guideline dhf who 09

7/30/2019 Guideline DHF WHO 09

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New edition2009

DENGUEGUIDELINES FOR DIAGNOSIS,

TREATMENT, PREVENTION AND CONTROL


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New edition2009

DENGUEGUIDELINES FOR DIAGNOSIS,

TREATMENT, PREVENTION AND CONTROL

A joint publication o the World Health Organization (WHO) and the Special Programme or Research

and Training in Tropical Diseases (TDR)


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WHO/HTM/NTD/DEN/2009.1Expiry date: 2014

World Health Organization 2009

All rights reserved. Publications o the World Health Organization can be obtained rom WHO Press,World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264;ax: +41 22 791 4857; e-mail: [email protected]). Requests or permission to reproduce or translateWHO publications whether or sale or or noncommercial distribution should be addressed to WHOPress, at the above address (ax: +41 22 791 4806; e-mail: [email protected]).

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All reasonable precautions have been taken by the World Health Organization to veriy the inormationcontained in this publication. However, the published material is being distributed without warranty o anykind, either expressed or implied. The responsibility or the interpretation and use o the material lies withthe reader. In no event shall the World Health Organization be liable or damages arising rom its use.

Printed in France

Cover and Layout: P. Tissot WHO/HTM/NTD

WHO Library Cataloguing-in-Publication Data

Dengue: guidelines or diagnosis, treatment, prevention and control -- New edition.

1.Dengue - diagnosis. 2.Dengue - therapy. 3.Dengue - prevention and control. 4.Endemic Diseases -prevention and control. 5.Fluid therapy. 6.Diagnosis, dierential. 7.Disease outbreaks - prevention andcontrol. 8.Mosquito control. 9.Guidelines. I.World Health Organization.

ISBN 978 92 4 154787 1 (NLM classiication: WC 528)


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iii

Introduction, Methodology, Acknowledgements, Abbreviations, Preace

CONTENTS

Preace -------------------------------------------------------------------------------------------------------------------------------------------------------vMethodology --------------------------------------------------------------------------------------------------------------------------------------------- viAcknowledgements -------------------------------------------------------------------------------------------------------------------------------- viiAbbreviations -------------------------------------------------------------------------------------------------------------------------------------------- ix

Chapter 1 Epidemiology, burden o disease and transmission1.1 Dengue epidemiology -----------------------------------------------------------------------------------------------31.2 Burden o disease --------------------------------------------------------------------------------------------------------121.3 Dengue in international travel --------------------------------------------------------------------------------131.4 Transmission ---------------------------------------------------------------------------------------------------------------------14

1.5 Reerences ------------------------------------------------------------------------------------------------------------------------17

Chapter 2 Clinical management and delivery o clinical services2.1 Overview --------------------------------------------------------------------------------------------------------------------------252.2 Delivery o clinical services and case management ---------------------------------292.3 Recommendations or treatment ----------------------------------------------------------------------------322.4 Reerences ------------------------------------------------------------------------------------------------------------------------54

Chapter 3 Vector management and delivery o vector control services

3.1 Overview --------------------------------------------------------------------------------------------------------------------------59

3.2 Methods o vector control -------------------------------------------------------------------------------------- 603.3 Delivery o vector control interventions -------------------------------------------------------------723.4 Reerences ------------------------------------------------------------------------------------------------------------------------86

Chapter 4 Laboratory diagnosis and diagnostic tests4.1 Overview --------------------------------------------------------------------------------------------------------------------------914.2 Considerations in the choice o diagnostic methods --------------------------------934.3 Current dengue diagnostic methods ----------------------------------------------------------------974.4 Future test developments ------------------------------------------------------------------------------------------- 1034.5 Quality assurance --------------------------------------------------------------------------------------------------------104

4.6 Biosaety issues --------------------------------------------------------------------------------------------------------------1044.7 Organization o laboratory services ------------------------------------------------------------------1044.8 Reerences ------------------------------------------------------------------------------------------------------------------------106

Chapter 5 Surveillance, emergency preparedness and response5.1 Overview --------------------------------------------------------------------------------------------------------------------------1115.2 Dengue surveillance ----------------------------------------------------------------------------------------------------1115.3 Dengue preparedness planning and response -------------------------------------------- 1235.4 Programme assessment --------------------------------------------------------------------------------------------- 1285.5 Reerences ------------------------------------------------------------------------------------------------------------------------132

Chapter 6 New avenues6.1 Overview --------------------------------------------------------------------------------------------------------------------------1376.2 Dengue vaccines ----------------------------------------------------------------------------------------------------------1376.3 Dengue antiviral drugs ---------------------------------------------------------------------------------------------- 1416.4 Reerences ------------------------------------------------------------------------------------------------------------------------144


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iv

Dengue: Guidelines or diagnosis, treatment, prevention and control


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PREFACE

Since the second edition o Dengue haemorrhagic ever: diagnosis, treatment, preventionand controlwas published by the World Health Organization (WHO) in 1997, themagnitude o the dengue problem has increased dramatically and has extendedgeographically to many previously unaected areas. It was then, and remains today,the most important arthropod-borne viral disease o humans.

Activities undertaken by WHO regarding dengue are most recently guided at the globalpolicy level by World Health Assembly resolution WHA55.17 (adopted by the Fity-ithWorld Health Assembly in 2002) and at the regional level by resolution CE140.R17 othe Pan American Sanitary Conerence (2007), resolution WPR/RC59.R6 o the WHO

Regional Committee or the Western Paciic (2008) and resolution SEA/RC61/R5 othe WHO Regional Committee or South-East Asia (2008).

This new edition has been produced to make widely available to health practitioners,laboratory personnel, those involved in vector control and other public health oicials,a concise source o inormation o worldwide relevance on dengue. The guidelinesprovide updated practical inormation on the clinical management and delivery oclinical services; vector management and delivery o vector control services; laboratorydiagnosis and diagnostic tests; and surveillance, emergency preparedness and response.Looking ahead, some indications o new and promising avenues o research are also

described. Additional and more detailed speciic guidance on the various specialistareas related to dengue are available rom other sources in WHO and elsewhere,some o which are cited in the reerences.

The contributions o, and review by, many experts both within and outside WHO haveacilitated the preparation o this publication through consultative and peer reviewprocesses. All contributors are grateully acknowledged, a list o whom appears underAcknowledgements. These guidelines are the result o collaboration between theWHO Department o Control Neglected Tropical Diseases, the WHO Department oEpidemic and Pandemic Alert and Response, and the Special Programme or Research

and Training in Tropical Diseases.

This publication is intended to contribute to prevention and control o the morbidity andmortality associated with dengue and to serve as an authoritative reerence source orhealth workers and researchers. These guidelines are not intended to replace nationalguidelines but to assist in the development o national or regional guidelines. They areexpected to remain valid or ive years (until 2014), although developments in researchcould change their validity, since many aspects o the prevention and control o dengueare currently being investigated in a variety o studies. The guidelines contain the mostup-to-date inormation at the time o writing. However, the results o studies are being

published regularly and should be taken into account. To address this challenge, theguide is also available on the Internet and will be updated regularly by WHO.


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METHODOLOGY

These guidelines were written using the ollowing methodology:1. Writing team

Each chapter was allocated to a WHO coordinator and at least one non-WHO leadwriter. The non-WHO lead writers received a small ee or their work. Declarations ointerest were obtained rom all lead writers and no conlicting interests were declared.The lead writers were chosen because o their expertise in the ield and their willingnessto undertake the work.

Since this guide has the broad scope o all aspects o prevention and control o dengue,

the lead writers were selected or technical expertise in the areas o epidemiology,pathogenesis and transmission, clinical aspects, vector control, laboratory aspects,surveillance and response, and drug and vaccine development.

