2018) Another promising technique of dengue vector control involves release of Wolbachia infected mosquitoes, which after mating with native female mosquitoes result in production of unviable eggs.66 Wolbachia is a bacterium that is naturally present in many insect species. Deliberate introduction of Wolbachia infection in Aedes aegypti male mosquitoes has been shown to suppress arbovirus replication in mosquitoes through cytoplasmic incompatibility that results in development of unviable eggs.66 It is hypothesized that Wolbachia-infected Aedes aegypti mosquitoes can interrupt dengue transmission through two mechanisms; reduction in mosquito population density and/or lifespan and reduction of mosquito competence to transmit dengue.66

Currently 10 countries over the world are involved in Wolbachia infected mosquito field release. Dr. Chong Chee-Seng from Environmental Health Institute in Singapore, Dato Dr. Fadzilah Kamaludin from Institute for Medical Research (IMR) in Malaysia and Dr. Adi Utarini Professor, Department of Heath and Policy Management, Universitas Gadjah Mada presented updates on Wolbachia projects in Singapore, Malaysia and Indonesia respectively.

Dr. Nazni Bt Wasi Ahmad from Institute For Medical Research, Malaysia highlighted the effect of different doses (30, 35, 40, 45 and 50 Gy) of gamma radiation on Aedes aegypti. Higher doses of radiation are associated with higher impact on fecundity, sex ratio, hatchability, adult emergence and longevity.67 (Shetty et al, 2016)


48

ADVA Lunch SymposiumCommunication and Advocacy: A Priority in a Dengue Vaccination ProgramModerators: Lucy Lum, Sally Gatchalian

Prof. Emeritus Lulu BravoUniversity of Philippines, Manila

The importance of advocacy and effective communication prior to dengue vaccination based on current experience in Philippines cannot be stressed. In November 2017 Sanofi announced that, “Based on up to six years of clinical data, the new analysis confirmed that Dengvaxia provides persistent protective benefit against dengue fever in those who had prior infection. For those not previously infected by dengue virus, however, the analysis found that in the longer term, more cases of severe disease could occur following vaccination upon a subsequent dengue infection” Following the report issued by Sanofi, an extremely negative reaction occurred in Philippines with widespread public panic and increasing political interest. In addition, there was a significant reduction in EPI vaccination resulting in measles outbreaks in Philippines. Several lessons have been learnt from the Philippines experience with dengue vaccination. Establishing good communication among all stakeholders and having a robust advocacy plan is extremely crucial prior to dengue vaccination program. There is a need to identify all partners and stakeholders, and conduct research and pilot project prior to the national or sub-national vaccine introduction. Vaccine should be considered as an investment in health and not as a political tool.

How to Mobilize Resources and Political Support for Dengue Control – Lessons from Malaria

Dr. Benjamin RolfeCEOofAsiaPacificLeadersMalariaAlliance(APLMA) The goal of Asia Pacific Leaders Malaria Alliance is to Eliminate malaria in Asia Pacific by 2030. Maintaining political commitment and finance are important for success of malaria control measures. Lessons learnt from malaria control can be useful in dengue management. In order to mobilize resources and political support for dengue control, there is a need to advocate for health system strengthening and health security, craft regional solutions based on national commitments, present an investment case and expand pool of champions.


49


SESSION 6:DENGUE VACCINES AND THEIR FUTURE


50

Plenary Lecture: Current Status of Dengue Vaccines – Challenges and OpportunitiesModerators: Tikki Pangestu, Zulkifli Issmail

Prof. Donald S. Shepard, Professor at Heller School for Social Policy and Management, Brandeis University, USA presented a talk on current status of dengue vaccines covering the dengue vaccine pipeline and role of pre-vaccine testing in minimizing hospitalizations.

Dengue Vaccines – Update of Vaccine Pipelines

Representatives from Sanofi, Takeda and MSD presented an update on dengue vaccine. Sanofi Pasteur’s CYD-TDV Dengue Vaccine has demonstrated efficacy against symptomatic dengue cases due to any serotype and regardless of severity. CYD-TDV protects against hospitalized and severe dengue for 5 years in those exposed to dengue prior to vaccination. However, there is a higher risk of hospitalization and severe dengue in those vaccinated individuals who have no previous exposure to dengue.37 Determination of pre-vaccination dengue infection status before vaccination is recommended. Takeda’s live-attenuated Tetravalent Dengue Vaccine candidate (TDV) is a DENV-2-based recombinant vaccine. Data from phase 1 and 2 studies confirm that TDV given at 2-dose (Month 0,3) schedule is immunogenic and elicits neutralizing antibodies against all 4 DENV serotypes that persist through 18 months regardless of serostatus at baseline.68 (Sáez-Llorens et al, 2018)


