[{"text": "New edition\n2009\nDENGUE \nGUIDELINES FOR DIAGNOSIS, \nTREATMENT, PREVENTION AND CONTROL\nTREATMENT, PREVENTION AND CONTROL\nTREATMENT, PREVENTION AND CONTROL", "page": 1, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "New edition\n2009\nDENGUE \nGUIDELINES FOR DIAGNOSIS, \nTREATMENT, PREVENTION AND CONTROL\nGUIDELINES FOR DIAGNOSIS, \nTREATMENT, PREVENTION AND CONTROL\nA joint publication of the World Health Organization (WHO) and the Special Programme for Research \nand Training in Tropical Diseases (TDR)", "page": 3, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "WHO/HTM/NTD/DEN/2009.1\nExpiry date: 2014\n\u00a9 World Health Organization 2009\nAll rights reserved. Publications of the World Health Organization can be obtained from WHO Press, \nWorld Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; \nfax: +41 22 791 4857; e-mail: bookorders@who.int). Requests for permission to reproduce or translate \nWHO publications \u2013 whether for sale or for noncommercial distribution \u2013 should be addressed to WHO \nPress, at the above address", "page": 4, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "d be addressed to WHO \nPress, at the above address (fax: +41 22 791 4806; e-mail: permissions@who.int).\nThe designations employed and the presentation of the material in this publication do not imply the \nexpression of any opinion whatsoever on the part of the World Health Organization concerning the legal \nstatus of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers \nor boundaries. Dotted lines on maps represent approximate border lines f", "page": 4, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "lines on maps represent approximate border lines for which there may not yet be \nfull agreement.\nThe mention of specific companies or of certain manufacturers\u2019 products does not imply that they are \nendorsed or recommended by the World Health Organization in preference to others of a similar nature \nthat are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished \nby initial capital letters.\nAll reasonable precautions have been taken by the World Health", "page": 4, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "e precautions have been taken by the World Health Organization to verify the information \ncontained in this publication.  However, the published material is being distributed without warranty of any \nkind, either expressed or implied.  The responsibility for the interpretation and use of the material lies with \nthe reader.  In no event shall the World Health Organization be liable for damages arising from its use.\nPrinted in France\nCover and Layout: P. Tissot WHO/HTM/NTD\nWHO Library Cataloguing-", "page": 4, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ut: P. Tissot WHO/HTM/NTD\nWHO Library Cataloguing-in-Publication Data\nDengue: guidelines for diagnosis, treatment, prevention and control -- New edition.\n1.Dengue - diagnosis. 2.Dengue - therapy. 3.Dengue - prevention and control. 4.Endemic Diseases - \nprevention and control. 5.Fluid therapy. 6.Diagnosis, differential. 7.Disease outbreaks - prevention and \ncontrol. 8.Mosquito control. 9.Guidelines. I.World Health Organization.\nISBN 978 92 4 154787 1\t\n\t\n\t\n(NLM classification: WC 528)", "page": 4, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "7 1\t\n\t\n\t\n(NLM classification: WC 528)", "page": 4, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "iii\nIntroduction, Methodology, Acknowledgements, Abbreviations, Preface\nCONTENTS\nPreface  -------------------------------------------------------------------------------------------------------------------------------------------------------v\nMethodology  \n---------------------------------------------------------------------------------------------------------------------------------------------vi\nAcknowledgements  \n--------------------------------------------------------------------------------", "page": 5, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "--------------------------------------------------------------------------------------------------vii\nAbbreviations  \n--------------------------------------------------------------------------------------------------------------------------------------------ix\nChapter 1 Epidemiology, burden of disease and transmission\n \n \n1.1  Dengue epidemiology \n-----------------------------------------------------------------------------------------------3\n \n \n1.2  Burden of disease \n-------------------------", "page": 5, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "1.2  Burden of disease \n--------------------------------------------------------------------------------------------------------12\n \n \n1.3  Dengue in international travel \n--------------------------------------------------------------------------------13\n \n \n1.4  Transmission \n---------------------------------------------------------------------------------------------------------------------14\n \n \n1.5 References \n---------------------------------------------------------------------------------", "page": 5, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "-----------------------------------------------------------------------------------------17\nChapter 2  Clinical management and delivery of clinical services\n \n \n2.1  Overview \n--------------------------------------------------------------------------------------------------------------------------25\n \n \n2.2  Delivery of clinical services and case management \n---------------------------------29\n \n \n2.3 Recommendations for treatment \n----------------------------------------------------------------", "page": 5, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "--------------------------------------------------------------32\n \n \n2.4 References \n------------------------------------------------------------------------------------------------------------------------54\n \nChapter 3  Vector management and delivery of vector control services \n \n \n3.1  Overview \n--------------------------------------------------------------------------------------------------------------------------59\n \n \n3.2  Methods of vector control  \n---------------------------------------", "page": 5, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "control  \n--------------------------------------------------------------------------------------60\n \n \n3.3  Delivery of vector control interventions \n-------------------------------------------------------------72\n \n \n3.4  References \n------------------------------------------------------------------------------------------------------------------------86\nChapter 4  Laboratory diagnosis and diagnostic tests\n \n \n4.1 Overview \n----------------------------------------------------------------------", "page": 5, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "------------------------------------------------------------------------------------------------------91 \n \n \n4.2  Considerations in the choice of diagnostic methods \n--------------------------------93\n \n \n4.3  Current dengue diagnostic methods  \n----------------------------------------------------------------97\n \n \n4.4  Future test developments \n-------------------------------------------------------------------------------------------103\n \n \n4.5  Quality assurance \n----------------------------", "page": 5, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "5  Quality assurance \n--------------------------------------------------------------------------------------------------------104\n \n \n4.6  Biosafety issues \n--------------------------------------------------------------------------------------------------------------104\n \n \n4.7 Organization of laboratory services \n------------------------------------------------------------------104\n \n \n4.8 References \n----------------------------------------------------------------------------------------------", "page": 5, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "----------------------------------------------------------------------------106\nChapter 5  Surveillance, emergency preparedness and response\n \n \n5.1  Overview \n--------------------------------------------------------------------------------------------------------------------------111\n \n \n5.2  Dengue surveillance \n----------------------------------------------------------------------------------------------------111\n \n \n5.3  Dengue preparedness planning and response \n----------------------------", "page": 5, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "lanning and response \n--------------------------------------------123\n \n \n5.4  Programme assessment ---------------------------------------------------------------------------------------------128\n \n \n5.5  References \n------------------------------------------------------------------------------------------------------------------------132\nChapter 6  New avenues\n \n \n6.1  Overview \n--------------------------------------------------------------------------------------------------------------------", "page": 5, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "--------------------------------------------------------137\n \n \n6.2  Dengue vaccines \n----------------------------------------------------------------------------------------------------------137\n \n \n6.3  Dengue antiviral drugs ----------------------------------------------------------------------------------------------141\n \n \n6.4 References \n------------------------------------------------------------------------------------------------------------------------144", "page": 5, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "----------------144", "page": 5, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "iv\nDengue: Guidelines for diagnosis, treatment, prevention and control", "page": 6, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "v\nIntroduction, Methodology, Acknowledgements, Abbreviations, Preface\nPREFACE\nSince the second edition of Dengue haemorrhagic fever: diagnosis, treatment, prevention \nand control was published by the World Health Organization (WHO) in 1997, the \nmagnitude of the dengue problem has increased dramatically and has extended \ngeographically to many previously unaffected areas. It was then, and remains today, \nthe most important arthropod-borne viral disease of humans.\nActivities undertaken by WHO reg", "page": 7, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "isease of humans.\nActivities undertaken by WHO regarding dengue are most recently guided at the global \npolicy level by World Health Assembly resolution WHA55.17 (adopted by the Fifty-fifth \nWorld Health Assembly in 2002) and at the regional level by resolution CE140.R17 of \nthe Pan American Sanitary Conference (2007), resolution WPR/RC59.R6 of the WHO \nRegional Committee for the Western Pacific (2008) and resolution SEA/RC61/R5 of \nthe WHO Regional Committee for South-East Asia (2008).\nThis new", "page": 7, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "nal Committee for South-East Asia (2008).\nThis new edition has been produced to make widely available to health practitioners, \nlaboratory personnel, those involved in vector control and other public health officials, \na concise source of information of worldwide relevance on dengue. The guidelines \nprovide updated practical information on the clinical management and delivery of \nclinical services; vector management and delivery of vector control services; laboratory \ndiagnosis and diagnostic te", "page": 7, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "services; laboratory \ndiagnosis and diagnostic tests; and surveillance, emergency preparedness and response. \nLooking ahead, some indications of new and promising avenues of research are also \ndescribed. Additional and more detailed specific guidance on the various specialist \nareas related to dengue are available from other sources in WHO and elsewhere, \nsome of which are cited in the references. \nThe contributions of, and review by, many experts both within and outside WHO have \nfacilitated t", "page": 7, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ts both within and outside WHO have \nfacilitated the preparation of this publication through consultative and peer review \nprocesses. All contributors are gratefully acknowledged, a list of whom appears under \n\u201cAcknowledgements\u201d. These guidelines are the result of collaboration between the \nWHO Department of Control Neglected Tropical Diseases, the WHO Department of \nEpidemic and Pandemic Alert and Response, and the Special Programme for Research \nand Training in Tropical Diseases.\nThis publicat", "page": 7, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "and Training in Tropical Diseases.\nThis publication is intended to contribute to prevention and control of the morbidity and \nmortality associated with dengue and to serve as an authoritative reference source for \nhealth workers and researchers. These guidelines are not intended to replace national \nguidelines but to assist in the development of national or regional guidelines. They are \nexpected to remain valid for five years (until 2014), although developments in research \ncould change their", "page": 7, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "hough developments in research \ncould change their validity, since many aspects of the prevention and control of dengue \nare currently being investigated in a variety of studies. The guidelines contain the most \nup-to-date information at the time of writing. However, the results of studies are being \npublished regularly and should be taken into account. To address this challenge, the \nguide is also available on the Internet and will be updated regularly by WHO.", "page": 7, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "gularly by WHO.", "page": 7, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "vi\nDengue: Guidelines for diagnosis, treatment, prevention and control\nMETHODOLOGY\nThese guidelines were written using the following methodology:\n1. Writing team\nEach chapter was allocated to a WHO coordinator and at least one non-WHO lead \nwriter. The non-WHO lead writers received a small fee for their work. Declarations of \ninterest were obtained from all lead writers and no conflicting interests were declared. \nThe lead writers were chosen because of their expertise in the field and their wil", "page": 8, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ause of their expertise in the field and their willingness \nto undertake the work.\nSince this guide has the broad scope of all aspects of prevention and control of dengue, \nthe lead writers were selected for technical expertise in the areas of epidemiology, \npathogenesis and transmission, clinical aspects, vector control, laboratory aspects, \nsurveillance and response, and drug and vaccine development. \n2. Peer review\nAll the chapters were submitted to peer review. The peer review groups were de", "page": 8, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ted to peer review. The peer review groups were determined \nby the WHO coordinator and the non-WHO lead writers of each chapter. The groups \nconsisted of five or more peer reviewers, who were not paid for their work. Declarations \nof interest were obtained from all peer reviewers. For those peer reviewers with potential \nconflicting interests, the interests are declared below.1 \nFor each chapter, the process of reaching agreement on disputed issues differed. For \nchapters 1, 3, 4 and 6, the comm", "page": 8, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "es differed. For \nchapters 1, 3, 4 and 6, the comments of the peer reviewers were discussed electronically \nwithin the group. Chapter 2 had a larger group whose members met for a consensus \ngroup discussion. Chapter 5 required extensive discussion, but consensus was reached \nwithout a consensus group meeting. Agreement on the chapter content was reached for \nall the groups.