2. Peer review

All the chapters were submitted to peer review. The peer review groups were determinedby the WHO coordinator and the non-WHO lead writers o each chapter. The groupsconsisted o ive or more peer reviewers, who were not paid or their work. Declarationso interest were obtained rom all peer reviewers. For those peer reviewers with potentialconlicting interests, the interests are declared below.1

For each chapter, the process o reaching agreement on disputed issues diered. Forchapters 1, 3, 4 and 6, the comments o the peer reviewers were discussed electronicallywithin the group. Chapter 2 had a larger group whose members met or a consensusgroup discussion. Chapter 5 required extensive discussion, but consensus was reachedwithout a consensus group meeting. Agreement on the chapter content was reached orall the groups.

3. Use o evidence

For each chapter, items are reerenced that (1) provide new data, (2) challenge currentpractice, (3) describe ongoing research and (4) relect key developments in knowledgeabout dengue prevention and control.

Priority was given to systematic reviews when available. Additional literature searcheswere conducted by the writing teams when items under 1--3 were identiied, andreerences rom personal collections o experts were added when appropriate under 4.The writing teams reerred to the items under 1--4 in the text, and lists o reerences wereadded at the end o each chapter.

1 Declared interests:

Chapter 1. Dr Anne Wilder Smith: principal investigator in dengue vaccine trial starting in 2009.

Chapter 4. Dr Mary Jane Cardosa: shareholder and director o company developing dengue diagnostic tests.

Chapter 6. Dr Robert Edelman: consultant or company involved in dengue vaccine research.


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ACKNOWLEDGEMENTS

This new edition o the dengue guidelines would not have been possible withoutthe initiative, practical experience o many years o working in dengue, and writingcontribution o Dr Michael B. Nathan, now retired rom the World Health Organization(WHO).

Dr Axel Kroeger o the Special Programme or Research and Training in Tropical Diseases(WHO/TDR) equally contributed to all parts o the guidelines.

Dr John Ehrenberg, Dr Chusak Prasittisuk and Dr Jose Luis San Martin, as WHO regionaladvisers on dengue, contributed their unique experience to all chapters.

Dr Renu Dayal Drager (WHO) and Dr Jeremy Farrar (the Wellcome Trust) contributedtechnical advice to several chapters.

Dr Raman Velayudhan (WHO) coordinated the inalization and publication o the guideand advised on all the chapters.

Dr Ola Horstick (WHO/TDR) assembled the evidence base, contributed to all chaptersand contributed to the inalization o the guide.

Special thanks are due to the editorial team o Mrs Karen Ciceri and Mr Patrick Tissotat WHO.

The ollowing individuals contributed to chapters as lead writers, advisers or peerreviewers:

Chapter 1

Lead writers: Dr Michael B. Nathan, Dr Renu Dayal-Drager, Dr Maria Guzman.Advisers and peer reviewers: Dr Olivia Brathwaite, Dr Scott Halstead, Dr Anand Joshi,Dr Romeo Montoya, Dr Cameron Simmons, Dr Thomas Jaenisch, Dr Annelies Wilder-

Smith, Dr Mary Wilson.

Chapter 2

Lead writers: Dr Jacqueline Deen, Dr Lucy Lum, Dr Eric Martinez, Dr Lian Huat Tan.Advisers and peer reviewers: Dr Jeremy Farrar, Dr Ivo Castelo Branco, Dr Eren Dimaano,Dr Eva Harris, Dr Nguyen Hung, Dr Ida Saitri Laksono, Dr Jose Martinez, Dr ErnestoBenjamn Pleites, Dr Rivaldo Venancio, Dr Elci Villegas, Dr Martin Weber, Dr BridgetWills.

Chapter 3Lead writers: Dr Philip McCall, Dr Linda Lloyd, Dr Michael B. Nathan.Advisers and peer reviewers: Dr Satish Appoo, Dr Roberto Barrera, Dr Robert Bos,Dr Mohammadu Kabir Cham, Dr Gary G. Clark, Dr Christian Frederickson, Dr Vu SinhNam, Dr Chang Moh Seng, Dr Tom W. Scott, Dr Indra Vithylingam, Dr Rajpal Yadav,Dr Andr Yebakima, Dr Raman Velayudhan, Dr Morteza Zaim.


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Chapter 4

Lead writers: Dr Philippe Buchy, Dr Rosanna Peeling.Advisers and peer reviewers: Dr Harvey Artsob, Dr Jane Cardosa, Dr Renu Dayal-Drager, Dr Duane Gubler, Dr Maria Guzman, Dr Elizabeth Hunsperger, Dr Lucy Lum,

Dr Eric Martinez, Dr Jose Pelegrino, Dr Susana Vazquez.

Chapter 5

Lead writers: Dr Duane Gubler, Dr Gary G. Clark, Dr Renu Dayal-Drager, Dr Dana Focks,Dr Axel Kroeger, Dr Angela Merianos, Dr Cathy Roth.Advisers and peer reviewers: Dr Pierre Formenty, Dr Reinhard Junghecker, Dr DominiqueLegros, Dr Silvia Runge-Ranzinger, Dr Jos Rigau-Prez.

Chapter 6

Lead writers: Dr Eva Harris, Dr Joachim Hombach, Dr Janis Lazdins-Held.Advisers and peer reviewers: Dr Bruno Canard, Dr Anne Durbin, Dr Robert Edelman,Dr Maria Guzman, Dr John Roehrig, Dr Subhash Vasudevan.


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ix


ABBREVIATIONS

a.i. ad interimADE antibody-dependent enhancementALT alanine amino transeraseAST aspartate amino transeraseBP blood pressureBSL biosaety levelBti Bacillus thuringiensis israelensisCD4 cluster o dierentiation 4, T helper cell surace glycoproteinCD8 cluster o dierentiation 8, T cell co-receptor transmembrane glycoprotein

CFR case-atality rateCOMBI communication or behavioural impactDALY disability-adjusted lie yearsDEET diethyl-meta-toluamideDENCO Dengue and Control study (multi-country study)DEN dengueDDT dichlorodiphenyltrichloroethaneDF dengue everDHF dengue haemorrhagic everDNA deoxyribonucleic acidDSS dengue shock syndromeDT tablet or direct applicationEC emulsiiable concentrateELISA enzyme-linked immunosorbent assayE/M envelop/membrane antigenFBC ull blood countFc-receptor ragment, crystallisable region, a cell receptor

FRhL etal rhesus lung cellsGAC E/M-speciic capture IgG ELISAGIS Geographical Inormation SystemGOARN Global Outbreak Alert and Response NetworkGPS global positioning systemGR granuleHI haemagglutination-inhibitionHIV/AIDS human immunodeiciency virus/acquired immunodeiciency syndromeICU intensive care unit

IEC inormation, education, communicationIgA immunoglobulin AIgG immunoglobulin GIgM immunoglobulin MINF gamma intereron gamma


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IPCS International Programme on Chemical SaetyIR3535 3-[N-acetyl-N-butyl]-aminopropionic acid ethyl esterITM insecticide treated materialIV intravenous

LAV live attenuated vaccineMAC-ELISA IgM antibody-capture enzyme-linked immunosorbent assayMIA microsphere-based immunoassaysMoE Ministry o EducationMoH Ministry o HealthNAAT nucleic acid ampliication testNASBA nucleic acid sequence based ampliicationNGO nongovernmental organizationNS non-structural proteinNSAID non-steroidal anti-inlammatory drugsOD optical densityORS oral rehydration solutionPAHO Pan American Health OrganizationPCR polymerase chain reactionPDVI Pediatric Dengue Vaccine InitiativepH measure o the acidity or basicity o a solutionprM a region o the dengue genome

PRNT plaque reduction and neutralization testRNA ribonucleic acidRT-PCR reverse transcriptase-polymerase chain reactionSC suspension concentrateTNF ala tumor necrosis actor alaT cells A group o lymphocytes important or cell-mediated immunityTDR Special Programme or Research and Training in Tropical DiseasesWBC white blood cellsWG Water-dispersible granule

WHO World Health OrganizaionWP wettable powderYF yellow ever


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Chapter 1: Epidemiology, burden o disease and transmission

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CHAPTER1

CHAPTER 1

EPIDEMIOLOGY, BURDEN OF DISEASEAND TRANSMISSION


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CHAPTER1

CHAPTER 1. EPIDEMIOLOGY, BURDEN OF DISEASE ANDTRANSMISSION

1.1 DENGUE EPIDEMIOLOGY

Dengue is the most rapidly spreading mosquito-borne viral disease in the world. In thelast 50 years, incidence has increased 30-old with increasing geographic expansionto new countries and, in the present decade, rom urban to rural settings (Figure 1.1). Anestimated 50 million dengue inections occur annually (Figure 1.2) and approximately2.5 billion people live in dengue endemic countries (1). The 2002 World HealthAssembly resolution WHA55.17 (2) urged greater commitment to dengue by WHOand its Member States. O particular signi cance is the 2005 World Health Assemblyresolution WHA58.3 on the revision o the International Health Regulations (IHR) (3),

which includes dengue as an example o a disease that may constitute a public healthemergency o international concern with implications or health security due to disruptionand rapid epidemic spread beyond national borders.