51


SYMPOSIUM 6:DENGUE VACCINES AND THEIR FUTURE

Moderators: Tikki Pangestu, Zulkifli Issmail


52

Dengue Immunization in Philippines

Prof. Juliet Sio AguilarProfessor and Chair of PediatricsHead of Dengue Investigative Task ForcePhilippine General Hospital

Following a statement release by Sanofi Pasteur on differences in vaccine performance based on prior dengue infection, certificate of product registration of Dengvaxia and vaccination program was suspended in Philippines. Interim guidelines on surveillance of adverse events following immunization, investigating deaths related to Dengvaxia vaccination, risk communication for Dengue/Dengvaxia immunization concerns and health financing for medical needs of Dengvaxia vaccines have been released. Capacity-building towards the development of centers of excellence for dengue management, continued dengue surveillance and increased public awareness will play a crucial role in tackling dengue. Capacity building in assessment of adverse events following immunization and continued research for diagnostic tests will be necessary.


53

Guideline for Dengue Vaccination

Dr. Sri Rezeki HadinegoroDepartment of Child Health, Indonesia

As per global strategy for dengue prevention and control, 2012-2020, WHO objectives include reduction in dengue mortality by at least 50% by 2020 and reduction in dengue morbidity by at least 25% by 2020.33 (WHO Global strategy for dengue prevention and control 2012-2020) The Strategic Advisory Group of Experts (SAGE) on immunization acknowledges that an integrated approach for dengue prevention and control should include sustained vector control, best evidence-based clinical care and vaccination.34 (WHO Weekly epidemiological record, 2018) Findings from the dengue anti–nonstructural protein (NS1) case-cohort study showed that the though the vaccine had a favorable effect on public health, seropositive and seronegative individuals reacted differently. Overall population benefit was seen in seropositive individuals aged 9 years or older; however, there was an increased risk in seronegative individuals.34

In November 2017, after the vaccine manufacturer warned that the dengue vaccine could increase the risk of severe dengue in seronegative recipients of all ages, there was a climate of fear and loss of public confidence and trust. Following which, WHO SAGE issued revised recommendations on use of dengue vaccine in April 2018. WHO/SAGE acknowledges the strong protective benefit of CYD-TDV in seropositive individuals.

In order to maximize the public health and minimize the impact on seronegative individuals, SAGE has recommended two main approaches.34 The preferred approach is pre-vaccination screening with only confirmed dengue-seropositive persons receiving vaccination. The alternate approach is using population seroprevalence, with mass vaccination in identified high seroprevalence areas without serological screening.34 Major challenge in pre-vaccination screening is that the tests need to be highly specific to minimize harm in sero-negative persons and highly sensitive to ensure seropositive persons would benefit. Such tests would need to be deliverable at point-of-care as rapid diagnostic tests (RDT). To date, no RDTs have been validated and licensed for the indication of screening for past dengue infection.34


54

Roadmap to Freedom from Dengue

Prof. Pratap SinghasivanonDean of the Faculty of Tropical Medicine, Mahidol UniversityDirector of SEAMEO TROPMED Thailand

Major challenges involved in dengue management include uncontrolled urbanization due to inadequate management of housing, piped water, sewage and waste, unrecognized high transmission potential of asymptomatic dengue and inadequate vector control strategies. As per global strategy for dengue prevention and control, 2012-2020, WHO objectives include reduction of dengue mortality by at least 50% by 2020 and reduction in dengue morbidity by at least 25% by 2020.33

In order to achieve the WHO goals it is essential to appreciate that dengue prevention and control is a shared responsibility. Unless everyone plays a role, dengue will not be controlled. Key actions should include social mobilization, vector control, case management, surveillance, outbreak response and research. Since a vaccine is essential for dengue control, advocacy is needed to shorten the time between vaccine discovery, vaccine introduction, and disease control. Individuals, communities, private sector and government agencies need to work together for elimination of dengue. A well thought out strategy is essential to enable implementation of effective tools for diagnosis, treatment and prevention to interrupt transmission. Knowledge of social, cultural and political factors, which may vary from area to area, will be important.