\n3. Use of evidence\nFor each chapter, items are referenced that (1) provide new data, (2) challenge current \npractice, (3) d", "page": 8, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "e new data, (2) challenge current \npractice, (3) describe ongoing research and (4) reflect key developments in knowledge \nabout dengue prevention and control. \nPriority was given to systematic reviews when available. Additional literature searches \nwere conducted by the writing teams when items under 1--3 were identified, and \nreferences from personal collections of experts were added when appropriate under 4. \nThe writing teams referred to the items under 1--4 in the text, and lists of referenc", "page": 8, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "tems under 1--4 in the text, and lists of references were \nadded at the end of each chapter.\n1\t Declared interests:\n\t Chapter 1. Dr Anne Wilder Smith: principal investigator in dengue vaccine trial starting in 2009.\n\t Chapter 4. Dr Mary Jane Cardosa: shareholder and director of company developing dengue diagnostic tests.\n\t Chapter 6. Dr Robert Edelman: consultant for company involved in dengue vaccine research.", "page": 8, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "vii\nIntroduction, Methodology, Acknowledgements, Abbreviations, Preface\nACKNOWLEDGEMENTS\nThis new edition of the dengue guidelines would not have been possible without \nthe initiative, practical experience of many years of working in dengue, and writing \ncontribution of Dr Michael B. Nathan, now retired from the World Health Organization \n(WHO). \nDr Axel Kroeger of the Special Programme for Research and Training in Tropical Diseases \n(WHO/TDR) equally contributed to all parts of the guidelines.", "page": 9, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ually contributed to all parts of the guidelines.\nDr John Ehrenberg, Dr Chusak Prasittisuk and Dr Jose Luis San Martin, as WHO regional \nadvisers on dengue, contributed their unique experience to all chapters.\nDr Renu Dayal Drager (WHO) and Dr Jeremy Farrar (the Wellcome Trust) contributed \ntechnical advice to several chapters.\nDr Raman Velayudhan (WHO) coordinated the finalization and publication of the guide \nand advised on all the chapters.\nDr Olaf Horstick (WHO/TDR) assembled the evidence ba", "page": 9, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "Olaf Horstick (WHO/TDR) assembled the evidence base, contributed to all chapters \nand contributed to the finalization of the guide.\nSpecial thanks are due to the editorial team of Mrs Karen Ciceri and Mr Patrick Tissot \nat WHO.\nThe following individuals contributed to chapters as lead writers, advisers or peer \nreviewers:\nChapter 1\nLead writers: Dr Michael B. Nathan, Dr Renu Dayal-Drager, Dr Maria Guzman.\nAdvisers and peer reviewers: Dr Olivia Brathwaite, Dr Scott Halstead, Dr Anand Joshi, \nDr", "page": 9, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "rathwaite, Dr Scott Halstead, Dr Anand Joshi, \nDr Romeo Montoya, Dr Cameron Simmons, Dr Thomas Jaenisch, Dr Annelies Wilder-\nSmith, Dr Mary Wilson.\nChapter 2\nLead writers: Dr Jacqueline Deen, Dr Lucy Lum, Dr Eric Martinez, Dr Lian Huat Tan.\nAdvisers and peer reviewers: Dr Jeremy Farrar, Dr Ivo Castelo Branco, Dr Efren Dimaano, \nDr Eva Harris, Dr Nguyen Hung, Dr Ida Safitri Laksono, Dr Jose Martinez, Dr Ernesto \nBenjam\u00edn Pleites, Dr Rivaldo Venancio, Dr Elci Villegas, Dr Martin Weber, Dr Bridget", "page": 9, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "io, Dr Elci Villegas, Dr Martin Weber, Dr Bridget \nWills.\nChapter 3\nLead writers: Dr Philip McCall, Dr Linda Lloyd, Dr Michael B. Nathan.\nAdvisers and peer reviewers: Dr Satish Appoo, Dr Roberto Barrera, Dr Robert Bos, \nDr Mohammadu Kabir Cham, Dr Gary G. Clark, Dr Christian Frederickson, Dr Vu Sinh \nNam, Dr Chang Moh Seng, Dr Tom W. Scott, Dr Indra Vithylingam, Dr Rajpal Yadav, \nDr Andr\u00e9 Yebakima, Dr Raman Velayudhan, Dr Morteza Zaim.", "page": 9, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "viii\nDengue: Guidelines for diagnosis, treatment, prevention and control\nChapter 4\nLead writers: Dr Philippe Buchy, Dr Rosanna Peeling.\nAdvisers and peer reviewers: Dr Harvey Artsob, Dr Jane Cardosa, Dr Renu Dayal-\nDrager, Dr Duane Gubler, Dr Maria Guzman, Dr Elizabeth Hunsperger, Dr Lucy Lum, \n \nDr Eric Martinez, Dr Jose Pelegrino, Dr Susana Vazquez. \nChapter 5\nLead writers: Dr Duane Gubler, Dr Gary G. Clark, Dr Renu Dayal-Drager, Dr Dana Focks, \n \nDr Axel Kroeger, Dr Angela Merianos, Dr Cathy", "page": 10, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "Dr Axel Kroeger, Dr Angela Merianos, Dr Cathy Roth.\nAdvisers and peer reviewers: Dr Pierre Formenty, Dr Reinhard Junghecker, Dr Dominique \nLegros, Dr Silvia Runge-Ranzinger, Dr Jos\u00e9 Rigau-P\u00e9rez. \nChapter 6\nLead writers: Dr Eva Harris, Dr Joachim Hombach, Dr Janis Lazdins-Held.\nAdvisers and peer reviewers: Dr Bruno Canard, Dr Anne Durbin, Dr Robert Edelman, \n \nDr Maria Guzman, Dr John Roehrig, Dr Subhash Vasudevan.", "page": 10, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ix\nIntroduction, Methodology, Acknowledgements, Abbreviations, Preface\nABBREVIATIONS\na.i. \nad interim\nADE \nantibody-dependent enhancement\nALT \nalanine amino transferase\nAST \naspartate amino transferase\nBP \nblood pressure\nBSL \nbiosafety level\nBti \nBacillus thuringiensis israelensis\nCD4 \ncluster of differentiation 4, T helper cell surface glycoprotein\nCD8 \ncluster of differentiation 8, T cell co-receptor transmembrane glycoprotein\nCFR \ncase-fatality rate\nCOMBI \ncommunication for behavioural impact", "page": 11, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "y rate\nCOMBI \ncommunication for behavioural impact\nDALY \ndisability-adjusted life years\nDEET \ndiethyl-meta-toluamide\nDENCO \nDengue and Control study (multi-country study)\nDEN \ndengue\nDDT \ndichlorodiphenyltrichloroethane\nDF \ndengue fever\nDHF \ndengue haemorrhagic fever\nDNA \ndeoxyribonucleic acid\nDSS \ndengue shock syndrome\nDT \ntablet for direct application\nEC \nemulsifiable concentrate\nELISA \nenzyme-linked immunosorbent assay\nE/M \nenvelop/membrane antigen\nFBC \nfull blood count\nFc-receptor fragment,", "page": 11, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "tigen\nFBC \nfull blood count\nFc-receptor fragment, crystallisable region, a cell receptor\nFRhL \nfetal rhesus lung cells\nGAC \nE/M-specific capture IgG ELISA\nGIS \nGeographical Information System\nGOARN \nGlobal Outbreak Alert and Response Network\nGPS \nglobal positioning system\nGR \ngranule\nHI \nhaemagglutination-inhibition\nHIV/AIDS \nhuman immunodeficiency virus/acquired immunodeficiency syndrome\nICU \nintensive care unit\nIEC \ninformation, education, communication\nIgA \nimmunoglobulin A\nIgG \nimmunoglobuli", "page": 11, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "unication\nIgA \nimmunoglobulin A\nIgG \nimmunoglobulin G\nIgM \nimmunoglobulin M\nINF gamma interferon gamma", "page": 11, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "x\nDengue: Guidelines for diagnosis, treatment, prevention and control\nIPCS\t\nInternational Programme on Chemical Safety\nIR3535\t\n3-[N-acetyl-N-butyl]-aminopropionic acid ethyl ester\nITM\t\ninsecticide treated material\nIV\t\nintravenous\nLAV\t\nlive attenuated vaccine\t\n\t\nMAC-ELISA\t IgM antibody-capture enzyme-linked immunosorbent assay\nMIA\t\nmicrosphere-based immunoassays\nMoE\t\nMinistry of Education\nMoH\t\nMinistry of Health\nNAAT\t\nnucleic acid amplification test\t\n\t\nNASBA\t\nnucleic acid sequence based amplifica", "page": 12, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "st\t\n\t\nNASBA\t\nnucleic acid sequence based amplification\nNGO\t\nnongovernmental organization\t\nNS\t\nnon-structural protein\nNSAID\t\nnon-steroidal anti-inflammatory drugs\nOD\t\noptical density\nORS\t\noral rehydration solution\nPAHO\t\nPan American Health Organization\nPCR\t\npolymerase chain reaction\nPDVI\t\nPediatric Dengue Vaccine Initiative\npH\t\nmeasure of the acidity or basicity of a solution\nprM\t\na region of the dengue genome\nPRNT\t\nplaque reduction and neutralization test\nRNA\t\nribonucleic acid\nRT-PCR\t\nreverse tr", "page": 12, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "tion test\nRNA\t\nribonucleic acid\nRT-PCR\t\nreverse transcriptase-polymerase chain reaction\nSC\t\nsuspension concentrate\nTNF alfa\t\ntumor necrosis factor alfa\nT cells\t\nA group of lymphocytes important for cell-mediated immunity\nTDR\t\nSpecial Programme for Research and Training in Tropical Diseases\nWBC\t\nwhite blood cells\nWG\t\nWater-dispersible granule\nWHO\t\nWorld Health Organizaion\nWP\t\nwettable powder\nYF\t\nyellow fever", "page": 12, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "Chapter 1: Epidemiology, burden of disease and transmission\n1\nCHAPTER 1\nCHAPTER 1\n \nEPIDEMIOLOGY, BURDEN OF DISEASE \nAND TRANSMISSION", "page": 13, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "Chapter 1: Epidemiology, burden of disease and transmission\n3\nCHAPTER 1\nCHAPTER 1. EPIDEMIOLOGY, BURDEN OF DISEASE AND \nTRANSMISSION\n1.1 DENGUE EPIDEMIOLOGY\nDengue is the most rapidly spreading mosquito-borne viral disease in the world. In the \nlast 50 years, incidence has increased 30-fold with increasing geographic expansion \nto new countries and, in the present decade, from urban to rural settings (Figure 1.1). An \nestimated 50 million dengue infections occur annually (Figure 1.2) and approxi", "page": 15, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "infections occur annually (Figure 1.2) and approximately \n2.5 billion people live in dengue endemic countries (1). The 2002 World Health \nAssembly resolution WHA55.17 (2) urged greater commitment to dengue by WHO \nand its Member States. Of particular signifi\n cance is the 2005 World Health Assembly \nresolution WHA58.3 on the revision of the International Health Regulations (IHR) (3), \nwhich includes dengue as an example of a disease that may constitute a public health \nemergency of international", "page": 15, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "titute a public health \nemergency of international concern with implications for health security due to disruption \nand rapid epidemic spread beyond national borders.\nFigure 1.1 Countries/areas at risk of dengue transmission, 2008\nData Source: World Health Organization Map \nProduction: Public Health Infrmation and Geographic \nInformation Systems (GIS) World Health Organization\nThe boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoev", "page": 15, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "o not imply the expression of any opinion whatsoever \non the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, \nor concerning the delimitation of its frontiers or boundaries. Dotted lines or maps represent approximate border lines for which \nthere may not yest be fi\n ll agreement.\ncountries or areas at risk \n(As of 1 November 2008)\nThe contour lines of the January and July isotherms indicate the potential geographical", "page": 15, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "July isotherms indicate the potential geographical limits of the northern and \nsouthern hemispheres for year-round survival of Adeas aegypti, the principal mosquito vector of dengue viruses.\nJuly isotherm\n10.C\nJanuary isotherm\n10.C\n \u00a9 World Health Organization 2008", "page": 15, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "Dengue: Guidelines for diagnosis, treatment, prevention and control\n4\nThe following sections give an overview of the epidemiology and burden of disease in \nthe different WHO regions. All data are from country reports from the WHO regional \noffices, unless referenced to a different source.\n\b\n1.1.1 \tDengue in Asia and the Pacific\nSome 1.8 billion (more than 70%) of the population at risk for dengue worldwide live in \nmember states of the WHO South-East Asia Region and Western Pacific Region, which", "page": 16, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "East Asia Region and Western Pacific Region, which \nbear nearly 75% of the current global disease burden due to dengue. The Asia Pacific \nDengue Strategic Plan for both regions (2008--2015) has been prepared in consultation \nwith member countries and development partners in response to the increasing threat \nfrom dengue, which is spreading to new geographical areas and causing high mortality \nduring the early phase of outbreaks. The strategic plan aims to aid countries to reverse \nthe rising tre", "page": 16, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "n aims to aid countries to reverse \nthe rising trend of dengue by enhancing their preparedness to detect, characterize and \ncontain outbreaks rapidly and to stop the spread to new areas.\nFigure 1.2 Average annual number of dengue fever (DF) and dengue haemorrhagic fever (DHF) cases \nreported to WHO, and of countries reporting dengue, 1955\u20132007\nNumber of cases\nNumber of countries\n70\n60\n50\n40\n30\n20\n1955-1959\n1960-1969\n1970-1979\n1980-1989\n1990-1999\n2000-2007\n10\n0\n1 000 000\n900 000\n800 000\n700 000\n6", "page": 16, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "2000-2007\n10\n0\n1 000 000\n900 000\n800 000\n700 000\n600 000\n500 000\n400 000\n300 000\n200 000\n100 000\n0\n908 \n122,174\n15,497\n295,554\n479,848\n925,896\nYear", "page": 16, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "Chapter 1: Epidemiology, burden of disease and transmission\n5\nCHAPTER 1\n1.1.1.1 Dengue in the WHO South-East Asia Region\nSince 2000, epidemic dengue has spread to new areas and has increased in the \nalready affected areas of the region. In 2003, eight countries -- Bangladesh, India, \nIndonesia, Maldives, Myanmar, Sri Lanka, Thailand and Timor-Leste -- reported dengue \ncases. In 2004, Bhutan reported the country\u2019s first dengue outbreak. In 2005, WHO\u2019s \nGlobal Outbreak Alert and Response Network (", "page": 17, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "HO\u2019s \nGlobal Outbreak Alert and Response Network (GOARN) responded to an outbreak with \na high case-fatality rate (3.55%) in Timor-Leste. In November 2006, Nepal reported \nindigenous dengue cases for the first time. The Democratic Peoples\u2019 Republic of Korea is \nthe only country of the South-East Region that has no reports of indigenous dengue.