Figure 1.1 Countries/areas at risk o dengue transmission, 2008

Data Source: World Health Organization MapProduction: Public Health Inrmation and GeographicInormation Systems (GIS) World Health Organization

The boundaries and names shown and the designations used on this map do not imply the expression o any opinion whatsoeveron the part o the World Health Organization concerning the legal status o any country, territory, city or area or o its authorities,or concerning the delimitation o its rontiers or boundaries. Dotted lines or maps represent approximate border lines or whichthere may not yest be ll agreement.

countries or areas at risk(As o 1 November 2008)

The contour lines o the January and July isotherms indicate the potential geographical limits o the northern andsouthern hemispheres or year-round survival oAdeas aegypti, the principal mosquito vector o dengue viruses.

July isotherm

10.C

January isotherm

10.C

World Health Organization 2008


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The ollowing sections give an overview o the epidemiology and burden o disease inthe dierent WHO regions. All data are rom country reports rom the WHO regionaloces, unless reerenced to a dierent source.

1.1.1 Dengue in Asia and the Pacic

Some 1.8 billion (more than 70%) o the population at risk or dengue worldwide live inmember states o the WHO South-East Asia Region and Western Pacic Region, whichbear nearly 75% o the current global disease burden due to dengue. The Asia PacicDengue Strategic Plan or both regions (2008--2015) has been prepared in consultationwith member countries and development partners in response to the increasing threatrom dengue, which is spreading to new geographical areas and causing high mortalityduring the early phase o outbreaks. The strategic plan aims to aid countries to reversethe rising trend o dengue by enhancing their preparedness to detect, characterize andcontain outbreaks rapidly and to stop the spread to new areas.

Figure 1.2 Average annual number o dengue ever (DF) and dengue haemorrhagic ever (DHF) casesreported to WHO, and o countries reporting dengue, 19552007

Num

bero

cases

Num

bero

countries

70

60

50

40

30

20

1955-1959 1960-1969 1970-1979 1980-1989 1990-1999 2000-2007

10

0

1 000 000

900 000

800 000

700 000

600 000

500 000

400 000

300 000

200 000

100 000

0908

122,174

15,497

295,554

479,848

925,896

Year


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1.1.1.1 Dengue in the WHO South-East Asia Region

Since 2000, epidemic dengue has spread to new areas and has increased in thealready aected areas o the region. In 2003, eight countries -- Bangladesh, India,

Indonesia, Maldives, Myanmar, Sri Lanka, Thailand and Timor-Leste -- reported denguecases. In 2004, Bhutan reported the countrys rst dengue outbreak. In 2005, WHOsGlobal Outbreak Alert and Response Network (GOARN) responded to an outbreak witha high case-atality rate (3.55%) in Timor-Leste. In November 2006, Nepal reportedindigenous dengue cases or the rst time. The Democratic Peoples Republic o Korea isthe only country o the South-East Region that has no reports o indigenous dengue.

The countries o the region have been divided into our distinct climatic zones withdierent dengue transmission potential. Epidemic dengue is a major public healthproblem in Indonesia, Myanmar, Sri Lanka, Thailand and Timor-Leste which are in the

tropical monsoon and equatorial zone where Aedes aegyptiis widespread in both urbanand rural areas, where multiple virus serotypes are circulating, and where dengue is aleading cause o hospitalization and death in children. Cyclic epidemics are increasingin requency and in-country geographic expansion is occurring in Bangladesh, Indiaand Maldives -- countries in the deciduous dry and wet climatic zone with multiple virusserotypes circulating. Over the past our years, epidemic dengue activity has spread toBhutan and Nepal in the sub-Himalayan oothills.

Reported case atality rates or the region are approximately 1%, but in India, Indonesiaand Myanmar, ocal outbreaks away rom the urban areas have reported case-atality

rates o 3--5%.

In Indonesia, where more than 35% o the countrys population lives in urban areas,150 000 cases were reported in 2007 (the highest on record) with over 25 000 casesreported rom both Jakarta and West Java. The case-atality rate was approximately1%.

In Myanmar in 2007 the states/divisions that reported the highest number o caseswere Ayayarwaddy, Kayin, Magway, Mandalay, Mon, Rakhine, Sagaing, Tanintharyiand Yangon. From January to September 2007, Myanmar reported 9578 cases. The

reported case-atality rate in Myanmar is slightly above 1%.

In Thailand, dengue is reported rom all our regions: Northern, Central, North-Easternand Southern. In June 2007, outbreaks were reported rom Trat province, Bangkok,Chiangrai, Phetchabun, Phitsanulok, Khamkaeng Phet, Nakhon Sawan and Phit Chit. Atotal o 58 836 cases were reported rom January to November 2007. The case-atalityrate in Thailand is below 0.2%.

Dengue prevention and control will be implemented through the Bi-regional DengueStrategy (2008--2015) o the WHO South-East Asia and Western Pacic regions. This

consists o six elements: (i) dengue surveillance, (ii) case management, (iii) outbreakresponse, (iv) integrated vector management, (v) social mobilization and communicationor dengue and (vi) dengue research (a combination o both ormative and operationalresearch). The strategy has been endorsed by resolution SEA/RC61/R5 o the WHORegional Committee or South-East Asia in 2008 (4).


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1.1.1.2 Dengue in the WHO Western Pacic Region

Dengue has emerged as a serious public health problem in the Western Pacic Region(5). Since the last major pandemic in 1998, epidemics have recurred in much o

the area. Lack o reporting remains one o the most important challenges in dengueprevention and control.

Between 2001 and 2008, 1 020 333 cases were reported in Cambodia, Malaysia,Philippines, and Viet Nam -- the our countries in the Western Pacic Region with thehighest numbers o cases and deaths. The combined death toll or these our countrieswas 4798 (ocial country reports). Compared with other countries in the same region,the number o cases and deaths remained highest in Cambodia and the Philippines in2008. Overall, case management has improved in the Western Pacic Region, leadingto a decrease in case atality rates.

Dengue has also spread throughout the Pacic Island countries and areas. Between2001 and 2008, the six most aected Pacic island countries and areas were FrenchPolynesia (35 869 cases), New Caledonia (6836 cases), Cook Islands (3735cases), American Samoa (1816 cases), Palau (1108 cases) and the Federal States oMicronesia (664 cases). The total number o deaths or the six island countries was 34(ocial country reports). Although no ocial reports have been submitted to WHO byKiribati, the country did experience a dengue outbreak in 2008, reporting a total o837 cases and causing great concern among the national authorities and among someo the other countries in the region.

Historically, dengue has been reported predominantly among urban and peri-urbanpopulations where high population density acilitates transmission. However, evidencerom recent outbreaks, as seen in Cambodia in 2007, suggests that they are nowoccurring in rural areas.

Implementing the Bi-regional Dengue Strategy or Asia and the Pacic (2008--2015) isa priority ollowing endorsement by the 2008 resolution WPR/RC59.R6 o the WHORegional Committee or the Western Pacic (6).