55

POSTER ABSTRACTS


56

Epidemiology of Dengue Fever in Taiz, Yemen During War

Khairallah A. Alghazaly, Boon-Teong Teoh, Mohammed A. K. Mahdy,and Sazaly AbuBakar

Institutions and Country TIDREC, University of Malaya, Malaysia

Abstract: The association between wars and the dengue transmission has long been well-recognized. Recently, the current civil war in Yemen which started in March 2015, caused widespread destruction of the country’s infrastructures and displaced more than 2.2 million people into living in cramp shelters with inadequate healthcare support. Taiz, a southwestern governorate in Yemen experienced among the fiercest fighting. In Taiz governorate an extreme spike in dengue cases was recorded since August 2015, soon after the start of the current civil war. A total of 1,178 cases were reported between week-32 to week-36 of 2015, in comparison to only 54 dengue-suspected cases during the same period in 2013. In this study, the laboratory diagnosis of dengue, the isolation of dengue virus (DENV) as well as a cross-sectional questionnaire survey about the knowledge, attitude and practices (KAP) towards dengue were conducted among febrile patients seen in the few surviving healthcare facilities within Taiz-city during the period between July and October 2016 at the height of the war. Dengue was laboratory confirmed in ~51% of the clinically suspected dengue patients seen in Taiz, Yemen in 2016. DENV-2 Cosmopolitan genotype is the pre-dominant causative virus. Also, people in Taiz city of Yemen have a vague understanding of the transmission of DF, their attitudes towards various aspects of the disease were weak and they rarely undertook preventive practices against the disease. Therefore, it is expected that the public health problems associated with dengue will worsen with the continuing civil war in Yemen.www.asiadenguesummit.org

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Standardization in Operationalized Maps: Essential Element in Monitoring the Annual Trend of Dengue Morbidity and Mortality

JRC Medina1, S Kawamura2, KE Hung2, F Furukawa2, KI Tiu3, D Nonaka1,PMR Hernandez1, FB Garcia4, M Kaneko2, J Kobayashi2

Institutions and Country:1 Department of Global Health, Graduate School of Health Sciences, University of the Ryukyus, Okinawa,

Japan2 Department of Environmental and Symbiotic Science, Rakuno Gakuen University, Hokkaido, Japan3 OfficeofTechnicalServices,DepartmentofHealth,Philippines4 College of Public Health, University of the Philippines Manila, Manila, Philippines

Background: Data visualization with maps is useful for dengue surveillance and monitoring the effectiveness of control strategies. However, variations in interpretation may arise depending on how variables are defined and operationalized. This study aimed to spatially and temporally describe dengue morbidities and mortalities across three map transformations.

Methods: Aggregated regional data of dengue cases from 2012 to 2017 in the Philippines was obtained from the Department of Health for a mixed-typed ecologic study. Annual cumulative incidence and mortality rates (both per 100,000) were estimated and indirectly standardized in each region. Choropleth maps were created using ArcGIS 10.5.1 (ESRI, 2016) to compare the variation across the transformations. To operationalize the maps, natural breaks were used for classification into five classes.

Results: Regions III, IVA, and NCR had the highest morbidity counts across years. However, incidence maps showed temporal persistence in CAR (2012- 2016) and Regions VI and VII (2016-2017). Visualizing the standardized morbidity rates validates the incidence maps. Most fatalities were reported almost consistently from Regions IVA, VI, VII, and XI, but the mortality rate maps excluded Region IVA. Mapping the standardized mortality rates supported the spatial distribution in the latter one.

Conclusion: The spatial distribution of dengue cases and mortalities across years varies depending on the operationalization of maps. Integration of standardization in disease mapping is essential to validate the interpretation of count and rate maps. This will be helpful in identifying and prioritizing foci where control efforts are mostly needed.


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Dynamic Modulation of DC-SIGN Receptor Expression on Platelets in Dengue

Sojit Tomo, SR Vijaykumar, M Sindhujadevi, MS Daisy, S Sevanthy, BP Agieshkumar, T Kadhiravan, R Rameshkumar, R Soundravally

Department of Biochemistry, Jawaharlal Institute of Post-graduate Medical Education and Research (JIPMER), Puducherry , INDIA.

Background: Platelet activation and Cells expressing DC-SIGN receptors have been reported to play a major role in dengue infection. The present study is designed to assess the expression of the receptor on platelet surface collected from dengue patients and to study its association of platelet RNA positive for dengue virus.