\nThe countries of the region have been divided into four distinct climatic zones with \ndifferent dengue transmission potential. Epidemic dengue is a major", "page": 17, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ransmission potential. Epidemic dengue is a major public health \nproblem in Indonesia, Myanmar, Sri Lanka, Thailand and Timor-Leste which are in the \ntropical monsoon and equatorial zone where Aedes aegypti is widespread in both urban \nand rural areas, where multiple virus serotypes are circulating, and where dengue is a \nleading cause of hospitalization and death in children. Cyclic epidemics are increasing \nin frequency and in-country geographic expansion is occurring in Bangladesh, India \nand", "page": 17, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "c expansion is occurring in Bangladesh, India \nand Maldives -- countries in the deciduous dry and wet climatic zone with multiple virus \nserotypes circulating. Over the past four years, epidemic dengue activity has spread to \nBhutan and Nepal in the sub-Himalayan foothills.\nReported case fatality rates for the region are approximately 1%, but in India, Indonesia \nand Myanmar, focal outbreaks away from the urban areas have reported case-fatality \nrates of 3--5%.\nIn Indonesia, where more than 35%", "page": 17, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "rates of 3--5%.\nIn Indonesia, where more than 35% of the country\u2019s population lives in urban areas, \n150 000 cases were reported in 2007 (the highest on record) with over 25 000 cases \nreported from both Jakarta and West Java. The case-fatality rate was approximately \n1%. \nIn Myanmar in 2007 the states/divisions that reported the highest number of cases \nwere Ayayarwaddy, Kayin, Magway, Mandalay, Mon, Rakhine, Sagaing, Tanintharyi \nand Yangon. From January to September 2007, Myanmar reported 957", "page": 17, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "om January to September 2007, Myanmar reported 9578 cases. The \nreported case-fatality rate in Myanmar is slightly above 1%.\nIn Thailand, dengue is reported from all four regions: Northern, Central, North-Eastern \nand Southern. In June 2007, outbreaks were reported from Trat province, Bangkok, \nChiangrai, Phetchabun, Phitsanulok, Khamkaeng Phet, Nakhon Sawan and Phit Chit. A \ntotal of 58 836 cases were reported from January to November 2007. The case-fatality \nrate in Thailand is below 0.2%.\nDen", "page": 17, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "case-fatality \nrate in Thailand is below 0.2%.\nDengue prevention and control will be implemented through the Bi-regional Dengue \nStrategy (2008--2015) of the WHO South-East Asia and Western Pacific regions. This \nconsists of six elements: (i) dengue surveillance, (ii) case management, (iii) outbreak \nresponse, (iv) integrated vector management, (v) social mobilization and communication \nfor dengue and (vi) dengue research (a combination of both formative and operational \nresearch). The strategy", "page": 17, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ormative and operational \nresearch). The strategy has been endorsed by resolution SEA/RC61/R5 of the WHO \nRegional Committee for South-East Asia in 2008 (4).", "page": 17, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "Dengue: Guidelines for diagnosis, treatment, prevention and control\n6\n1.1.1.2 Dengue in the WHO Western Pacific Region\nDengue has emerged as a serious public health problem in the Western Pacific Region \n(5). Since the last major pandemic in 1998, epidemics have recurred in much of \nthe area. Lack of reporting remains one of the most important challenges in dengue \nprevention and control. \nBetween 2001 and 2008, 1 020 333 cases were reported in Cambodia, Malaysia, \nPhilippines, and Viet Nam -- t", "page": 18, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ambodia, Malaysia, \nPhilippines, and Viet Nam -- the four countries in the Western Pacific Region with the \nhighest numbers of cases and deaths. The combined death toll for these four countries \nwas 4798 (official country reports). Compared with other countries in the same region, \nthe number of cases and deaths remained highest in Cambodia and the Philippines in \n2008. Overall, case management has improved in the Western Pacific Region, leading \nto a decrease in case fatality rates.\nDengue has", "page": 18, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "to a decrease in case fatality rates.\nDengue has also spread throughout the Pacific Island countries and areas. Between \n2001 and 2008, the six most affected Pacific island countries and areas were French \nPolynesia (35 869 cases), New Caledonia (6836 cases), Cook Islands (3735 \ncases), American Samoa (1816 cases), Palau (1108 cases) and the Federal States of \nMicronesia (664 cases). The total number of deaths for the six island countries was 34 \n(official country reports). Although no official", "page": 18, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "(official country reports). Although no official reports have been submitted to WHO by \nKiribati, the country did experience a dengue outbreak in 2008, reporting a total of \n837 cases and causing great concern among the national authorities and among some \nof the other countries in the region. \nHistorically, dengue has been reported predominantly among urban and peri-urban \npopulations where high population density facilitates transmission. However, evidence \nfrom recent outbreaks, as seen in", "page": 18, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ever, evidence \nfrom recent outbreaks, as seen in Cambodia in 2007, suggests that they are now \noccurring in rural areas.\nImplementing the Bi-regional Dengue Strategy for Asia and the Pacific (2008--2015) is \na priority following endorsement by the 2008 resolution WPR/RC59.R6 of the WHO \nRegional Committee for the Western Pacific (6).\n\b\n1.1.2 \tDengue in the Americas\nInterruption of dengue transmission in much the WHO Region of the Americas resulted \nfrom the Ae. aegypti eradication campaign in t", "page": 18, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ed \nfrom the Ae. aegypti eradication campaign in the Americas, mainly during the 1960s \nand early 1970s. However, vector surveillance and control measures were not sustained \nand there were subsequent reinfestations of the mosquito, followed by outbreaks in the \nCaribbean, and in Central and South America (7). Dengue fever has since spread with \ncyclical outbreaks occurring every 3--5 years. The biggest outbreak occurred in 2002 \nwith more than 1 million reported cases. \nFrom 2001 to 2007, more", "page": 18, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "million reported cases. \nFrom 2001 to 2007, more than 30 countries of the Americas notified a total of 4 332 \n731 cases of dengue (8). The number of cases of dengue haemorrhagic fever (DHF) \nin the same period was 106 037. The total number of dengue deaths from 2001 to", "page": 18, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "Chapter 1: Epidemiology, burden of disease and transmission\n7\nCHAPTER 1\n2007 was 1299, with a DHF case fatality rate of 1.2%. The four serotypes of the \ndengue virus (DEN-1, DEN-2, DEN-3 and DEN-4) circulate in the region. In Barbados, \nColombia, Dominican Republic, El Salvador, Guatemala, French Guyana, Mexico, \nPeru, Puerto Rico and Venezuela, all four serotypes were simultaneously identified in one \nyear during this period. \nBy subregion of the Americas, dengue is characterized as described b", "page": 19, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "e Americas, dengue is characterized as described below. All data \nare from the Pan American Health Organization (PAHO) (8).\nThe Southern Cone countries\nArgentina, Brazil, Chile, Paraguay and Uruguay are located in this subregion. In the \nperiod from 2001 to 2007, 64.6% (2 798 601) of all dengue cases in the Americas \nwere notified in this subregion, of which 6733 were DHF with a total of 500 deaths. \nSome 98.5% of the cases were notified by Brazil, which also reports the highest case \nfatality r", "page": 19, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "l, which also reports the highest case \nfatality rate in the subregion. In the subregion, DEN-1, -2 and -3 circulate.\nAndean countries\nThis subregion includes Bolivia, Colombia, Ecuador, Peru and Venezuela, and \ncontributed 19% (819 466) of dengue cases in the Americas from 2001 to 2007. It is \nthe subregion with the highest number of reported DHF cases, with 58% of all cases (61 \n341) in the Americas, and 306 deaths.  Colombia and Venezuela have most cases in \nthe subregion (81%), and in Colomb", "page": 19, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "most cases in \nthe subregion (81%), and in Colombia there were most dengue deaths (225, or 73%). \nIn Colombia, Peru and Venezuela all four dengue serotypes were identified.\nCentral American countries and Mexico\nDuring 2001\u20132007, a total of 545 049 cases, representing 12.5% of dengue in the \nAmericas, was reported, with 35 746 cases of DHF and 209 deaths. Nicaragua had \n64 deaths (31%), followed by Honduras with 52 (25%) and Mexico with 29 (14%). \nCosta Rica, Honduras and Mexico reported the hig", "page": 19, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "Costa Rica, Honduras and Mexico reported the highest number of cases in this period. \nDEN-1, -2 and -3 were the serotypes most frequently reported. \nCaribbean countries\nIn this subregion 3.9% (168 819) of the cases of dengue were notified, with 2217 DHF \ncases and 284 deaths. Countries with the highest number of dengue cases in the Latin \nCaribbean were Cuba, Puerto Rico and the Dominican Republic, whereas in the English \nand French Caribbean, Martinique, Trinidad and Tobago and French Guiana", "page": 19, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "Martinique, Trinidad and Tobago and French Guiana reported \nthe highest numbers of cases. The Dominican Republic reported 77% of deaths (220) \nduring the period 2001--2007. All four serotypes circulate in the Caribbean area, but \npredominantly DEN-1 and -2. \nNorth American countries\nThe majority of the notified cases of dengue in Canada and the United States are \npersons who had travelled to endemic areas in Asia, the Caribbean, or Central or South \nAmerica (9). From 2001 to 2007, 796 cases of d", "page": 19, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "th \nAmerica (9). From 2001 to 2007, 796 cases of dengue were reported in the United \nStates, the majority imported. Nevertheless, outbreaks of dengue in Hawaii have been \nreported, and there were outbreaks sporadically with local transmission in Texas at the \nborder with Mexico (10,11).", "page": 19, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "Dengue: Guidelines for diagnosis, treatment, prevention and control\n8\nThe Regional Dengue Programme of PAHO focuses public policies towards a multisectoral \nand interdisciplinary integration. This allows the formulation, implementation, monitoring \nand evaluation of national programmes through the Integrated Management Strategy \nfor Prevention and Control of Dengue (EGI-dengue, from its acronym in Spanish). This \nhas six key components: (i) social communication (using Communication for Behaviour", "page": 20, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "l communication (using Communication for Behavioural \nImpact (COMBI)), (ii) entomology, (iii) epidemiology, (iv) laboratory diagnosis, (v) case \nmanagement and (vi) environment. This strategy has been endorsed by PAHO resolutions \n(12\u201315). Sixteen countries and three subregions (Central America, Mercosur and the \nAndean subregion) agreed to use EGI-dengue as a strategy and are in the process of \nimplementation.\n\b\n1.1.3 \tDengue in the WHO African Region\nAlthough dengue exists in the WHO African R", "page": 20, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "Region\nAlthough dengue exists in the WHO African Region, surveillance data are poor. \nOutbreak reports exist, although they are not complete, and there is evidence that \ndengue outbreaks are increasing in size and frequency (16). Dengue is not officially \nreported to WHO by countries in the region. Dengue-like illness has been recorded \nin Africa though usually without laboratory confirmation and could be due to infection \nwith dengue virus or with viruses such as chikungunya that produce simila", "page": 20, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "th viruses such as chikungunya that produce similar clinical \nsymptoms. \nDengue has mostly been documented in Africa from published reports of serosurveys \nor from diagnosis in travellers returning from Africa, and dengue cases from countries \nin Sub-Saharan Africa. A serosurvey (17) suggests that dengue existed in Africa as far \nback as 1926--1927, when the disease caused an epidemic in Durban, South Africa. \nCases of dengue imported from India were detected in the 1980s (18).\nFor eastern Afric", "page": 20, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "were detected in the 1980s (18).\nFor eastern Africa, the available evidence so far indicates that DEN-1, -2 and -3 appear to \nbe common causes of acute fever. Examples of this are outbreaks in the Comoros in various \nyears (1948, 1984 and 1993, DEN-1 and -2) (19) and Mozambique (1984--1985, \nDEN-3) (20).\nIn western Africa in the 1960s, DEN-1, -2 and -3 were isolated for the first time from \nsamples taken from humans in Nigeria (21). Subsequent dengue outbreaks have been \nreported from different", "page": 20, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ngue outbreaks have been \nreported from different countries, as for example from Burkina Faso (1982, DEN-2) (22) \nand Senegal (1999, DEN-2) (23). Also DEN-2 and DEN-3 cases were confirmed in \nC\u00f4te d\u2019Ivoire in 2006 and 2008.\nDespite poor surveillance for dengue in Africa, it is clear that epidemic dengue fever \ncaused by all four dengue serotypes has increased dramatically since 1980, with most \nepidemics occurring in eastern Africa, and to a smaller extent in western Africa, though \nthis situati", "page": 20, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ler extent in western Africa, though \nthis situation may be changing in 2008. \nWhile dengue may not appear to be a major public health problem in Africa compared \nto the widespread incidence of malaria and HIV/AIDS, the increasing frequency \nand severity of dengue epidemics worldwide calls for a better understanding of the \nepidemiology of dengue infections with regard to the susceptibility of African populations \nto dengue and the interference between dengue and the other major communicable \ndi", "page": 20, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "etween dengue and the other major communicable \ndiseases of the continent. \n\b", "page": 20, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "Chapter 1: Epidemiology, burden of disease and transmission\n9\nCHAPTER 1\n1.1.4 \tDengue in the WHO Eastern Mediterranean Region (Figure 1.3)\nOutbreaks of dengue have been documented in the Eastern Mediterranean Region \npossibly as early as 1799 in Egypt (24). The frequency of reported outbreaks continue \nto increase, with outbreaks for example in Sudan (1985, DEN-1 and -2) (25) and in \nDjibouti (1991, DEN-2) (26). \nRecent outbreaks of suspected dengue have been recorded in Pakistan, Saudi Arabia,", "page": 21, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "gue have been recorded in Pakistan, Saudi Arabia, \nSudan and Yemen, 2005--2006 (24). In Pakistan, the first confirmed outbreak of DHF \noccurred in 1994. A DEN-3 epidemic with DHF was first reported in 2005 (27). \nSince then, the expansion of dengue infections with increasing frequency and severity \nhas been reported from large cities in Pakistan as far north as the North-West Frontier \nProvince in 2008. Dengue is now a reportable disease in Pakistan. A pertinent issue \nfor this region is the nee", "page": 21, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "tan. A pertinent issue \nfor this region is the need to better understand the epidemiological situation of dengue \nin areas that are endemic for Crimean-Congo haemorrhagic fever and co-infections of \nthese pathogens.