1.1.2 Dengue in the Americas

Interruption o dengue transmission in much the WHO Region o the Americas resultedrom the Ae. aegyptieradication campaign in the Americas, mainly during the 1960sand early 1970s. However, vector surveillance and control measures were not sustainedand there were subsequent reinestations o the mosquito, ollowed by outbreaks in theCaribbean, and in Central and South America (7). Dengue ever has since spread withcyclical outbreaks occurring every 3--5 years. The biggest outbreak occurred in 2002with more than 1 million reported cases.

From 2001 to 2007, more than 30 countries o the Americas notied a total o 4 332731 cases o dengue (8). The number o cases o dengue haemorrhagic ever (DHF)in the same period was 106 037. The total number o dengue deaths rom 2001 to


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2007 was 1299, with a DHF case atality rate o 1.2%. The our serotypes o thedengue virus (DEN-1, DEN-2, DEN-3 and DEN-4) circulate in the region. In Barbados,Colombia, Dominican Republic, El Salvador, Guatemala, French Guyana, Mexico,Peru, Puerto Rico and Venezuela, all our serotypes were simultaneously identied in one

year during this period.By subregion o the Americas, dengue is characterized as described below. All dataare rom the Pan American Health Organization (PAHO) (8).

The Southern Cone countriesArgentina, Brazil, Chile, Paraguay and Uruguay are located in this subregion. In theperiod rom 2001 to 2007, 64.6% (2 798 601) o all dengue cases in the Americaswere notied in this subregion, o which 6733 were DHF with a total o 500 deaths.

Some 98.5% o the cases were notied by Brazil, which also reports the highest caseatality rate in the subregion. In the subregion, DEN-1, -2 and -3 circulate.

Andean countriesThis subregion includes Bolivia, Colombia, Ecuador, Peru and Venezuela, andcontributed 19% (819 466) o dengue cases in the Americas rom 2001 to 2007. It isthe subregion with the highest number o reported DHF cases, with 58% o all cases (61341) in the Americas, and 306 deaths. Colombia and Venezuela have most cases inthe subregion (81%), and in Colombia there were most dengue deaths (225, or 73%).In Colombia, Peru and Venezuela all our dengue serotypes were identied.

Central American countries and MexicoDuring 20012007, a total o 545 049 cases, representing 12.5% o dengue in theAmericas, was reported, with 35 746 cases o DHF and 209 deaths. Nicaragua had64 deaths (31%), ollowed by Honduras with 52 (25%) and Mexico with 29 (14%).Costa Rica, Honduras and Mexico reported the highest number o cases in this period.DEN-1, -2 and -3 were the serotypes most requently reported.

Caribbean countriesIn this subregion 3.9% (168 819) o the cases o dengue were notied, with 2217 DHF

cases and 284 deaths. Countries with the highest number o dengue cases in the LatinCaribbean were Cuba, Puerto Rico and the Dominican Republic, whereas in the Englishand French Caribbean, Martinique, Trinidad and Tobago and French Guiana reportedthe highest numbers o cases. The Dominican Republic reported 77% o deaths (220)during the period 2001--2007. All our serotypes circulate in the Caribbean area, butpredominantly DEN-1 and -2.

North American countriesThe majority o the notied cases o dengue in Canada and the United States arepersons who had travelled to endemic areas in Asia, the Caribbean, or Central or South

America (9). From 2001 to 2007, 796 cases o dengue were reported in the UnitedStates, the majority imported. Nevertheless, outbreaks o dengue in Hawaii have beenreported, and there were outbreaks sporadically with local transmission in Texas at theborder with Mexico (10,11).


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The Regional Dengue Programme o PAHO ocuses public policies towards a multisectoraland interdisciplinary integration. This allows the ormulation, implementation, monitoringand evaluation o national programmes through the Integrated Management Strategyor Prevention and Control o Dengue (EGI-dengue, rom its acronym in Spanish). This

has six key components: (i) social communication (using Communication or BehaviouralImpact (COMBI)), (ii) entomology, (iii) epidemiology, (iv) laboratory diagnosis, (v) casemanagement and (vi) environment. This strategy has been endorsed by PAHO resolutions(1215). Sixteen countries and three subregions (Central America, Mercosur and theAndean subregion) agreed to use EGI-dengue as a strategy and are in the process oimplementation.

1.1.3 Dengue in the WHO Arican Region

Although dengue exists in the WHO Arican Region, surveillance data are poor.Outbreak reports exist, although they are not complete, and there is evidence thatdengue outbreaks are increasing in size and requency (16). Dengue is not ociallyreported to WHO by countries in the region. Dengue-like illness has been recordedin Arica though usually without laboratory conrmation and could be due to inectionwith dengue virus or with viruses such as chikungunya that produce similar clinicalsymptoms.

Dengue has mostly been documented in Arica rom published reports o serosurveysor rom diagnosis in travellers returning rom Arica, and dengue cases rom countries

in Sub-Saharan Arica. A serosurvey (17) suggests that dengue existed in Arica as arback as 1926--1927, when the disease caused an epidemic in Durban, South Arica.Cases o dengue imported rom India were detected in the 1980s (18).

For eastern Arica, the available evidence so ar indicates that DEN-1, -2 and -3 appear tobe common causes o acute ever. Examples o this are outbreaks in the Comoros in variousyears (1948, 1984 and 1993, DEN-1 and -2) (19) and Mozambique (1984--1985,DEN-3) (20).

In western Arica in the 1960s, DEN-1, -2 and -3 were isolated or the rst time rom

samples taken rom humans in Nigeria (21). Subsequent dengue outbreaks have beenreported rom dierent countries, as or example rom Burkina Faso (1982, DEN-2) (22)and Senegal (1999, DEN-2) (23). Also DEN-2 and DEN-3 cases were conrmed inCte dIvoire in 2006 and 2008.

Despite poor surveillance or dengue in Arica, it is clear that epidemic dengue evercaused by all our dengue serotypes has increased dramatically since 1980, with mostepidemics occurring in eastern Arica, and to a smaller extent in western Arica, thoughthis situation may be changing in 2008.

While dengue may not appear to be a major public health problem in Arica comparedto the widespread incidence o malaria and HIV/AIDS, the increasing requencyand severity o dengue epidemics worldwide calls or a better understanding o theepidemiology o dengue inections with regard to the susceptibility o Arican populationsto dengue and the intererence between dengue and the other major communicablediseases o the continent.


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CHAPTER1

1.1.4 Dengue in the WHO Eastern Mediterranean Region (Figure 1.3)

Outbreaks o dengue have been documented in the Eastern Mediterranean Regionpossibly as early as 1799 in Egypt (24). The requency o reported outbreaks continue

to increase, with outbreaks or example in Sudan (1985, DEN-1 and -2) (25) and inDjibouti (1991, DEN-2) (26).

Recent outbreaks o suspected dengue have been recorded in Pakistan, Saudi Arabia,Sudan and Yemen, 2005--2006 (24). In Pakistan, the rst conrmed outbreak o DHFoccurred in 1994. A DEN-3 epidemic with DHF was rst reported in 2005 (27).Since then, the expansion o dengue inections with increasing requency and severityhas been reported rom large cities in Pakistan as ar north as the North-West FrontierProvince in 2008. Dengue is now a reportable disease in Pakistan. A pertinent issueor this region is the need to better understand the epidemiological situation o dengue

in areas that are endemic or Crimean-Congo haemorrhagic ever and co-inections othese pathogens.

Yemen is also aected by the increasing requency and geographic spread o epidemicdengue, and the number o cases has risen since the major DEN-3 epidemic thatoccurred in the western al-Hudeidah governorate in 2005. In 2008 dengue aectedthe southern province o Shabwa.