Methods: This was an analytical cross-sectional study carried out in JIPMER hospital, Puducherry. 44 patients with dengue infection (cases) and 44 patients with non dengue acute other febrile illness(controls) were recruited. Venous blood was collected on :admission day, day 3 and on discharge. Platelet rich plasma extracted was assessed for DC-SIGN levels using BD FACS Calibur™. Platelets separated from cases were subjected to RNA extraction and detected the presence of viral RNA.

Results: The study observed a decreased expression of DC-SIGN on platelets in cases compared to controls on all the time points. An increasing trend of expression of DC-SIGN on platelets in cases during the course of infection with decrease in expression in cases who were positive for NS1 antigen was observed. Dengue viral RNA was detected only in 16 cases out of 30 cases. DC-SIGN expression was found to be decreased in patients positive for platelet DENV RNA when compared with patients negative for platelet DENV RNA.

Conclusion: Our results suggest that DC-SIGN which is a receptor for viral capture, might be down regulated on platelets in patients with dengue infection. This could be part of protective response from the host to prevent platelets from taking part in the ongoing conflict between immune system and dengue virus.


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Therapeutic Potential of Mushroom Extracts in Vitro Dengue Virus Infection

E Kavithambigai, T Ravindran, R Jegadeesh, IPJH Kazuya and S Vikineswary

Virology Unit, Infectious Disease Research Centre, Institute for Medical Research, Ministry of Health, Kuala Lumpur, Malaysia

Background: Dengue disease is a mosquito-borne viral infection that has become a major public health concern worldwide. At present, no effective anti-dengue agents available for treatment of dengue infection. In this study, culinary and medicinal mushrooms were selected to evaluate their anti-dengue activity as they possess a wide range of pharmacological properties. Method: Mushrooms selected for this study were Cordyceps militaris, Lignosus rhinocerotis, Pleurotus giganteus, Hericium erinaceus, Schizophyllum commune and Ganoderma lucidium. Hot aqueous extract (HAE), ethanol extracts (EE) and its fractions, hexane soluble (HSE), ethyl acetate soluble (ESE) and aqueous soluble (ASE) extracts were prepared from selected mushrooms. Cytotoxic effect of extracts was evaluated by MTT assay. The antiviral effect against DENV2 in Vero cells was evaluated by plaque reduction assay and real-time RT-PCR. The anti-inflammatory effect of extracts was studied using human monocytes infected with DENV-2 by measuring the cytokine coincide with dengue infection, IFN-γ, TNF-α, IL-1β, IL-6, IL-8 and IL-10.

Results: HAE and ASE of L. rhinocerotis, P. giganteus, H. erinaceus and S. commune were least toxic to Vero cells and showed very prominent anti-dengue activities during simultaneous and post internalization treatment. They also showed broad spectrum of anti-dengue activity by inhibiting all other dengue serotypes. Chemical composition analysis showed that the major components in mushroom HAE and AF were glucan and proteins. Mushroom extracts also showed prominent anti-inflammatory effect towards IFN-γ, IL-10, TNF-α, IL-6 and IL-1β.

Conclusion: The anti-viral and anti-inflammatory activity showed by mushroom extracts had proven that mushroom extracts have a great potential to develop as a therapeutic agent for treatment of dengue infection.


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An Insight of an Outbreak Investigation Report of Dengue in Samdrup Jongkhar, Bhutan, 2017

S Zangmo1, K Dorji2, K Wangdi3, K Dendup3, P Tshewang3, D Pemo3

1 Central Regional Referral Hospital, Gelephu Bhutan;2 SamdrupJongkhar General Hospital, SamdrupJongkhar &, Sarpang, Bhutan.3 Royal Centre for Disease Control, Serbithang, Thimphu, Bhutan

Background: Dengue was first identified in Phuntsholing, Bhutan in 2004, since then, it has spread throughout its neighbouring southern district towns causing large outbreaks. We conducted an epidemiological, socio-demographic and entomological survey to determine the causes of outbreak and to provide preventive and control measures to the administration.

Methods: All confirmed cases of dengue fever diagnosed on basis of NS1 Ag and IgM rapid test kits at Samdrup Jongkhar District hospital were studied for their socio-demographic profile. An entomological survey was done for vector identification and control measures. A total of 187 confirmed cases were studied.

Results: Demographically, Dengue affected maximum number of Businessmen followed by Civil servants between 20-40 years of age with male predominance. The cases peaked during the monsoon and post monsoon season. The patients invariably presented with fever followed by headache, retro-orbital pain, myalgia and rash and very few had bleeding manifestations. House Index was recorded high in all areas of the town. The species identified was mainly Ae.aegyptii. > 60% of the population were aware about Dengue but unaware about preventive measures. >70% of the population stored water at home and <10% of the population changed the stored water.