\nYemen is also affected by the increasing frequency and geographic spread of epidemic \ndengue, and the number of cases has risen since the major DEN-3 epidemic that \noccurred in the western al-Hudeidah governorate in 2005. In 2008 dengue affected \nthe southern province of Shabwa.\nSinc", "page": 21, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ue affected \nthe southern province of Shabwa.\nSince the first case of DHF died in Jeddah in 1993, Saudi Arabia has reported three \nmajor epidemics: a DEN-2 epidemic in 1994 with 469 cases of dengue, 23 cases of \nDHF\n, two cases of dengue shock syndrome (DSS) and two deaths; a DEN-1 epidemic \nin 2006 with 1269 cases of dengue, 27 cases of DHF, 12 cases of DSS and six\nFigure 1.3 Outbreaks of dengue fever in the WHO Eastern Mediterranean Region, 1994\u20132005\nDEN-2:\n1994: \t 673 \t suspected cases,  \t\n28", "page": 21, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "4\u20132005\nDEN-2:\n1994: \t 673 \t suspected cases,  \t\n289\t confirmed cases\n1995: \t 136 \t suspected cases, \t\n6\t confirmed cases\n1996: \t\n57 \t suspected cases,\t\n2 \t confirmed cases \n1997: \t\n62 \t suspected cases,\t\n15\t confirmed cases \n1998: \t\n31 \t suspected cases, \t\n0\t confirmed cases \n1999: \t\n26 \t suspected cases, \t\n3\t confirmed cases\n2000: \t\n17 \t suspected cases, \t\n0\t confirmed cases \n2001:\t\n7 \t suspected cases, \t\n0\t confirmed cases\n2005: \t\n32 \t suspected (confirmed)\nAl-Hudaydah, Mukkala, Shaabwa\n(1994,", "page": 21, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "d (confirmed)\nAl-Hudaydah, Mukkala, Shaabwa\n(1994, DEN-3, no data);\nAl-Hudaydah, Yemen\n(September 2000, DEN-2, 653 suspected cases, 80 deaths (CFR = 12%));\nAl-Hudaydah, Yemen\n(March 2004, 45 suspected cases, 2 deaths);\nAl-Hudaydah, Mukkala\n(March 2005, 403 suspected cases, 2 deaths);\nSomalia (1982, 1993, DEN-2)\nDjibouti (1991-1992, DEN-2)\nSudan (No data)", "page": 21, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "Dengue: Guidelines for diagnosis, treatment, prevention and control\n10\ndeaths; and a DEN-3 epidemic in 2008 with 775 cases of dengue, nine cases of \nDHF\n, four cases of DSS and four deaths. A pertinent issue for the IHR is that Jeddah is \na Haj entry point -- as well as being the largest commercial port in the country, and the \nlargest city with the busiest airport in the western region -- with large numbers of people \ncoming from high-burden dengue countries such as Indonesia, Malaysia and Thai", "page": 22, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "gue countries such as Indonesia, Malaysia and Thailand, \nin addition to the dengue-affected countries of the region.\n\b\n1.1.5 \tDengue in other regions\nAs described above, dengue is now endemic in all WHO regions except the WHO \nEuropean Region. Data available for the European region (http://data.euro.who.int/\ncisid/) indicate that most cases in the region have been reported by European Union \nmember states, either as incidents in overseas territories or importations from endemic \ncountries. [See", "page": 22, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ies or importations from endemic \ncountries. [See also a report from the European Centre for Disease Prevention and \nControl (28)]. However, in the past, dengue has been endemic in some Balkan and \nMediterranean countries of the region, and imported cases in the presence of known \nmosquito vectors (e.g. Aedes albopictus) cannot exclude future disease spread.\nGlobally, reporting on dengue cases shows cyclical variation with high epidemic years \nand non-epidemic years. Dengue often presents in the", "page": 22, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "d non-epidemic years. Dengue often presents in the form of large outbreaks. There is, \nhowever, also a seasonality of dengue, with outbreaks occurring in different periods of \nthe year. This seasonality is determined by peak transmission of the disease, influenced \nby characteristics of the host, the vector and the agent. \n\b\n1.1.6 \tDengue case classification\nDengue has a wide spectrum of clinical presentations, often with unpredictable clinical \nevolution and outcome. While most patients recover", "page": 22, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "evolution and outcome. While most patients recover following a self-limiting non-severe \nclinical course, a small proportion progress to severe disease, mostly characterized by \nplasma leakage with or without haemorrhage. Intravenous rehydration is the therapy \nof choice; this intervention can reduce the case fatality rate to less than 1% of severe \ncases. The group progressing from non-severe to severe disease is difficult to define, but \nthis is an important concern since appropriate treatment", "page": 22, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "s an important concern since appropriate treatment may prevent these patients from \ndeveloping more severe clinical conditions.\nTriage, appropriate treatment, and the decision as to where this treatment should be \ngiven (in a health care facility or at home) are influenced by the case classification for \ndengue. This is even more the case during the frequent dengue outbreaks worldwide, \nwhere health services need to be adapted to cope with the sudden surge in demand.\nChanges in the epidemiology", "page": 22, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "dden surge in demand.\nChanges in the epidemiology of dengue, as described in the previous sections, lead \nto problems with the use of the existing WHO classification. Symptomatic dengue virus \ninfections were grouped into three categories: undifferentiated fever, dengue fever (DF) \nand dengue haemorrhagic fever (DHF). DHF was further classified into four severity \ngrades, with grades III and IV being defined as dengue shock syndrome (DSS) (29). \nThere have been many reports of difficulties in th", "page": 22, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "There have been many reports of difficulties in the use of this classification (30\u201332), \nwhich were summarized in a systematic literature review (33). Difficulties in applying \nthe criteria for DHF in the clinical situation, together with the increase in clinically", "page": 22, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "Chapter 1: Epidemiology, burden of disease and transmission\n11\nCHAPTER 1\nsevere dengue cases which did not fulfi\n l the strict criteria of DHF, led to the request \nfor the classifi\n cation to be reconsidered. Currently the classifi\n cation into DF/DHF/DSS \ncontinues to be widely used. (29) \n \nA WHO/TDR-supported prospective clinical multicentre study across dengue-endemic \nregions was set up to collect evidence about criteria for classifying dengue into levels of \nseverity. The study fi\n ndings", "page": 23, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ue into levels of \nseverity. The study fi\n ndings confi\n rmed that, by using a set of clinical and/or laboratory \nparameters, one sees a clear-cut difference between patients with severe dengue and \nthose with non-severe dengue. However, for practical reasons it was desirable to split \nthe large group of patients with non-severe dengue into two subgroups -- patients with \nwarning signs and those without them. Criteria for diagnosing dengue (with or without \nwarning signs) and severe dengue are p", "page": 23, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "or without \nwarning signs) and severe dengue are presented in Figure 1.4. It must be kept in mind \nthat even dengue patients without warning signs may develop severe dengue. \nExpert consensus groups in Latin America (Havana, Cuba, 2007), South-East Asia \n(Kuala Lumpur, Malaysia, 2007), and at WHO headquarters in Geneva, Switzerland \nin 2008 agreed that:\n\u201cdengue is one disease entity with different clinical presentations and often with \nunpredictable clinical evolution and outcome\u201d; \nthe classifi", "page": 23, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ble clinical evolution and outcome\u201d; \nthe classifi\n cation into levels of severity has a high potential for being of practical use in \nthe clinicians\u2019 decision as to where and how intensively the patient should be observed \nand treated (i.e. triage, which is particularly useful in outbreaks), in more consistent \nreporting in the national and international surveillance system, and as an end-point \nmeasure in dengue vaccine and drug trials.\nFigure 1.4 Suggested dengue case classifi\n cation and lev", "page": 23, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "1.4 Suggested dengue case classifi\n cation and levels of severity\nProbable dengue\nlive in /travel to dengue endemic area. \nFever and 2 of the following criteria:\n\u2022 Nausea, vomiting\n\u2022 Rash\n\u2022 Aches and pains\n\u2022 Tourniquet test positive\n\u2022 Leukopenia\n\u2022 Any warning sign\nLaboratory-confi\n rmed dengue\n(important when no sign of plasma leakage)\nWarning signs*\n\u2022 Abdominal pain or tenderness\n\u2022 Persistent vomiting\n\u2022 Clinical fl\n uid accumulation\n\u2022 Mucosal bleed\n\u2022 Lethargy, restlessness\n\u2022 Liver enlargment >2", "page": 23, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "eed\n\u2022 Lethargy, restlessness\n\u2022 Liver enlargment >2 cm\n\u2022 Laboratory: increase in HCT  \n \n concurrent with rapid decrease   \n in platelet count\n*(requiring strict observation and medical \nintervention)\nSevere plasma leakage\nleading to:\n\u2022 Shock (DSS)\n\u2022 Fluid accumulation with respiratory\n distress\nSevere bleeding\nas evaluated by clinician\nSevere organ involvement\n\u2022 Liver: AST or ALT >=1000\n\u2022 CNS: Impaired consciousness\n\u2022 Heart and other organs\nCRITERIA FOR DENGUE \u00b1 WARNING SIGNS\nCRITERIA FOR SEVERE", "page": 23, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "RIA FOR DENGUE \u00b1 WARNING SIGNS\nCRITERIA FOR SEVERE DENGUE\nDENGUE \u00b1 WARNING SIGNS\nSEVERE DENGUE\n1. Severe plasma leakage\n2. Severe haemorrhage\n3.Severe organ impairment\nwithout\nwith warning \nsigns", "page": 23, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "Dengue: Guidelines for diagnosis, treatment, prevention and control\n12\nThis model for classifying dengue has been suggested by an expert group (Geneva, \nSwitzerland, 2008) and is currently being tested in 18 countries by comparing its \nperformance in practical settings to the existing WHO case classification. The process \nwill be finalized in 2010. For practical reasons this guide adapts the distinction between \ndengue and severe dengue.\nAdditionally the guide uses three categories for case mana", "page": 24, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ally the guide uses three categories for case management (A, B, C) (Chapter 2).\n1.2 BURDEN OF DISEASE\nDengue inflicts a significant health, economic and social burden on the populations of \nendemic areas. Globally the estimated number of disability-adjusted life years (DALYs) \nlost to dengue in 2001 was 528 (34). In Puerto Rico, an estimated yearly mean of 580 \nDALYs per million population were lost to dengue between 1984 and 1994  --  similar \nto the cumulative total of DALYs lost to malaria, t", "page": 24, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "o the cumulative total of DALYs lost to malaria, tuberculosis, intestinal helminths and the \nchildhood disease cluster in all of Latin America and the Caribbean (35).\nThe number of cases reported annually to WHO ranged from 0.4 to 1.3 million \nin the decade 1996 -- 2005. As an infectious disease, the number of cases varies \nsubstantially from year to year. Underreporting and misdiagnoses are major obstacles to \nunderstanding the full burden of dengue (36).\nAvailable data from South-East Asia is", "page": 24, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ngue (36).\nAvailable data from South-East Asia is largely derived from hospitalized cases among \nchildren but the burden due to uncomplicated dengue fever is also considerable. In a \nprospective study of schoolchildren in northern Thailand the mean annual burden of \ndengue over a five-year period was 465.3 DALYs per million, with non-hospitalized \npatients with dengue illness contributing 44 -- 73% of the total (37). \nStudies on the cost of dengue were conducted in eight countries in 2005-2006:", "page": 24, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "e were conducted in eight countries in 2005-2006: five \nin the Americas (Brazil, El Salvador, Guatemala, Panama, Venezuela) and three in \nAsia (Cambodia, Malaysia, Thailand) (38). As dengue also affected other household \nmembers who helped care for the dengue patient, an average episode represented \n14.8 lost days for ambulatory patients and 18.9 days for hospitalized patients. The \noverall cost of a non-fatal ambulatory case averaged US$ 514, while the cost of a \nnon-fatal hospitalized case ave", "page": 24, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ile the cost of a \nnon-fatal hospitalized case averaged US$ 1491. On average, a hospitalized case \nof dengue cost three times what an ambulatory case costs. Combining the ambulatory \nand hospitalized patients and factoring in the risk of death, the overall cost of a dengue \ncase is US$ 828. Merging this number with the average annual number of officially \nreported dengue cases from the eight countries studied in the period 2001 -- 2005 \n(532 000 cases) gives a cost of officially reported dengue", "page": 24, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "cases) gives a cost of officially reported dengue of US$ 440 million. This \nvery conservative estimate ignores not only the underreporting of cases but also the \nsubstantial costs associated with dengue surveillance and vector control programmes. \nThis study showed that a treated dengue episode imposes substantial costs on both the \nhealth sector and the overall economy. If a vaccine were able to prevent much of this \nburden, the economic gains would be substantial.", "page": 24, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ould be substantial.", "page": 24, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "Chapter 1: Epidemiology, burden of disease and transmission\n13\nCHAPTER 1\nChildren are at a higher risk of severe dengue (39). Intensive care is required for severely \nill patients, including intravenous fluids, blood or plasma transfusion and medicines.\nDengue afflicts all levels of society but the burden may be higher among the poorest who \ngrow up in communities with inadequate water supply and solid waste infrastructure, \nand where conditions are most favourable for multiplication of the main", "page": 25, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "are most favourable for multiplication of the main vector, Ae. \naegypti.