Since the rst case o DHF died in Jeddah in 1993, Saudi Arabia has reported threemajor epidemics: a DEN-2 epidemic in 1994 with 469 cases o dengue, 23 cases o

DHF, two cases o dengue shock syndrome (DSS) and two deaths; a DEN-1 epidemicin 2006 with 1269 cases o dengue, 27 cases o DHF, 12 cases o DSS and six

Figure 1.3 Outbreaks o dengue ever in the WHO Eastern Mediterranean Region, 19942005

DEN-2:1994: 673 suspected cases, 289 conrmed cases

1995: 136 suspected cases, 6 conrmed cases


1997: 62 suspected cases, 15 conrmed cases1998: 31 suspected cases, 0 conrmed cases




2005: 32 suspected (conrmed)

Al-Hudaydah, Mukkala, Shaabwa(1994, DEN-3, no data);

Al-Hudaydah, Yemen(September 2000, DEN-2, 653 suspected cases, 80 deaths (CFR = 12%));

Al-Hudaydah, Yemen(March 2004, 45 suspected cases, 2 deaths);

Al-Hudaydah, Mukkala(March 2005, 403 suspected cases, 2 deaths);

Somalia (1982, 1993, DEN-2)Djibouti (1991-1992, DEN-2)

Sudan(No data)


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deaths; and a DEN-3 epidemic in 2008 with 775 cases o dengue, nine cases oDHF, our cases o DSS and our deaths. A pertinent issue or the IHR is that Jeddah isa Haj entry point -- as well as being the largest commercial port in the country, and thelargest city with the busiest airport in the western region -- with large numbers o people

coming rom high-burden dengue countries such as Indonesia, Malaysia and Thailand,in addition to the dengue-aected countries o the region.

1.1.5 Dengue in other regions

As described above, dengue is now endemic in all WHO regions except the WHOEuropean Region. Data available or the European region (http://data.euro.who.int/cisid/) indicate that most cases in the region have been reported by European Unionmember states, either as incidents in overseas territories or importations rom endemic

countries. [See also a report rom the European Centre or Disease Prevention andControl (28)]. However, in the past, dengue has been endemic in some Balkan andMediterranean countries o the region, and imported cases in the presence o knownmosquito vectors (e.g. Aedes albopictus) cannot exclude uture disease spread.

Globally, reporting on dengue cases shows cyclical variation with high epidemic yearsand non-epidemic years. Dengue oten presents in the orm o large outbreaks. There is,however, also a seasonality o dengue, with outbreaks occurring in dierent periods othe year. This seasonality is determined by peak transmission o the disease, infuencedby characteristics o the host, the vector and the agent.

1.1.6 Dengue case classication

Dengue has a wide spectrum o clinical presentations, oten with unpredictable clinicalevolution and outcome. While most patients recover ollowing a sel-limiting non-severeclinical course, a small proportion progress to severe disease, mostly characterized byplasma leakage with or without haemorrhage. Intravenous rehydration is the therapyo choice; this intervention can reduce the case atality rate to less than 1% o severecases. The group progressing rom non-severe to severe disease is dicult to dene, butthis is an important concern since appropriate treatment may prevent these patients romdeveloping more severe clinical conditions.

Triage, appropriate treatment, and the decision as to where this treatment should begiven (in a health care acility or at home) are infuenced by the case classication ordengue. This is even more the case during the requent dengue outbreaks worldwide,where health services need to be adapted to cope with the sudden surge in demand.

Changes in the epidemiology o dengue, as described in the previous sections, leadto problems with the use o the existing WHO classication. Symptomatic dengue virusinections were grouped into three categories: undierentiated ever, dengue ever (DF)and dengue haemorrhagic ever (DHF). DHF was urther classied into our severitygrades, with grades III and IV being dened as dengue shock syndrome (DSS) (29).There have been many reports o diculties in the use o this classication (3032),which were summarized in a systematic literature review (33). Diculties in applyingthe criteria or DHF in the clinical situation, together with the increase in clinically


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severe dengue cases which did not ul l the strict criteria o DHF, led to the requestor the classi cation to be reconsidered. Currently the classi cation into DF/DHF/DSScontinues to be widely used. (29)

A WHO/TDR-supported prospective clinical multicentre study across dengue-endemicregions was set up to collect evidence about criteria or classiying dengue into levels oseverity. The study ndings con rmed that, by using a set o clinical and/or laboratoryparameters, one sees a clear-cut dierence between patients with severe dengue andthose with non-severe dengue. However, or practical reasons it was desirable to splitthe large group o patients with non-severe dengue into two subgroups -- patients withwarning signs and those without them. Criteria or diagnosing dengue (with or withoutwarning signs) and severe dengue are presented in Figure 1.4. It must be kept in mindthat even dengue patients without warning signs may develop severe dengue.

Expert consensus groups in Latin America (Havana, Cuba, 2007), South-East Asia(Kuala Lumpur, Malaysia, 2007), and at WHO headquarters in Geneva, Switzerlandin 2008 agreed that:

dengue is one disease entity with dierent clinical presentations and oten withunpredictable clinical evolution and outcome;

the classi cation into levels o severity has a high potential or being o practical use inthe clinicians decision as to where and how intensively the patient should be observedand treated (i.e. triage, which is particularly useul in outbreaks), in more consistent

reporting in the national and international surveillance system, and as an end-pointmeasure in dengue vaccine and drug trials.

Figure 1.4 Suggested dengue case classication and levels o severity

Probable denguelive in /travel to dengue endemic area.

Fever and 2 o the ollowing criteria:

Nausea,vomiting

Rash

Achesandpains

Tourniquettestpositive

LeukopeniaAnywarningsign

Laboratory-conrmed dengue(important when no sign o plasma leakage)

Warning signs*Abdominalpainortenderness

Persistentvomiting

Clinicaluidaccumulation

Mucosalbleed

Lethargy,restlessness

Liverenlargment>2cm

Laboratory:increaseinHCT concurrent with rapid decrease

in platelet count

*(requiring strict observation and medicalintervention)

Severe plasma leakageleading to:

Shock(DSS)

Fluidaccumulationwithrespiratory

distress

Severe bleedingas evaluated by clinician

Severe organ involvementLiver:ASTorALT>=1000

CNS:Impairedconsciousness

Heartandotherorgans

CRITERIA FOR DENGUE WARNING SIGNS CRITERIA FOR SEVERE DENGUE

DENGUE WARNING SIGNS SEVERE DENGUE

1. Severe plasma leakage

2. Severe haemorrhage

3.Severe organ impairmentwithout

with warningsigns


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This model or classiying dengue has been suggested by an expert group (Geneva,Switzerland, 2008) and is currently being tested in 18 countries by comparing itsperormance in practical settings to the existing WHO case classication. The processwill be nalized in 2010. For practical reasons this guide adapts the distinction between

dengue and severe dengue.Additionally the guide uses three categories or case management (A, B, C) (Chapter 2).

1.2 BURDEN OF DISEASE

Dengue inficts a signicant health, economic and social burden on the populations oendemic areas. Globally the estimated number o disability-adjusted lie years (DALYs)lost to dengue in 2001 was 528 (34). In Puerto Rico, an estimated yearly mean o 580

DALYs per million population were lost to dengue between 1984 and 1994 -- similarto the cumulative total o DALYs lost to malaria, tuberculosis, intestinal helminths and thechildhood disease cluster in all o Latin America and the Caribbean (35).

The number o cases reported annually to WHO ranged rom 0.4 to 1.3 millionin the decade 1996 -- 2005. As an inectious disease, the number o cases variessubstantially rom year to year. Underreporting and misdiagnoses are major obstacles tounderstanding the ull burden o dengue (36).

Available data rom South-East Asia is largely derived rom hospitalized cases among

children but the burden due to uncomplicated dengue ever is also considerable. In aprospective study o schoolchildren in northern Thailand the mean annual burden odengue over a ve-year period was 465.3 DALYs per million, with non-hospitalizedpatients with dengue illness contributing 44 -- 73% o the total (37).