Conclusion: The 2017 outbreak was exacerbated drinking water shortage, where the tenants had to store water in buckets and containers indoor for weeks or more. Community collaboration and support is crucial for prevention of future outbreaks, particularly through the elimination of breeding places for Aedes aegypti.


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Risk and Prognostic Factors for Severe Dengue in Adult Population in IntensiveCare Unit, Hospital Raja Perempuan Zainab II, Kota Bharu,Kelantan

SN Ibrahim, MN Ali, M Shaary, WN Wan Ismail, M Omar, NA Nik Mohamad

Department of Anaesthesiology & Intensive Care Unit, Hospital Raja Perempuan Zainab II, Kota Bharu,Kelantan / Malaysia

Background: The understanding of the associated risk and prognostic factor for development of severe dengue is fundamental to improved clinical outcome of the patient. This study was initiated to identify risk and prognostic factor severe dengue in adult patient admitted into Intensive Care Unit.

Method: This was a retrospective cross-sectional study involved 129 adult patients with laboratory-confirmed dengue fever infection who were admitted in the intensive care unit, Hospital Raja Perempuan Zainab 11 from 1 January 2014 till 31 December 2015. The patients were categorized into two groups. ”World Health Organization 1997, 2009 criteria for dengue severity was applied to defined severe and non-severe group. The medical record of the entire recruited patient was recorded for the following information; demographic factor, clinical manifestation, laboratory examination, the complication in intensive care unit and the clinical outcome. Logistic regression modeling was performed to determine factor independently associated with dengue severity and poor outcome.

Result: Data of 129 patients were analyzed. Seventy-four patients were enrolled in severe group and another fifty-five patients were enrolled in non-severe group. Mean age of the patient is 36.2[33.32-39.08] and 59% are females and another 40.3% are males. The most common comorbidities included hypertension (24%), diabetes mellitus (11.6%) and ischemic heart disease (2.3%). Seven variables were significantly associated with severity of dengue fever at univariable level. However, only two variables were significance after multivariable analysis, namely aspartate aminotransferase (AST) (OR: 1.001[1.00, 1.00], P=0.021); and creatinine (OR: 1.014[1.00, 1.03], P= 0.019) Seven variables were significantly associated with poor outcome of dengue fever at univariable level. However, only one variable was significant after multivariable analysis, namely the SOFA score (OR: 1.94 [1.35, 2.77], P < 0.001)

Conclusion: In this study, an elevated aspartate aminotransferase (AST) and creatinine level increase the risk of development of severe dengue. Patient with higher SOFA score was associated with poor dengue outcome.


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CALL FOR ACTION ONDENGUE PREVENTION AND CONTROL


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Call for Action

As an outcome of the 3rd Asian Dengue Summit, the experts agreed on and formulated the following as Call for Action in an effort to control and prevent dengue in Asia.

• Dengue prevention and control is a shared responsibility with multi-sectorial partnership between individuals, communities, healthcare professionals, policy makers, and private sector and government agencies.

• Key actions in dengue prevention and control should include:- Robust disease surveillance, epidemic preparedness and outbreak response

capacity- Community-effective and sustained implementation of vector control- Availability of best-evidence based clinical care- Vaccination of seropositive individuals in areas with high seroprevalence- Political commitment - Public awareness and social mobilization

• There is a need to strengthen the national surveillance systems to enhance monitoring of epidemiological and clinical trends.

• Rigorous implementation of integrated vector management is essential to achieve sustained community-effectiveness.

• In order to provide the best possible evidence-based care to dengue patients and allow justification for resource allocation, a stronger and broader evidence base should be generated.

• Continuous vaccine advocacy and effective communication of benefits and risks associated with dengue vaccine will play an important role in restoring public, healthcare professional and policy makers’ confidence in vaccine efficacy and safety.

• Pilot projects must be conducted prior to the national or sub-national vaccine introduction. Post licensure follow-up to monitor the safety and effectiveness profiles of the vaccine is essential.

• Development of rapid, accurate and affordable point of care rapid diagnostic tests to identify seropositive individuals should be prioritized.

• The remarkably more infectious nature of asymptomatic dengue infection and its role in constant prevalence of the disease needs to be acknowledged. Further research on human to mosquito transmission is warranted.


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