\n1.3 DENGUE IN INTERNATIONAL TRAVEL\nTravellers play an essential role in the global epidemiology of dengue infections, as \nviraemic travellers carry various dengue serotypes and strains into areas with mosquitoes \nthat can transmit infection (40). Furthermore, travellers perform another essential service \nin providing early alerts to events in other parts of the world. Travellers often transport \nthe dengue virus from areas", "page": 25, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "lers often transport \nthe dengue virus from areas in tropical developing countries, where limited laboratory \nfacilities exist, to developed countries with laboratories that can identify virus serotypes \n(41). Access to research facilities makes it possible to obtain more detailed information \nabout a virus, including serotype and even sequencing, when that information would be \nvaluable. Systematic collection of clinical specimens and banking of serum or isolates \nmay have future benefits as ne", "page": 25, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "serum or isolates \nmay have future benefits as new technologies become available. \nFrom the data collected longitudinally over a decade by the GeoSentinel Surveillance \nNetwork (www.geosentinel.org) it was possible, for example, to examine month-by-\nmonth morbidity from a sample of 522 cases of dengue as a proportion of all diagnoses \nin 24 920 ill returned travellers seen at 33 surveillance sites. Travel-related dengue \ndemonstrated a defined seasonality for multiple regions (South-East Asia,", "page": 25, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "easonality for multiple regions (South-East Asia, South Central \nAsia, Caribbean, South America) (42). \nInformation about dengue in travellers, using sentinel surveillance, can be shared rapidly \nto alert the international community to the onset of epidemics in endemic areas where \nthere is no surveillance and reporting of dengue, as well as the geographic spread of \nvirus serotypes and genotypes to new areas which increases the risk of severe dengue. \nThe information can also assist clinicians", "page": 25, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ngue. \nThe information can also assist clinicians in temperate regions -- most of whom are not \ntrained in clinical tropical diseases -- to be alert for cases of dengue fever in ill returned \ntravellers. The clinical manifestations and complications of dengue can also be studied \nin travellers (most of them adult and non-immune) as dengue may present differently \ncompared with the endemic population (most of them in the paediatric age group and \nwith pre-existing immunity). The disadvantage of s", "page": 25, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "with pre-existing immunity). The disadvantage of such sentinel surveillance, however, is \nthe lack of a denominator: true risk incidence cannot be determined. An increase in \ncases in travellers could be due to increased travel activity to dengue endemic areas, \nfor instance.", "page": 25, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "Dengue: Guidelines for diagnosis, treatment, prevention and control\n14\n1.4 TRANSMISSION\n\b\n1.4.1 \tThe virus\nDengue virus (DEN) is a small single-stranded RNA virus comprising four distinct serotypes \n(DEN-1 to -4). These closely related serotypes of the dengue virus belong to the genus \nFlavivirus, family Flaviviridae. \nThe mature particle of the dengue virus is spherical with a diameter of 50nm containing \nmultiple copies of the three structural proteins, a host-derived membrane bilayer and a \ns", "page": 26, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "proteins, a host-derived membrane bilayer and a \nsingle copy of a positive-sense, single-stranded RNA genome. The genome is cleaved \nby host and viral proteases in three structural proteins (capsid, C, prM, the precursor of \nmembrane, M, protein and envelope, E) and seven nonstructural proteins (NS).\nDistinct genotypes or lineages (viruses highly related in nucleotide sequence) have \nbeen identified within each serotype, highlighting the extensive genetic variability of \nthe dengue serotypes. Pu", "page": 26, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "e genetic variability of \nthe dengue serotypes. Purifying selection appears to be a dominant theme in dengue \nviral evolution, however, such that only viruses that are \u201cfit\u201d for both human and vector \nare maintained. Among them, \u201cAsian\u201d genotypes of DEN-2 and DEN-3 are frequently \nassociated with severe disease accompanying secondary dengue infections (43\u201345). \nIntra-host viral diversity (quasispecies) has also been described in human hosts.\n\b\n1.4.2 \tThe vectors\nThe various serotypes of the deng", "page": 26, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "4.2 \tThe vectors\nThe various serotypes of the dengue virus are transmitted to humans through the bites \nof infected Aedes mosquitoes, principally Ae. aegypti. This mosquito is a tropical \nand subtropical species widely distributed around the world, mostly between latitudes \n \n35 0N and 35 0S. These geographical limits correspond approximately to a winter \nisotherm of 10 0C. Ae. aegypti has been found as far north as 45 0N, but such \ninvasions have occurred during warmer months and the mosquitoes", "page": 26, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "e occurred during warmer months and the mosquitoes have not survived \nthe winters. Also, because of lower temperatures, Ae. aegypti is relatively uncommon \nabove 1000 metres. The immature stages are found in water-filled habitats, mostly in \nartificial containers closely associated with human dwellings and often indoors. Studies \nsuggest that most female Ae. aegypti may spend their lifetime in or around the houses \nwhere they emerge as adults. This means that people, rather than mosquitoes, rapi", "page": 26, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "is means that people, rather than mosquitoes, rapidly \nmove the virus within and between communities. Dengue outbreaks have also been \nattributed to Aedes albopictus, Aedes polynesiensis and several species of the Aedes \nscutellaris complex. Each of these species has a particular ecology, behaviour and \ngeographical distribution. In recent decades Aedes albopictus has spread from Asia to \nAfrica, the Americas and Europe, notably aided by the international trade in used tyres \nin which eggs are d", "page": 26, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "rnational trade in used tyres \nin which eggs are deposited when they contain rainwater. The eggs can remain viable \nfor many months in the absence of water (Chapter 3). \n\b", "page": 26, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "Chapter 1: Epidemiology, burden of disease and transmission\n15\nCHAPTER 1\n1.4.2 \tThe host\nAfter an incubation period of 4--10 days, infection by any of the four virus serotypes \ncan produce a wide spectrum of illness, although most infections are asymptomatic \nor subclinical (Chapter 2). Primary infection is thought to induce lifelong protective \nimmunity to the infecting serotype (46). Individuals suffering an infection are protected \nfrom clinical illness with a different serotype within 2--3 m", "page": 27, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "al illness with a different serotype within 2--3 months of the primary infection \nbut with no long-term cross-protective immunity.\nIndividual risk factors determine the severity of disease and include secondary infection, \nage, ethnicity and possibly chronic diseases (bronchial asthma, sickle cell anaemia and \ndiabetes mellitus). Young children in particular may be less able than adults to compensate \nfor capillary leakage and are consequently at greater risk of dengue shock. \nSeroepidemiologica", "page": 27, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "greater risk of dengue shock. \nSeroepidemiological studies in Cuba and Thailand consistently support the role of \nsecondary heterotypic infection as a risk factor for severe dengue, although there are \na few reports of severe cases associated with primary infection (47\u201350). The time \ninterval between infections and the particular viral sequence of infections may also be of \nimportance. For instance, a higher case fatality rate was observed in Cuba when DEN-\n2 infection followed a DEN-1 infectio", "page": 27, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ba when DEN-\n2 infection followed a DEN-1 infection after an interval of 20 years compared to an \ninterval of four years. Severe dengue is also regularly observed during primary infection \nof infants born to dengue-immune mothers. Antibody-dependent enhancement (ADE) of \ninfection has been hypothesized (51,52) as a mechanism to explain severe dengue in \nthe course of a secondary infection and in infants with primary infections. In this model, \nnon-neutralizing, cross-reactive antibodies raised d", "page": 27, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "n-neutralizing, cross-reactive antibodies raised during a primary infection, or acquired \npassively at birth, bind to epitopes on the surface of a heterologous infecting virus and \nfacilitate virus entry into Fc-receptor-bearing cells. The increased number of infected cells \nis predicted to result in a higher viral burden and induction of a robust host immune \nresponse that includes inflammatory cytokines and mediators, some of which may \ncontribute to capillary leakage. During a secondary infec", "page": 27, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ute to capillary leakage. During a secondary infection, cross-reactive memory T \ncells are also rapidly activated, proliferate, express cytokines and die by apoptosis in a \nmanner that generally correlates with overall disease severity. Host genetic determinants \nmight influence the clinical outcome of infection (53,54), though most studies have been \nunable to adequately address this issue. Studies in the American region show the rates \nof severe dengue to be lower in individuals of African anc", "page": 27, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "e dengue to be lower in individuals of African ancestry than those in other ethnic \ngroups. (54)\nThe dengue virus enters via the skin while an infected mosquito is taking a bloodmeal. \nDuring the acute phase of illness the virus is present in the blood and its clearance \nfrom this compartment generally coincides with defervescence. Humoral and cellular \nimmune responses are considered to contribute to virus clearance via the generation \nof neutralizing antibodies and the activation of CD4+ and C", "page": 27, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "lizing antibodies and the activation of CD4+ and CD8+ T lymphocytes. In \naddition, innate host defence may limit infection by the virus. After infection, serotype-\nspecific and cross-reactive antibodies and CD4+ and CD8+ T cells remain measurable \nfor years.\nPlasma leakage, haemoconcentration and abnormalities in homeostasis characterize \nsevere dengue. The mechanisms leading to severe illness are not well defined but the \nimmune response, the genetic background of the individual and the virus c", "page": 27, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "netic background of the individual and the virus characteristics \nmay all contribute to severe dengue.", "page": 27, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "Dengue: Guidelines for diagnosis, treatment, prevention and control\n16\nRecent data suggest that endothelial cell activation could mediate plasma leakage \n(55,56). Plasma leakage is thought to be associated with functional rather than \ndestructive effects on endothelial cells. Activation of infected monocytes and T cells, the \ncomplement system and the production of mediators, monokines, cytokines and soluble \nreceptors may also be involved in endothelial cell dysfunction.\nThrombocytopenia may be", "page": 28, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "othelial cell dysfunction.\nThrombocytopenia may be associated with alterations in megakaryocytopoieses by \nthe infection of human haematopoietic cells and impaired progenitor cell growth, \nresulting in platelet dysfunction (platelet activation and aggregation), increased \ndestruction or consumption (peripheral sequestration and consumption). Haemorrhage \nmay be a consequence of the thrombocytopenia and associated platelet dysfunction \nor disseminated intravascular coagulation. In summary, a tran", "page": 28, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ated intravascular coagulation. In summary, a transient and reversible \nimbalance of inflammatory mediators, cytokines and chemokines occurs during severe \ndengue, probably driven by a high early viral burden, and leading to dysfunction of \nvascular endothelial cells, derangement of the haemocoagulation system then to plasma \nleakage, shock and bleeding.\n\b\n1.4.4 Transmission of the dengue virus\nHumans are the main amplifying host of the virus. Dengue virus circulating in the blood of \nviraemic h", "page": 28, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ngue virus circulating in the blood of \nviraemic humans is ingested by female mosquitoes during feeding. The virus then infects \nthe mosquito mid-gut and subsequently spreads systemically over a period of 8--12 days. \nAfter this extrinsic incubation period, the virus can be transmitted to other humans during \nsubsequent probing or feeding. The extrinsic incubation period is influenced in part \nby environmental conditions, especially ambient temperature. Thereafter the mosquito \nremains infective", "page": 28, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "rature. Thereafter the mosquito \nremains infective for the rest of its life. Ae. aegypti is one of the most efficient vectors \nfor arboviruses because it is highly anthropophilic, frequently bites several times before \ncompleting oogenesis, and thrives in close proximity to humans. Vertical transmission \n(transovarial transmission) of dengue virus has been demonstrated in the laboratory \nbut rarely in the field. The significance of vertical transmission for maintenance of the \nvirus is not well", "page": 28, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "mission for maintenance of the \nvirus is not well understood. Sylvatic dengue strains in some parts of Africa and Asia \nmay also lead to human infection, causing mild illness. Several factors can influence \nthe dynamics of virus transmission -- including environmental and climate factors, host-\npathogen interactions and population immunological factors. Climate directly influences \nthe biology of the vectors and thereby their abundance and distribution; it is consequently \nan important determina", "page": 28, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "bution; it is consequently \nan important determinant of vector-borne disease epidemics.", "page": 28, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "Chapter 1: Epidemiology, burden of disease and transmission\n17\nCHAPTER 1\nREFERENCES\n1.\t WHO. Dengue and dengue haemorrhagic fever. Factsheet No 117, revised May \n2008. \nGeneva, \nWorld \nHealth \nOrganization, \n2008 \n(http://www.who.int/mediacentre/\nfactsheets/fs117/en/).\n2.\t WHO. Dengue fever and dengue haemorrhagic fever prevention and control. 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Geneva, World \nHealth Organization, Special Programme for Research and Training in Tropical Diseases, \n2007 (pp 29--34) (Document TDR/SWG/07).\n17. Kokernot RH, Smithburn KC, Weinbren MP. Neutralising antibodies to arthropod-\nborne viruses in human and animals in the Union of South Africa.