Studies on the cost o dengue were conducted in eight countries in 2005-2006: vein the Americas (Brazil, El Salvador, Guatemala, Panama, Venezuela) and three inAsia (Cambodia, Malaysia, Thailand) (38). As dengue also aected other householdmembers who helped care or the dengue patient, an average episode represented14.8 lost days or ambulatory patients and 18.9 days or hospitalized patients. The

overall cost o a non-atal ambulatory case averaged US$ 514, while the cost o anon-atal hospitalized case averaged US$ 1491. On average, a hospitalized caseo dengue cost three times what an ambulatory case costs. Combining the ambulatoryand hospitalized patients and actoring in the risk o death, the overall cost o a denguecase is US$ 828. Merging this number with the average annual number o ociallyreported dengue cases rom the eight countries studied in the period 2001 -- 2005(532 000 cases) gives a cost o ocially reported dengue o US$ 440 million. Thisvery conservative estimate ignores not only the underreporting o cases but also thesubstantial costs associated with dengue surveillance and vector control programmes.This study showed that a treated dengue episode imposes substantial costs on both the

health sector and the overall economy. I a vaccine were able to prevent much o thisburden, the economic gains would be substantial.


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Children are at a higher risk o severe dengue (39). Intensive care is required or severelyill patients, including intravenous fuids, blood or plasma transusion and medicines.

Dengue aficts all levels o society but the burden may be higher among the poorest who

grow up in communities with inadequate water supply and solid waste inrastructure,and where conditions are most avourable or multiplication o the main vector, Ae.aegypti.

1.3 DENGUE IN INTERNATIONAL TRAVEL

Travellers play an essential role in the global epidemiology o dengue inections, asviraemic travellers carry various dengue serotypes and strains into areas with mosquitoesthat can transmit inection (40). Furthermore, travellers perorm another essential service

in providing early alerts to events in other parts o the world. Travellers oten transportthe dengue virus rom areas in tropical developing countries, where limited laboratoryacilities exist, to developed countries with laboratories that can identiy virus serotypes(41). Access to research acilities makes it possible to obtain more detailed inormationabout a virus, including serotype and even sequencing, when that inormation would bevaluable. Systematic collection o clinical specimens and banking o serum or isolatesmay have uture benets as new technologies become available.

From the data collected longitudinally over a decade by the GeoSentinel SurveillanceNetwork (www.geosentinel.org) it was possible, or example, to examine month-by-

month morbidity rom a sample o 522 cases o dengue as a proportion o all diagnosesin 24 920 ill returned travellers seen at 33 surveillance sites. Travel-related denguedemonstrated a dened seasonality or multiple regions (South-East Asia, South CentralAsia, Caribbean, South America) (42).

Inormation about dengue in travellers, using sentinel surveillance, can be shared rapidlyto alert the international community to the onset o epidemics in endemic areas wherethere is no surveillance and reporting o dengue, as well as the geographic spread ovirus serotypes and genotypes to new areas which increases the risk o severe dengue.The inormation can also assist clinicians in temperate regions -- most o whom are not

trained in clinical tropical diseases -- to be alert or cases o dengue ever in ill returnedtravellers. The clinical maniestations and complications o dengue can also be studiedin travellers (most o them adult and non-immune) as dengue may present dierentlycompared with the endemic population (most o them in the paediatric age group andwith pre-existing immunity). The disadvantage o such sentinel surveillance, however, isthe lack o a denominator: true risk incidence cannot be determined. An increase incases in travellers could be due to increased travel activity to dengue endemic areas,or instance.


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1.4 TRANSMISSION

1.4.1 The virus

Dengue virus (DEN) is a small single-stranded RNA virus comprising our distinct serotypes(DEN-1 to -4). These closely related serotypes o the dengue virus belong to the genusFlavivirus, amily Flaviviridae.

The mature particle o the dengue virus is spherical with a diameter o 50nm containingmultiple copies o the three structural proteins, a host-derived membrane bilayer and asingle copy o a positive-sense, single-stranded RNA genome. The genome is cleavedby host and viral proteases in three structural proteins (capsid, C, prM, the precursor omembrane, M, protein and envelope, E) and seven nonstructural proteins (NS).

Distinct genotypes or lineages (viruses highly related in nucleotide sequence) havebeen identied within each serotype, highlighting the extensive genetic variability othe dengue serotypes. Puriying selection appears to be a dominant theme in dengueviral evolution, however, such that only viruses that are t or both human and vectorare maintained. Among them, Asian genotypes o DEN-2 and DEN-3 are requentlyassociated with severe disease accompanying secondary dengue inections (4345).Intra-host viral diversity (quasispecies) has also been described in human hosts.

1.4.2 The vectors

The various serotypes o the dengue virus are transmitted to humans through the biteso inected Aedes mosquitoes, principally Ae. aegypti. This mosquito is a tropicaland subtropical species widely distributed around the world, mostly between latitudes35 0N and 35 0S. These geographical limits correspond approximately to a winterisotherm o 10 0C. Ae. aegypti has been ound as ar north as 45 0N, but suchinvasions have occurred during warmer months and the mosquitoes have not survivedthe winters. Also, because o lower temperatures, Ae. aegyptiis relatively uncommonabove 1000 metres. The immature stages are ound in water-lled habitats, mostly inarticial containers closely associated with human dwellings and oten indoors. Studiessuggest that most emale Ae. aegyptimay spend their lietime in or around the houseswhere they emerge as adults. This means that people, rather than mosquitoes, rapidlymove the virus within and between communities. Dengue outbreaks have also beenattributed to Aedes albopictus, Aedes polynesiensis and several species o the Aedesscutellaris complex. Each o these species has a particular ecology, behaviour andgeographical distribution. In recent decades Aedes albopictus has spread rom Asia toArica, the Americas and Europe, notably aided by the international trade in used tyresin which eggs are deposited when they contain rainwater. The eggs can remain viable

or many months in the absence o water (Chapter 3).


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1.4.2 The host

Ater an incubation period o 4--10 days, inection by any o the our virus serotypescan produce a wide spectrum o illness, although most inections are asymptomatic

or subclinical (Chapter 2). Primary inection is thought to induce lielong protectiveimmunity to the inecting serotype (46). Individuals suering an inection are protectedrom clinical illness with a dierent serotype within 2--3 months o the primary inectionbut with no long-term cross-protective immunity.

Individual risk actors determine the severity o disease and include secondary inection,age, ethnicity and possibly chronic diseases (bronchial asthma, sickle cell anaemia anddiabetes mellitus). Young children in particular may be less able than adults to compensateor capillary leakage and are consequently at greater risk o dengue shock.

Seroepidemiological studies in Cuba and Thailand consistently support the role osecondary heterotypic inection as a risk actor or severe dengue, although there area ew reports o severe cases associated with primary inection (4750). The timeinterval between inections and the particular viral sequence o inections may also be oimportance. For instance, a higher case atality rate was observed in Cuba when DEN-2 inection ollowed a DEN-1 inection ater an interval o 20 years compared to aninterval o our years. Severe dengue is also regularly observed during primary inectiono inants born to dengue-immune mothers. Antibody-dependent enhancement (ADE) oinection has been hypothesized (51,52) as a mechanism to explain severe dengue inthe course o a secondary inection and in inants with primary inections. In this model,

non-neutralizing, cross-reactive antibodies raised during a primary inection, or acquiredpassively at birth, bind to epitopes on the surace o a heterologous inecting virus andacilitate virus entry into Fc-receptor-bearing cells. The increased number o inected cellsis predicted to result in a higher viral burden and induction o a robust host immuneresponse that includes infammatory cytokines and mediators, some o which maycontribute to capillary leakage. During a secondary inection, cross-reactive memory Tcells are also rapidly activated, prolierate, express cytokines and die by apoptosis in amanner that generally correlates with overall disease severity. Host genetic determinantsmight infuence the clinical outcome o inection (53,54), though most studies have beenunable to adequately address this issue. Studies in the American region show the rates

o severe dengue to be lower in individuals o Arican ancestry than those in other ethnicgroups. (54)

The dengue virus enters via the skin while an inected mosquito is taking a bloodmeal.During the acute phase o illness the virus is present in the blood and its clearancerom this compartment generally coincides with deervescence. Humoral and cellularimmune responses are considered to contribute to virus clearance via the generationo neutralizing antibodies and the activation o CD4+ and CD8+ T lymphocytes. Inaddition, innate host deence may limit inection by the virus. Ater inection, serotype-specic and cross-reactive antibodies and CD4+ and CD8+ T cells remain measurable

or years.

Plasma leakage, haemoconcentration and abnormalities in homeostasis characterizesevere dengue. The mechanisms leading to severe illness are not well dened but theimmune response, the genetic background o the individual and the virus characteristicsmay all contribute to severe dengue.


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Recent data suggest that endothelial cell activation could mediate plasma leakage(55,56). Plasma leakage is thought to be associated with unctional rather thandestructive eects on endothelial cells. Activation o inected monocytes and T cells, thecomplement system and the production o mediators, monokines, cytokines and soluble

receptors may also be involved in endothelial cell dysunction.Thrombocytopenia may be associated with alterations in megakaryocytopoieses bythe inection o human haematopoietic cells and impaired progenitor cell growth,resulting in platelet dysunction (platelet activation and aggregation), increaseddestruction or consumption (peripheral sequestration and consumption). Haemorrhagemay be a consequence o the thrombocytopenia and associated platelet dysunctionor disseminated intravascular coagulation. In summary, a transient and reversibleimbalance o infammatory mediators, cytokines and chemokines occurs during severedengue, probably driven by a high early viral burden, and leading to dysunction o

vascular endothelial cells, derangement o the haemocoagulation system then to plasmaleakage, shock and bleeding.

1.4.4 Transmission o the dengue virus

Humans are the main ampliying host o the virus. Dengue virus circulating in the blood oviraemic humans is ingested by emale mosquitoes during eeding. The virus then inectsthe mosquito mid-gut and subsequently spreads systemically over a period o 8--12 days.Ater this extrinsic incubation period, the virus can be transmitted to other humans during

subsequent probing or eeding. The extrinsic incubation period is infuenced in partby environmental conditions, especially ambient temperature. Thereater the mosquitoremains inective or the rest o its lie. Ae. aegyptiis one o the most ecient vectorsor arboviruses because it is highly anthropophilic, requently bites several times beorecompleting oogenesis, and thrives in close proximity to humans. Vertical transmission(transovarial transmission) o dengue virus has been demonstrated in the laboratorybut rarely in the eld. The signicance o vertical transmission or maintenance o thevirus is not well understood. Sylvatic dengue strains in some parts o Arica and Asiamay also lead to human inection, causing mild illness. Several actors can infuencethe dynamics o virus transmission -- including environmental and climate actors, host-

pathogen interactions and population immunological actors. Climate directly infuencesthe biology o the vectors and thereby their abundance and distribution; it is consequentlyan important determinant o vector-borne disease epidemics.


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Chapter 2: Clinical management and delivery o clinical services

CHAPTER

2

CHAPTER 2

CLINICAL MANAGEMENT AND

DELIVERY OF CLINICAL SERVICES


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CHAPTER

2

CHAPTER 2. CLINICAL MANAGEMENT AND DELIVERY OF CLINICALSERVICES

2.1 OVERVIEW

Dengue inection is a systemic and dynamic disease. It has a wide clinical spectrumthat includes both severe and non-severe clinical maniestations (1). Ater the incubationperiod, the illness begins abruptly and is ollowed by the three phases -- ebrile, criticaland recovery (Figure 2.1).

For a disease that is complex in its maniestations, management is relatively simple,inexpensive and very eective in saving lives so long as correct and timely interventionsare instituted. The key is early recognition and understanding o the clinical problemsduring the dierent phases o the disease, leading to a rational approach to casemanagement and a good clinical outcome. An overview o good and bad clinicalpractices is given in Textbox A.

Activities (triage and management decisions) at the primary and secondary care levels(where patients are rst seen and evaluated) are critical in determining the clinicaloutcome o dengue. A well-managed ront-line response not only reduces the numbero unnecessary hospital admissions but also saves the lives o dengue patients. Earlynoti cation o dengue cases seen in primary and secondary care is crucial or identiyingoutbreaks and initiating an early response (Chapter 5). Dierential diagnosis needs tobe considered (Textbox B).

Figure 2.1 The course o dengue illness*

Days o illness

Temperature

Potential clinical issues

Laboratory changes

Serology and virology

Dehydration Shock Reabsorptionbleeding fuid overload

1 2 3 4 5 6 7 8 9 10

Organ impairment

Hematocrit

Platelet

ViraemiaIgM/IgG

Febrile Critical Recovery phasesCourse o dengue illness:

40

* Source: adapted rom Yip (2) by chapter authors.


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2.1.1 Febrile phase

Patients typically develop high-grade ever suddenly. This acute ebrile phase usuallylasts 27 days and is oten accompanied by acial fushing, skin erythema, generalized

body ache, myalgia, arthralgia and headache (1). Some patients may have sorethroat, injected pharynx and conjunctival injection. Anorexia, nausea and vomitingare common. It can be dicult to distinguish dengue clinically rom non-dengue ebrilediseases in the early ebrile phase. A positive tourniquet test in this phase increases theprobability o dengue (3,4). In addition, these clinical eatures are indistinguishablebetween severe and non-severe dengue cases. Thereore monitoring or warning signsand other clinical parameters (Textbox C) is crucial to recognizing progression to thecritical phase.

Mild haemorrhagic maniestations like petechiae and mucosal membrane bleeding

(e.g. nose and gums) may be seen (3,5). Massive vaginal bleeding (in women ochildbearing age) and gastrointestinal bleeding may occur during this phase but is notcommon (5). The liver is oten enlarged and tender ater a ew days o ever (3). Theearliest abnormality in the ull blood count is a progressive decrease in total white cellcount, which should alert the physician to a high probability o dengue.

2.1.2 Critical phase

Around the time o deervescence, when the temperature drops to 37.538oC or less

and remains below this level, usually on days 37 o illness, an increase in capillarypermeability in parallel with increasing haematocrit levels may occur (6,7). This marksthe beginning o the critical phase. The period o clinically signicant plasma leakageusually lasts 2448 hours.

Progressive leukopenia (3) ollowed by a rapid decrease in platelet count usually precedesplasma leakage. At this point patients without an increase in capillary permeability willimprove, while those with increased capillary permeability may become worse as aresult o lost plasma volume. The degree o plasma leakage varies. Pleural eusion andascites may be clinically detectable depending on the degree o plasma leakage and

the volume o fuid therapy. Hence chest x-ray and abdominal ultrasound can be useultools or diagnosis. The degree o increase above the baseline haematocrit oten refectsthe severity o plasma leakage.

Shock occurs when a critical volume o plasma is lost through leakage. It is otenpreceded by warning signs. The body temperature may be subnormal when shockoccurs. With prolonged shock, the consequent organ hypoperusion results in progressiveorgan impairment, metabolic acidosis and disseminated intravascular coagulation. Thisin turn leads to severe haemorrhage causing the haematocrit to decrease in severeshock. Instead o the leukopenia usually seen during this phase o dengue, the total

white cell count may increase in patients with severe bleeding. In addition, severe organimpairment such as severe hepatitis, encephalitis or myocarditis and/or severe bleedingmay also develop without obvious plasma leakage or shock (8).

Those who improve ater deervescence are said to have non-severe dengue. Somepatients progress to the critical phase o plasma leakage without deervescence and, in


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these patients, changes in the ull blood count should be used to guide the onset o thecritical phase and plasma leakage.

Those who deteriorate will maniest with warning signs. This is called dengue with

warning signs (Textbox C). Cases o dengue with warning signs will probably recoverwith early intravenous rehydration. Some cases will deteriorate to severe dengue (seebelow).

2.1.3 Recovery phase

I the patient survives the 2448 hour critical phase, a gradual reabsorption oextravascular compartment fuid takes place in the ollowing 4872 hours. Generalwell-being improves, appetite returns, gastrointestinal symptoms abate, haemodynamic

status stabilizes and diuresis ensues. Some patients may have a rash o isles o whitein the sea o red (9). Some may experience generalized pruritus. Bradycardia andelectrocardiographic changes are common during this stage.