\nJournal of Immunology, 1956, 77:313\u2013322.\n18. Blackburn NK, Rawal R. Dengue fever imported from India: a report of 3 cases. \nSouth African Medical Journal, 1987, 21:386\u2013287.\n19. Boisier P et al. D", "page": 30, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "Journal, 1987, 21:386\u2013287.\n19. Boisier P et al. Dengue 1 epidemic in the Grand Comoro Island (Federal Islamic \nRepublic of the Comores), March-May 1993. Annales de la Soci\u00e9t\u00e9 Belge de M\u00e9decine \nTropicale, 1993, 74:217\u2013229.\n20. Gubler DJ et al. Dengue 3 Virus Transmission in Africa. American Journal of Tropical \nMedicine and Hygiene, 1986, 35(6):1280--1284.\n21. Carey DE et al. Dengue virus from febrile patients in Nigeria 1964\u201368. Lancet, \n1971, 1:105\u2013106.\n22. Gonzalez JP et al. Dengue in Burkin", "page": 30, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "1:105\u2013106.\n22. Gonzalez JP et al. Dengue in Burkina Faso: seasonal epidemics in the urban area \nof Ouagadougu. Bulletin de la Soci\u00e9t\u00e9 de pathologie exotique et de ses filiales, 1985, \n78:7\u201314.\n23. Diallo M et al. Amplification of the sylvatic cycle of dengue virus type 2, Senegal, \n1999--2000: entomologic findings and epidemiologic considerations. Emerging \nInfectious Diseases (serial online), 2003, March (date cited). Accessible at http://\nwww.cdc.gov/ncidod/EID/vol9no3/02-0219.htm.", "page": 30, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "dc.gov/ncidod/EID/vol9no3/02-0219.htm.", "page": 30, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "Chapter 1: Epidemiology, burden of disease and transmission\n19\nCHAPTER 1\n24. WHO/EMRO. World Health Organization, Regional Office for the Eastern \nMediterranean, Division of Communicable Disease Control, Newsletter, I2005, 6:7\u20138. \n(http://www.emro.who.int/pdf/dcdnewsletter6.pdf).\n25. Hyams KC et al. Evaluation of febrile patients in Port Sudan, Sudan: isolation of \ndengue virus. American Journal of Tropical Medicine and Hygiene, 1986, 35:860\u2013\n865.\n26. Rodier GR et al. Epidemic dengue 2 in the ci", "page": 31, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": ".\n26. Rodier GR et al. Epidemic dengue 2 in the city of Djibouti 1991\u20131992. Transactions \nof the Royal Society of Tropical Medicine and Hygiene, 1996, 90:237\u2013240.\n27. Bushra J. Dengue Virus Serotype 3, Karachi, Pakistan. Emerging Infectious Diseases, \n2007, 13(1). \n28. European Centre for Disease Prevention and Control. Dengue worldwide: an \noverview of the current situation and implications for Europe, Eurosurveillance, 2007, \n12(25). (http://www.eurosurveillance.org/ViewArticle.aspx?Publicatio", "page": 31, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "w.eurosurveillance.org/ViewArticle.aspx?PublicationType=W&Vol\nume=12&Issue=25&OrderNumber=1).\n29. WHO. Dengue haemorrhagic fever: diagnosis, treatment, prevention and control, \n2nd ed. Geneva, World Health Organization, 1997.\n30. Guha-Sapir D, Schimmer B.  Dengue fever: new paradigms for a changing \nepidemiology. Emerging Themes in Epidemiology, 2005 (Open access journal, http://\nwww.ete-online.com/content/2/1/1).\n31. Deen J et al. The WHO dengue classification and case definitions: time for a", "page": 31, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "classification and case definitions: time for a \nreassessment. Lancet, 2006, 368:170--173.\n32. Rigau-Perez J. Severe dengue: the need for new case definitions. Lancet Infectious \nDiseases, 2006, 6:297\u2013302.\n33. Bandyopadhyay S, Lum LC, Kroeger A. Classifying dengue: a review of the \ndifficulties in using the WHO case classification for dengue haemorrhagic fever. Tropical \nMedicine and International Health, 2006, 11(8):1238--1255.\n34. Cattand P et al. Tropical diseases lacking adequate control me", "page": 31, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "al. Tropical diseases lacking adequate control measures: dengue, \nleishmaniasis, and African trypanosomiasis. Disease control priorities in developing \ncountries, 2nd ed. New York, NY, Oxford University Press, 2006 (pp 451\u2013466).\n35. Meltzer MI et al. Using disability-adjusted life years to assess the economic impact \nof dengue in Puerto Rico: 1984\u20131994. American Journal of Tropical Medicine and \nHygiene, 1998, 59:265\u2013271.\n36. Suaya JA, Shepard DS, Beatty ME. Dengue burden of disease and costs o", "page": 31, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "S, Beatty ME. Dengue burden of disease and costs of illness. \nWorking paper 3.2 in: Report of the Scientific Working Group meeting on Dengue, Geneva, \n1\u20135 October 2006. Geneva, World Health Organization, Special Programme for Research \nand Training in Tropical Diseases, 2007 (pp 35--49) (Document TDR/SWG/07).", "page": 31, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "Dengue: Guidelines for diagnosis, treatment, prevention and control\n20\n37. Anderson K et al. Burden of symptomatic dengue infection in children at primary \nschool in Thailand: a prospective study. Lancet, 2007, 369(9571):1452--1459.\n38. Suaya JA, Shepard DS, Siqueira JB, Martelli CT, Lum LCS, Tan LH, Kongsin S, \nJiamton S, Garrido F\n, Montoya R, Armien B, Huy R, Castillo L, Caram M, Sah BK, \nSughayyar R, Tyo KR, Halstead SB. Costs of dengue cases in 8 countries in the Americas \nand Asia: A prosp", "page": 32, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "in 8 countries in the Americas \nand Asia: A prospective study. American Journal of Tropical Medicine and Hygiene, \n2009, 80:846--855.\n39. Guzman MG. Effect of age on outcome of secondary dengue 2 infections. \nInternational Journal of Infectious Diseases, 2002, 6(2):118--124.\n40. Wilder-Smith A, Wilson ME. Sentinel surveillance for dengue: international travellers \n(unpublished report).\n41. Wilson ME. The traveler and emerging infections: sentinel, courier, transmitter. \nJournal of Applied Micro", "page": 32, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "l, courier, transmitter. \nJournal of Applied Microbiology, 2003, 94:1S--11S.\n42. Schwartz E. Seasonality, annual trends, and characteristics of dengue among ill \nreturned travelers, 1997\u20132006. Emerging Infectious Diseases, 2008, 14(7).\n43. Leitmeyer KC. Dengue virus structural differences that correlate with pathogenesis. \nJournal of Virology, 1999, 73(6):4738--4747.\n44. Lanciotti RS et al. Molecular evolution and epidemiology of dengue-3 viruses. \nJournal of General Virology, 1994, 75(Pt 1):65-", "page": 32, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": ". \nJournal of General Virology, 1994, 75(Pt 1):65--75.\n45. Messer WB. Emergence and global spread of a dengue serotype 3, subtype III \nvirus. Emerging Infectious Diseases, 2003, 9(7):800--809.\n46. Halstead SB. Etiologies of the experimental dengues of Siler and Simmons. American \nJournal of Tropical Medicine and Hygiene, 1974, 23:974--982.\n47. Halstead SB, Nimmannitya S, Cohen SN. Observations related to pathogenesis \nof dengue hemorrhagic fever. IV. Relation of disease severity to antibody resp", "page": 32, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "IV. Relation of disease severity to antibody response and \nvirus recovered. Yale Journal of Biology and Medicine, 1970, 42:311\u2013328.\n48. Sangkawibha N et al. Risk factors in dengue shock syndrome: a prospective \nepidemiologic study in Rayong, Thailand. I. The 1980 outbreak. American Journal of \nEpidemiology, 1984;120:653--669.\n49. Guzman MG et al. Epidemiologic studies on dengue in Santiago de Cuba, 1997. \nAmerican Journal of Epidemiology, 2000, 152(9):793--799.\n50. Halstead SB. Pathophysiology", "page": 32, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "152(9):793--799.\n50. Halstead SB. Pathophysiology and pathogenesis of dengue haemorrhagic fever. In: \nThongchareon P, ed. Monograph on dengue/dengue haemorrhagic fever. New Delhi, \nWorld Health Organization, Regional Office for South-East Asia, 1993 (pp 80--103).", "page": 32, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "Chapter 1: Epidemiology, burden of disease and transmission\n21\nCHAPTER 1\n51. Halstead SB. Antibody, macrophages, dengue virus infection, shock, and \nhemorrhage: a pathogenetic cascade. Reviews of Infectious Diseases, 1989, 11(Suppl \n4):S830--S839.\n52. Halstead SB, Heinz FX. Dengue virus: molecular basis of cell entry and pathogenesis, \n25-27 June 2003, Vienna, Austria. Vaccine, 2005, 23(7):849--856.\n53. Kouri GP, Guzman MG. Dengue haemorrhagic fever/dengue shock syndrome: \nlessons from the Cuban", "page": 33, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ver/dengue shock syndrome: \nlessons from the Cuban epidemic, 1981. Bulletin of the World Health Organization, \n1989, 67(4):375--380.\n54. Sierra B, Kouri G, Guzman MG. Race: a risk factor for dengue hemorrhagic fever. \nArchives of Virology, 2007, 152(3):533--542.\n55. Avirutnan P et al. Dengue virus infection of human endothelial cells leads to \nchemokine production, complement activation, and apoptosis. Journal of Immunology, \n1998, 161:6338--6346.\n56. Cardier JE et al. Proinflammatory factors pr", "page": 33, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": ".\n56. Cardier JE et al. Proinflammatory factors present in sera from patients with acute \ndengue infection induce activation and apoptosis of human microvascular endothelial \ncells: possible role of TNF-alpha in endothelial cell damage in dengue. Cytokine, \n2005, 30(6):359--365.", "page": 33, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "22\nDengue: Guidelines for diagnosis, treatment, prevention and control", "page": 34, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "23\nChapter 2: Clinical management and delivery of clinical services\nCHAPTER 2\nCHAPTER 2\n \nCLINICAL MANAGEMENT AND  \nDELIVERY OF CLINICAL SERVICES", "page": 35, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "24\nDengue: Guidelines for diagnosis, treatment, prevention and control", "page": 36, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "25\nChapter 2: Clinical management and delivery of clinical services\nCHAPTER 2\nCHAPTER 2. CLINICAL MANAGEMENT AND DELIVERY OF CLINICAL \nSERVICES\n2.1 OVERVIEW\nDengue infection is a systemic and dynamic disease. It has a wide clinical spectrum \nthat includes both severe and non-severe clinical manifestations (1). After the incubation \nperiod, the illness begins abruptly and is followed by the three phases -- febrile, critical \nand recovery (Figure 2.1). \nFor a disease that is complex in its manifes", "page": 37, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": ".1). \nFor a disease that is complex in its manifestations, management is relatively simple, \ninexpensive and very effective in saving lives so long as correct and timely interventions \nare instituted. The key is early recognition and understanding of the clinical problems \nduring the different phases of the disease, leading to a rational approach to case \nmanagement and a good clinical outcome. An overview of good and bad clinical \npractices is given in Textbox A.\nActivities (triage and manageme", "page": 37, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "iven in Textbox A.\nActivities (triage and management decisions) at the primary and secondary care levels \n(where patients are fi\n rst seen and evaluated) are critical in determining the clinical \noutcome of dengue. A well-managed front-line response not only reduces the number \nof unnecessary hospital admissions but also saves the lives of dengue patients. Early \nnotifi\n cation of dengue cases seen in primary and secondary care is crucial for identifying \noutbreaks and initiating an early respon", "page": 37, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ntifying \noutbreaks and initiating an early response (Chapter 5). Differential diagnosis needs to \nbe considered (Textbox B).\n \nFigure 2.1 The course of dengue illness*\nDays of illness\nTemperature\nPotential clinical issues\nLaboratory changes\nSerology and virology\nDehydration  \nShock  \nReabsorption\n \nbleeding   \nfl\n uid overload\n        1     2     3     4     5     6     7     8     9     10\nOrgan impairment\nHematocrit\nPlatelet\nViraemia\nIgM/IgG\nFebrile \nCritical \nRecovery phases\nCourse of dengue", "page": 37, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ebrile \nCritical \nRecovery phases\nCourse of dengue illness:\n40\u00b0\n* Source: adapted from Yip (2) by chapter authors.", "page": 37, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "26\nDengue: Guidelines for diagnosis, treatment, prevention and control\n2.1.1 Febrile phase\nPatients typically develop high-grade fever suddenly. This acute febrile phase usually \nlasts 2\u20137 days and is often accompanied by facial flushing, skin erythema, generalized \nbody ache, myalgia, arthralgia and headache (1). Some patients may have sore \nthroat, injected pharynx and conjunctival injection. Anorexia, nausea and vomiting \nare common. It can be difficult to distinguish dengue clinically from n", "page": 38, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "difficult to distinguish dengue clinically from non-dengue febrile \ndiseases in the early febrile phase. A positive tourniquet test in this phase increases the \nprobability of dengue (3,4). In addition, these clinical features are indistinguishable \nbetween severe and non-severe dengue cases. Therefore monitoring for warning signs \nand other clinical parameters (Textbox C) is crucial to recognizing progression to the \ncritical phase.\nMild haemorrhagic manifestations like petechiae and mucosal m", "page": 38, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "rhagic manifestations like petechiae and mucosal membrane bleeding \n(e.g. nose and gums) may be seen (3,5). Massive vaginal bleeding (in women of \nchildbearing age) and gastrointestinal bleeding may occur during this phase but is not \ncommon (5). The liver is often enlarged and tender after a few days of fever (3). The \nearliest abnormality in the full blood count is a progressive decrease in total white cell \ncount, which should alert the physician to a high probability of dengue. \n\b\n2.1.2 Crit", "page": 38, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ian to a high probability of dengue. \n\b\n2.1.2 Critical phase\nAround the time of defervescence, when the temperature drops to 37.5\u201338oC or less \nand remains below this level, usually on days 3\u20137 of illness, an increase in capillary \npermeability in parallel with increasing haematocrit levels may occur (6,7). This marks \nthe beginning of the critical phase. The period of clinically significant plasma leakage \nusually lasts 24\u201348 hours.