The haematocrit stabilizes or may be lower due to the dilutional eect o reabsorbedfuid. White blood cell count usually starts to rise soon ater deervescence but therecovery o platelet count is typically later than that o white blood cell count.

Respiratory distress rom massive pleural eusion and ascites will occur at any time iexcessive intravenous fuids have been administered. During the critical and/or recovery

phases, excessive fuid therapy is associated with pulmonary oedema or congestiveheart ailure.

The various clinical problems during the dierent phases o dengue can be summarizedas in Table 2.1.

Table 2.1 Febrile, critical and recovery phases in dengue

1 Febrile phase Dehydration; high ever may cause neurological disturbances and ebrileseizures in young children

2 Critical phase Shock rom plasma leakage; severe haemorrhage; organ impairment

3 Recovery phase Hypervolaemia (only i intravenous fuid therapy has been excessive and/orhas extended into this period)

2.1.4 Severe dengue

Severe dengue is dened by one or more o the ollowing: (i) plasma leakage that maylead to shock (dengue shock) and/or fuid accumulation, with or without respiratorydistress, and/or (ii) severe bleeding, and/or (iii) severe organ impairment.

As dengue vascular permeability progresses, hypovolaemia worsens and results inshock. It usually takes place around deervescence, usually on day 4 or 5 (rangedays 37) o illness, preceded by the warning signs. During the initial stage o shock,the compensatory mechanism which maintains a normal systolic blood pressure alsoproduces tachycardia and peripheral vasoconstriction with reduced skin perusion,


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resulting in cold extremities and delayed capillary rell time. Uniquely, the diastolicpressure rises towards the systolic pressure and the pulse pressure narrows as theperipheral vascular resistance increases. Patients in dengue shock oten remain consciousand lucid. The inexperienced physician may measure a normal systolic pressure and

misjudge the critical state o the patient. Finally, there is decompensation and bothpressures disappear abruptly. Prolonged hypotensive shock and hypoxia may lead tomulti-organ ailure and an extremely dicult clinical course (Textbox D).

The patient is considered to have shock i the pulse pressure (i.e. the dierence betweenthe systolic and diastolic pressures) is 20 mm Hg in children or he/she has signso poor capillary perusion (cold extremities, delayed capillary rell, or rapid pulserate). In adults, the pulse pressure o 20 mm Hg may indicate a more severe shock.Hypotension is usually associated with prolonged shock which is oten complicated bymajor bleeding.

Patients with severe dengue may have coagulation abnormalities, but these are usually notsucient to cause major bleeding. When major bleeding does occur, it is almost alwaysassociated with proound shock since this, in combination with thrombocytopaenia,hypoxia and acidosis, can lead to multiple organ ailure and advanced disseminatedintravascular coagulation. Massive bleeding may occur without prolonged shock ininstances when acetylsalicylic acid (aspirin), ibuproen or corticosteroids have beentaken.

Unusual maniestations, including acute liver ailure and encephalopathy, may be

present, even in the absence o severe plasma leakage or shock. Cardiomyopathyand encephalitis are also reported in a ew dengue cases. However, most deaths romdengue occur in patients with proound shock, particularly i the situation is complicatedby fuid overload.

Severe dengue should be considered i the patient is rom an area o dengue riskpresenting with ever o 27 days plus any o the ollowing eatures:

Thereisevidenceofplasmaleakage,suchas:

high or progressively rising haematocrit;

pleural eusions or ascites; circulatory compromise or shock (tachycardia, cold and clammy extremities,

capillary rell time greater than three seconds, weak or undetectable pulse,narrow pulse pressure or, in late shock, unrecordable blood pressure).

Thereissignicantbleeding.

Thereisanalteredlevelofconsciousness(lethargyorrestlessness,coma, convulsions).

Thereisseveregastrointestinalinvolvement(persistentvomiting,increasingorintense abdominal pain, jaundice).

Thereissevereorganimpairment(acuteliverfailure,acuterenalfailure, encephalopathy or encephalitis, or other unusual maniestations, cardiomyopathy)or other unusual maniestations.


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2.2 DELIVERY OF CLINICAL SERVICES AND CASE MANAGEMENT

2.2.1 Introduction

Reducing dengue mortality requires an organized process that guarantees earlyrecognition o the disease, and its management and reerral when necessary. The keycomponent o the process is the delivery o good clinical services at all levels o healthcare, rom primary to tertiary levels. Most dengue patients recover without requiringhospital admission while some may progress to severe disease. Simple but eectivetriage principles and management decisions applied at the primary and secondary carelevels, where patients are rst seen and evaluated, can help in identiying those at risko developing severe disease and needing hospital care. This should be complementedby prompt and appropriate management o severe dengue in reerral centres.

Activities at the rst level o care should ocus on:

recognizing that the ebrile patient could have dengue;

notiying early to the public health authorities that the patient is a suspected caseo dengue;

managing patients in the early ebrile phase o dengue;

recognizing the early stage o plasma leakage or critical phase and initiatingfuid therapy;

recognizing patients with warning signs who need to be reerred or admission

and/or intravenous fuid therapy to a secondary health care acility; recognizing and managing severe plasma leakage and shock, severe bleeding

and severe organ impairment promptly and adequately.

2.2.2. Primary and secondary health care centres

At primary and secondary levels, health care acilities are responsible or emergency/ambulatory triage assessment and treatment.

Triage is the process o rapidly screening patients soon ater their arrival in the hospitalor health acility in order to identiy those with severe dengue (who require immediateemergency treatment to avert death), those with warning signs (who should be givenpriority while waiting in the queue so that they can be assessed and treated withoutdelay), and non-urgent cases (who have neither severe dengue nor warning signs).

During the early ebrile phase, it is oten not possible to predict clinically whether a patientwith dengue will progress to severe disease. Various orms o severe maniestationsmay unold only as the disease progresses through the critical phase, but the warning

signs are good indicators o a higher risk o developing severe dengue. Thereore, thepatient should have daily outpatient health care assessments or disease progressionwith careul checking or maniestations o severe dengue and warning signs.

Health care workers at the rst levels o care should apply a stepwise approach, assuggested in Table 2.2.


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Table 2.2 A stepwise approach to the management o dengue

Step I. Overall assessment

I.1 History, including inormation on symptoms, past medical and amily history

I.2 Physical examination, including ull physical and mental assessment

I.3 Investigation, including routine laboratory and dengue-specic laboratory

Step II. Diagnosis, assessment o disease phase and severity

Step III. Management

III.1 Disease notication

III.2 Management decisions. Depending on the clinical maniestations and other circumstances,patients may:

be sent home (Group A);

be reerred or in-hospital management (Group B);

require emergency treatment and urgent reerral (Group C).

Section 2.3 gives treatment recommendations or the groups AC.

2.2.3 Reerral centres

Reerral centres receiving severely ill dengue patients must be able to give promptattention to reerred cases. Beds should be made available to those patients who meetthe admission criteria, even i elective cases have to be deerred. I possible, there

should be a designated area to cohort dengue patients, and a high-dependency unitor closer monitoring o those with shock. These units should be staed by doctorsand nurses who are trained to recognize high-risk patients and to institute appropriatetreatment and monitoring.

A number o criteria may be used to decide when to transer a patient to a high-dependency unit. These include:

early presentation with shock (on days 2 or 3 o illness);

severe plasma leakage and/or shock;

undetectable pulse and blood pressure; severe bleeding;

fuid overload;

organ impairment (such as hepatic damage, cardiomyopathy, encephalopathy,encephalitis and other unusual complications).

2.2.4 Resources needed

In the detection and management o dengue, a range o resources is needed to delivergood clinical services at all levels. Resources include (10):

Human resources: The most important resource is trained doctors and nurses.Adequate health personnel should be allocated to the rst level o care to helpin triage and emergency management. I possible, dengue units sta

guideline dhf who 09

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