\nProgressive leukopenia (3) followed by a rapid decrease in pla", "page": 38, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "leukopenia (3) followed by a rapid decrease in platelet count usually precedes \nplasma leakage. At this point patients without an increase in capillary permeability will \nimprove, while those with increased capillary permeability may become worse as a \nresult of lost plasma volume. The degree of plasma leakage varies. Pleural effusion and \nascites may be clinically detectable depending on the degree of plasma leakage and \nthe volume of fluid therapy. Hence chest x-ray and abdominal ultrasound ca", "page": 38, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "apy. Hence chest x-ray and abdominal ultrasound can be useful \ntools for diagnosis. The degree of increase above the baseline haematocrit often reflects \nthe severity of plasma leakage. \nShock occurs when a critical volume of plasma is lost through leakage. It is often \npreceded by warning signs. The body temperature may be subnormal when shock \noccurs. With prolonged shock, the consequent organ hypoperfusion results in progressive \norgan impairment, metabolic acidosis and disseminated intravasc", "page": 38, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ent, metabolic acidosis and disseminated intravascular coagulation. This \nin turn leads to severe haemorrhage causing the haematocrit to decrease in severe \nshock. Instead of the leukopenia usually seen during this phase of dengue, the total \nwhite cell count may increase in patients with severe bleeding. In addition, severe organ \nimpairment such as severe hepatitis, encephalitis or myocarditis and/or severe bleeding \nmay also develop without obvious plasma leakage or shock (8). \nThose who impr", "page": 38, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "vious plasma leakage or shock (8). \nThose who improve after defervescence are said to have non-severe dengue. Some \npatients progress to the critical phase of plasma leakage without defervescence and, in", "page": 38, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "27\nChapter 2: Clinical management and delivery of clinical services\nCHAPTER 2\nthese patients, changes in the full blood count should be used to guide the onset of the \ncritical phase and plasma leakage. \nThose who deteriorate will manifest with warning signs. This is called dengue with \nwarning signs (Textbox C). Cases of dengue with warning signs will probably recover \nwith early intravenous rehydration. Some cases will deteriorate to severe dengue (see \nbelow). \n\b\n2.1.3 Recovery phase \nIf the", "page": 39, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "gue (see \nbelow). \n\b\n2.1.3 Recovery phase \nIf the patient survives the 24\u201348 hour critical phase, a gradual reabsorption of \nextravascular compartment fluid takes place in the following 48\u201372 hours. General \nwell-being improves, appetite returns, gastrointestinal symptoms abate, haemodynamic \nstatus stabilizes and diuresis ensues. Some patients may have a rash of \u201cisles of white \nin the sea of red\u201d (9). Some may experience generalized pruritus. Bradycardia and \nelectrocardiographic changes are c", "page": 39, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "radycardia and \nelectrocardiographic changes are common during this stage. \nThe haematocrit stabilizes or may be lower due to the dilutional effect of reabsorbed \nfluid. White blood cell count usually starts to rise soon after defervescence but the \nrecovery of platelet count is typically later than that of white blood cell count.\nRespiratory distress from massive pleural effusion and ascites will occur at any time if \nexcessive intravenous fluids have been administered. During the critical and/", "page": 39, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "s have been administered. During the critical and/or recovery \nphases, excessive fluid therapy is associated with pulmonary oedema or congestive \nheart failure.\nThe various clinical problems during the different phases of dengue can be summarized \nas in Table 2.1.\n\b\nTable 2.1 Febrile, critical and recovery phases in dengue\n\t\n1\t\nFebrile phase\t\nDehydration; high fever may cause neurological disturbances and febrile  \n\t\n\t\n\t\nseizures in young children\n\t\n2\t\nCritical phase\t\nShock from plasma leakage;", "page": 39, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "n\n\t\n2\t\nCritical phase\t\nShock from plasma leakage; severe haemorrhage; organ impairment\n\t\n3\t\nRecovery phase\t\nHypervolaemia (only if intravenous fluid therapy has been excessive and/or  \n\t\n\t\n\t\nhas extended into this period)\n2.1.4 Severe dengue \nSevere dengue is defined by one or more of the following: (i) plasma leakage that may \nlead to shock (dengue shock) and/or fluid accumulation, with or without respiratory \ndistress, and/or (ii) severe bleeding, and/or (iii) severe organ impairment.\nAs dengu", "page": 39, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ng, and/or (iii) severe organ impairment.\nAs dengue vascular permeability progresses, hypovolaemia worsens and results in \nshock. It usually takes place around defervescence, usually on day 4 or 5 (range \ndays 3\u20137) of illness, preceded by the warning signs. During the initial stage of shock, \nthe compensatory mechanism which maintains a normal systolic blood pressure also \nproduces tachycardia and peripheral vasoconstriction with reduced skin perfusion,", "page": 39, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "fusion,", "page": 39, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "28\nDengue: Guidelines for diagnosis, treatment, prevention and control\nresulting in cold extremities and delayed capillary refill time. Uniquely, the diastolic \npressure rises towards the systolic pressure and the pulse pressure narrows as the \nperipheral vascular resistance increases. Patients in dengue shock often remain conscious \nand lucid. The inexperienced physician may measure a normal systolic pressure and \nmisjudge the critical state of the patient. Finally, there is decompensation and", "page": 40, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "the patient. Finally, there is decompensation and both \npressures disappear abruptly. Prolonged hypotensive shock and hypoxia may lead to \nmulti-organ failure and an extremely difficult clinical course (Textbox D).\nThe patient is considered to have shock if the pulse pressure (i.e. the difference between \nthe systolic and diastolic pressures) is \u2264 20 mm Hg in children or he/she has signs \nof poor capillary perfusion (cold extremities, delayed capillary refill, or rapid pulse \nrate). In adults, t", "page": 40, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "illary refill, or rapid pulse \nrate). In adults, the pulse pressure of \u2264 20 mm Hg may indicate a more severe shock. \nHypotension is usually associated with prolonged shock which is often complicated by \nmajor bleeding.\nPatients with severe dengue may have coagulation abnormalities, but these are usually not \nsufficient to cause major bleeding. When major bleeding does occur, it is almost always \nassociated with profound shock since this, in combination with thrombocytopaenia, \nhypoxia and acidos", "page": 40, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "nation with thrombocytopaenia, \nhypoxia and acidosis, can lead to multiple organ failure and advanced disseminated \nintravascular coagulation. Massive bleeding may occur without prolonged shock in \ninstances when acetylsalicylic acid (aspirin), ibuprofen or corticosteroids have been \ntaken. \n \nUnusual manifestations, including acute liver failure and encephalopathy, may be \npresent, even in the absence of severe plasma leakage or shock. Cardiomyopathy \nand encephalitis are also reported in a few", "page": 40, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "pathy \nand encephalitis are also reported in a few dengue cases. However, most deaths from \ndengue occur in patients with profound shock, particularly if the situation is complicated \nby fluid overload. \nSevere dengue should be considered if the patient is from an area of dengue risk \npresenting with fever of 2\u20137 days plus any of the following features:\n \n\u2022 There is evidence of plasma leakage, such as:\n\t\n\t\n\u2013\t high or progressively rising haematocrit;\n\t\n\t\n\u2013\t pleural effusions or ascites;\n\t\n\t\n\u2013\t c", "page": 40, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "rit;\n\t\n\t\n\u2013\t pleural effusions or ascites;\n\t\n\t\n\u2013\t circulatory compromise or shock (tachycardia, cold and clammy extremities, \n \n\t\n\t\n\t\ncapillary refill time greater than three seconds, weak or undetectable pulse, \t\n\t\n\t\n\t\nnarrow pulse pressure or, in late shock, unrecordable blood pressure).\n \n\u2022 There is significant bleeding.\n \n\u2022 There is an altered level of consciousness (lethargy or restlessness, coma,   \n\t\n\t\nconvulsions).\n \n\u2022 There is severe gastrointestinal involvement (persistent vomiting, inc", "page": 40, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "rointestinal involvement (persistent vomiting, increasing or  \n\t\n\t\nintense abdominal pain, jaundice).\n \n\u2022 There is severe organ impairment (acute liver failure, acute renal failure,  \n \n\t\n\t\nencephalopathy or encephalitis, or other unusual manifestations, cardiomyopathy) \n\t\n\t\nor other unusual manifestations.", "page": 40, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "29\nChapter 2: Clinical management and delivery of clinical services\nCHAPTER 2\n2.2 Delivery of clinical services and case management\n2.2.1 \tIntroduction\nReducing dengue mortality requires an organized process that guarantees early \nrecognition of the disease, and its management and referral when necessary. The key \ncomponent of the process is the delivery of good clinical services at all levels of health \ncare, from primary to tertiary levels. Most dengue patients recover without requiring \nhospi", "page": 41, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "t dengue patients recover without requiring \nhospital admission while some may progress to severe disease. Simple but effective \ntriage principles and management decisions applied at the primary and secondary care \nlevels, where patients are first seen and evaluated, can help in identifying those at risk \nof developing severe disease and needing hospital care. This should be complemented \nby prompt and appropriate management of severe dengue in referral centres.\nActivities at the first level of", "page": 41, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "eferral centres.\nActivities at the first level of care should focus on:\n\t\n\t\n\u2013\t recognizing that the febrile patient could have dengue;\n\t\n\t\n\u2013\t notifying early to the public health authorities that the patient is a suspected case \n \n\t\n\t\n\t\nof dengue;\n\t\n\t\n\u2013\t managing patients in the early febrile phase of dengue;\n\t\n\t\n\u2013\t recognizing the early stage of plasma leakage or critical phase and initiating \n \n\t\n\t\n\t\nfluid therapy;\n\t\n\t\n\u2013\t recognizing patients with warning signs who need to be referred for admi", "page": 41, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ith warning signs who need to be referred for admission \n \n\t\n\t\n\t\nand/or intravenous fluid therapy to a secondary health care facility;\n\t\n\t\n\u2013\t recognizing \nand \nmanaging \nsevere \nplasma \nleakage \nand \nshock, \nsevere \nbleeding \n \n\t\n\t\n\t\nand severe organ impairment promptly and adequately.\n\b\n2.2.2. Primary and secondary health care centres\nAt primary and secondary levels, health care facilities are responsible for emergency/\nambulatory triage assessment and treatment.\nTriage is the process of rapidl", "page": 41, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ent and treatment.\nTriage is the process of rapidly screening patients soon after their arrival in the hospital \nor health facility in order to identify those with severe dengue (who require immediate \nemergency treatment to avert death), those with warning signs (who should be given \npriority while waiting in the queue so that they can be assessed and treated without \ndelay), and non-urgent cases (who have neither severe dengue nor warning signs).\nDuring the early febrile phase, it is often not", "page": 41, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": ").\nDuring the early febrile phase, it is often not possible to predict clinically whether a patient \nwith dengue will progress to severe disease. Various forms of severe manifestations \nmay unfold only as the disease progresses through the critical phase, but the warning \nsigns are good indicators of a higher risk of developing severe dengue. Therefore, the \npatient should have daily outpatient health care assessments for disease progression \nwith careful checking for manifestations of severe de", "page": 41, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "h careful checking for manifestations of severe dengue and warning signs. \nHealth care workers at the first levels of care should apply a stepwise approach, as \nsuggested in Table 2.2.", "page": 41, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "30\nDengue: Guidelines for diagnosis, treatment, prevention and control\nTable 2.2 A stepwise approach to the management of dengue\n\t\nStep I. Overall assessment \n\t\nI.1\t\nHistory, including information on symptoms, past medical and family history\n\t\nI.2\t\nPhysical examination, including full physical and mental assessment\n\t\nI.3 \t Investigation, including routine laboratory and dengue-specific laboratory\n\t\nStep II. Diagnosis, assessment of disease phase and severity \n\t\nStep III. Management \n\t\nIII.1\t Dis", "page": 42, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "and severity \n\t\nStep III. Management \n\t\nIII.1\t Disease notification\n\t\nIII.2\t Management decisions. Depending on the clinical manifestations and other circumstances, \t\n\t\n\t\n\t\npatients may:\n\t\n\t\n\u2013\t\nbe sent home (Group A);\n\t\n\t\n\u2013\t\nbe referred for in-hospital management (Group B);\n\t\n\t\n\u2013\t\nrequire emergency treatment and urgent referral (Group C).\nSection 2.3 gives treatment recommendations for the groups A\u2013C.\n\b\n2.2.3 \tReferral centres\nReferral centres receiving severely ill dengue patients must be able", "page": 42, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ceiving severely ill dengue patients must be able to give prompt \nattention to referred cases. Beds should be made available to those patients who meet \nthe admission criteria, even if elective cases have to be deferred. If possible, there \nshould be a designated area to cohort dengue patients, and a high-dependency unit \nfor closer monitoring of those with shock. These units should be staffed by doctors \nand nurses who are trained to recognize high-risk patients and to institute appropriate \ntr", "page": 42, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "igh-risk patients and to institute appropriate \ntreatment and monitoring.\nA number of criteria may be used to decide when to transfer a patient to a high-\ndependency unit. These include:\n\t\n\t\n\u2013\t early presentation with shock (on days 2 or 3 of illness);\n\t\n\t\n\u2013\t severe plasma leakage and/or shock;\n\t\n\t\n\u2013\t undetectable pulse and blood pressure;\n\t\n\t\n\u2013\t severe bleeding;\n\t\n\t\n\u2013\t fluid overload;\n\t\n\t\n\u2013\t organ \nimpairment \n(such \nas \nhepatic \ndamage, \ncardiomyopathy, \nencephalopathy, \n \n\t\n\t\n\t\nencephalitis a", "page": 42, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "myopathy, \nencephalopathy, \n \n\t\n\t\n\t\nencephalitis and other unusual complications).\n\b\n2.2.4 \tResources needed\nIn the detection and management of dengue, a range of resources is needed to deliver \ngood clinical services at all levels. Resources include (10):\n \n\u2022 Human resources: The most important resource is trained doctors and nurses. \t\n\t\n\t\nAdequate health personnel should be allocated to the first level of care to help \n \n\t\n\t\nin triage and emergency management. If possible, dengue units staffed", "page": 42, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ency management. If possible, dengue units staffed by", "page": 42, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "31\nChapter 2: Clinical management and delivery of clinical services\nCHAPTER 2\n\t\n\t\nexperienced personnel could be set up at referral centres to receive referred \t\n\t\n\t\ncases, particularly during dengue outbreaks, when the number of personnel main \n\t\n\t\nneed to be increased.\n \n\u2022 Special area: A well equipped and well staffed area should be designated for \t\n\t\n\t\ngiving immediate and transitory medical care to patients who require intravenous \n \n\t\n\t\nfluid therapy until they can be transferred to a ward", "page": 43, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "id therapy until they can be transferred to a ward or referral health facility.\n \n\u2022 Laboratory resources: The most important laboratory investigation is that of serial \n \n\t\n\t\nhaematocrit levels and full blood counts. These investigations should be easily \t\n\t\n\t\naccessible from the health centre. Results should be available within two hours \t\n\t\n\t\nin severe cases of dengue. If no proper laboratory services are available, the \t\n\t\n\t\nminimum standard is the point-of-care testing of haematocrit by capi", "page": 43, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "s the point-of-care testing of haematocrit by capillary (finger \t\n\t\n\t\nprick) blood sample with the use of a microcentrifuge.\n \n\u2022 Consumables: Intravenous fluids such as crystalloids, colloids and intravenous \t\n\t\n\t\ngiving sets should be available.\n \n\u2022 Drugs: There should be adequate stocks of antipyretics and oral rehydration salts. \n \n\t\n\t\nIn severe cases, additional drugs are necessary (vitamin K1, Ca gluconate, \t\n\t\n\t\nNaHCO3, glucose, furosemide, KCl solution, vasopressor, and inotropes).\n \n\u2022 Co", "page": 43, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "KCl solution, vasopressor, and inotropes).\n \n\u2022 Communication: Facilities should be provided for easy communication, especially \n \n\t\n\t\nbetween secondary and tertiary levels of care and laboratories, including \t\t\n\t\n\t\nconsultation by telephone.\n \n\u2022 Blood bank: Blood and blood products will be required by only a small \t\n\t\n\t\n\t\npercentage of patients but should be made readily available to those who need \n \n\t\n\t\nthem.\n\b\n2.2.5 \tEducation and training\nTo ensure the presence of adequate staffing at all l", "page": 43, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ensure the presence of adequate staffing at all levels, the education and training \nof doctors, nurses, auxiliary health care workers and laboratory staff are priorities. \nEducational programmes that are customized for different levels of health care and that \nreflect local capacity should be supported and implemented widely. The educational \nprogrammes should develop capacities for effective triage and should improve \nrecognition, clinical management and laboratory diagnosis of dengue.\nNationa", "page": 43, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "gement and laboratory diagnosis of dengue.\nNational committees should monitor and evaluate clinical management and outcomes. \nReview committees at different levels (e.g. national, state, district, hospital) should review \nall dengue deaths, and, if possible, all cases of severe dengue, evaluate the health care \ndelivery system, and provide feedback to doctors on how to improve care. \nIn dengue-endemic countries, the knowledge of dengue, the vectors and transmission \nof disease should be incorpor", "page": 43, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "rs and transmission \nof disease should be incorporated into the school curriculum. The population should \nalso be educated about dengue in order to empower patients and their families in their \nown care \u2013 so that they are prepared to seek medical care at the right time, avoid self-\nmedication, identify skin bleedings, consider the day of defervescence (and during 48 \nhours) as the time when complications usually occur, and look for warning signs such as \nintense and continuous abdominal pain and", "page": 43, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "such as \nintense and continuous abdominal pain and frequent vomiting. \nThe mass media can give an important contribution if they are correctly briefed. \nWorkshops and other meetings with journalists, editors, artists and executives can", "page": 43, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "32\nDengue: Guidelines for diagnosis, treatment, prevention and control\ncontribute to drawing up the best strategy for health education and communication \nwithout alarming the public.\nDuring dengue epidemics, nursing and medical students together with community \nactivists can visit homes with the double purpose of providing health education and \nactively tracing dengue cases. This has been shown to be feasible, inexpensive and \neffective (11) and must be coordinated with the primary health care u", "page": 44, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "must be coordinated with the primary health care units. It is useful \nto have printed information about dengue illness and the warning signs for distribution \nto members of the community. Medical care providers must include health education \nactivities such as disease prevention in their daily work.\n2.3 Recommendations for treatment\n2.3.1 A stepwise approach to the management of dengue (see Table 2.2)\n2.3.1.1 Step I\u2014Overall assessment\nHistory\nThe history should include:\n\t\n\t\n\u2013\t date of onset of f", "page": 44, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "history should include:\n\t\n\t\n\u2013\t date of onset of fever/illness;\n\t\n\t\n\u2013\t quantity of oral intake;\n\t\n\t\n\u2013\t assessment for warning signs (Textbox C);\n\t\n\t\n\u2013\t diarrhoea;\n\t\n\t\n\u2013\t change in mental state/seizure/dizziness;\n\t\n\t\n\u2013\t urine output (frequency, volume and time of last voiding);\n\t\n\t\n\u2013\t other important relevant histories, such as family or neighbourhood dengue, \n\t\n\t\n\t\ntravel to dengue endemic areas, co-existing conditions (e.g. infancy, \t\n\t\n\t\n\t\npregnancy, obesity, diabetes mellitus, hypertension),", "page": 44, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "nancy, obesity, diabetes mellitus, hypertension), jungle trekking and \n\t\n\t\n\t\nswimming in waterfall (consider leptospirosis, typhus, malaria), recent \t \t\n\t\n\t\n\t\nunprotected sex or drug abuse (consider acute HIV seroconversion illness).\nPhysical examination\nThe physical examination should include:\n\t\n\t\n\u2013\t assessment of mental state;\n\t\n\t\n\u2013\t assessment of hydration status;\n\t\n\t\n\u2013\t assessment of haemodynamic status (Textbox D);\n\t\n\t\n\u2013\t checking for tachypnoea/acidotic breathing/pleural effusion;\n\t\n\t\n\u2013\t c", "page": 44, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "noea/acidotic breathing/pleural effusion;\n\t\n\t\n\u2013\t checking for abdominal tenderness/hepatomegaly/ascites;\n\t\n\t\n\u2013\t examination for rash and bleeding manifestations;\n\t\n\t\n\u2013\t tourniquet test (repeat if previously negative or if there is no bleeding \t\n\t\n\t\n\t\n\t\nmanifestation).\nInvestigation\nA full blood count should be done at the first visit. A haematocrit test in the early febrile \nphase establishes the patient\u2019s own baseline haematocrit. A decreasing white blood \ncell count makes dengue very likely. A", "page": 44, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "hite blood \ncell count makes dengue very likely. A rapid decrease in platelet count in parallel with \na rising haematocrit compared to the baseline is suggestive of progress to the plasma", "page": 44, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "33\nChapter 2: Clinical management and delivery of clinical services\nCHAPTER 2\nleakage/critical phase of the disease. In the absence of the patient\u2019s baseline, age-specific \npopulation haematocrit levels could be used as a surrogate during the critical phase.\nLaboratory tests should be performed to confirm the diagnosis. However, it is not necessary \nfor the acute management of patients, except in cases with unusual manifestations (Chapter \n4).\nAdditional tests should be considered as indicated (", "page": 45, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ditional tests should be considered as indicated (and if available). These should include \ntests of liver function, glucose, serum electrolytes, urea and creatinine, bicarbonate or \nlactate, cardiac enzymes, ECG and urine specific gravity.\n2.3.1.2 Step II\u2014Diagnosis, assessment of disease phase and severity \nOn the basis of evaluations of the history, physical examination and/or full blood count \nand haematocrit, clinicians should be able to determine whether the disease is dengue, \nwhich phase i", "page": 45, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "mine whether the disease is dengue, \nwhich phase it is in (febrile, critical or recovery), whether there are warning signs, the \nhydration and haemodynamic status of the patient, and whether the patient requires \nadmission (Textboxes E and F).\n2.3.1.3 Step III\u2014Management\nDisease notification\nIn dengue-endemic countries, cases of suspected, probable and confirmed dengue should \nbe notified as soon as possible so that appropriate public health measures can be initiated \n(Chapter 5). Laboratory con", "page": 45, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ures can be initiated \n(Chapter 5). Laboratory confirmation is not necessary before notification, but should be \nobtained. In non-endemic countries, usually only confirmed cases will be notified.\nSuggested criteria for early notification of suspected cases are that the patient lives in or \nhas travelled to a dengue-endemic area, has fever for three days or more, has low or \ndecreasing white cell counts, and/or has thrombocytopaenia \u00b1 positive tourniquet test.\nIn dengue-endemic countries, the lat", "page": 45, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "rniquet test.\nIn dengue-endemic countries, the later the notification, the more difficult it is to prevent \ndengue transmission.\nManagement decisions \nDepending on the clinical manifestations and other circumstances, patients may (12) be sent \nhome (Group A), be referred for in-hospital management (Group B), or require emergency \ntreatment and urgent referral (Group C).\n2.3.2 Treatment according to groups A\u2013C\n2.3.2.1 Group A \u2013 patients who may be sent home (see the home care card for dengue \nin", "page": 45, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "sent home (see the home care card for dengue \nin Textbox G)\nThese are patients who are able to tolerate adequate volumes of oral fluids and pass urine \nat least once every six hours, and do not have any of the warning signs, particularly when \nfever subsides.", "page": 45, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "34\nDengue: Guidelines for diagnosis, treatment, prevention and control\nAmbulatory patients should be reviewed daily for disease progression (decreasing white \nblood cell count, defervescence and warning signs) until they are out of the critical \nperiod. Those with stable haematocrit can be sent home after being advised to return to \nthe hospital immediately if they develop any of the warning signs and to adhere to the \nfollowing action plan: \n \n\u2022 Encourage oral intake of oral rehydration solutio", "page": 46, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "Encourage oral intake of oral rehydration solution (ORS), fruit juice and other fluids \n\t\n\t\ncontaining electrolytes and sugar to replace losses from fever and vomiting. \t\n\t\n\t\nAdequate oral fluid intake may be able to reduce the number of hospitalizations \n\t\n\t\n(13). [Caution: fluids containing sugar/glucose may exacerbate hyperglycaemia \n \n\t\n\t\nof physiological stress from dengue and diabetes mellitus.]\n \n\u2022 Give paracetamol for high fever if the patient is uncomfortable. The interval of \n\t\n\t\npara", "page": 46, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "atient is uncomfortable. The interval of \n\t\n\t\nparacetamol dosing should not be less than six hours. Tepid sponge if the patient \n \n\t\n\t\nstill has high fever. Do not give acetylsalicylic acid (aspirin), ibuprofen or other \t\n\t\n\t\nnon-steroidal anti-inflammatory agents (NSAIDs) as these drugs may aggravate \t\n\t\n\t\ngastritis or bleeding. Acetylsalicylic acid (aspirin) may be associated with Reye\u2019s \n \n\t\n\t\nSyndrome.\n \n\u2022 Instruct the care-givers that the patient should be brought to hospital immediately", "page": 46, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "tient should be brought to hospital immediately \n \n\t\n\t\nif any of the following occur: no clinical improvement, deterioration around the \t\n\t\n\t\ntime of defervescence, severe abdominal pain, persistent vomiting, cold and \t\n\t\n\t\nclammy extremities, lethargy or irritability/restlessness, bleeding (e.g. black \t\n\t\n\t\nstools or coffee-ground vomiting), not passing urine for more than 4\u20136 hours.\nPatients who are sent home should be monitored daily by health care providers \nfor temperature pattern, volume o", "page": 46, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "care providers \nfor temperature pattern, volume of fluid intake and losses, urine output (volume and \nfrequency), warning signs, signs of plasma leakage and bleeding, haematocrit, and \nwhite blood cell and platelet counts (see group B).\n2.3.2.2 Group B \u2013 patients who should be referred for in-hospital management\nPatients may need to be admitted to a secondary health care centre for close observation, \nparticularly as they approach the critical phase. These include patients with warning \nsigns,", "page": 46, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "hase. These include patients with warning \nsigns, those with co-existing conditions that may make dengue or its management more \ncomplicated (such as pregnancy, infancy, old age, obesity, diabetes mellitus, renal \nfailure, chronic haemolytic diseases), and those with certain social circumstances (such \nas living alone, or living far from a health facility without reliable means of transport).\nIf the patient has dengue with warning signs, the action plan should be as follows:\n \n \n\u2022 Obtain a refer", "page": 46, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "on plan should be as follows:\n \n \n\u2022 Obtain a reference haematocrit before fluid therapy. Give only isotonic solutions \n\t\n\t\nsuch as 0.9% saline, Ringer\u2019s lactate, or Hartmann\u2019s solution. Start with 5\u20137 ml/ \n\t\n\t\nkg/hour for 1\u20132 hours, then reduce to 3\u20135 ml/kg/hr for 2\u20134 hours, and then \t\n\t\n\t\nreduce to 2\u20133 ml/kg/hr or less according to the clinical response (Textboxes H, \n \n\t\n\t\nJ and K).\n \n\u2022 Reassess the clinical status and repeat the haematocrit. If the haematocrit remains \n\t\n\t\nthe same or rises o", "page": 46, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "f the haematocrit remains \n\t\n\t\nthe same or rises only minimally, continue with the same rate (2\u20133 ml/kg/hr) \t\n\t\n\t\nfor another 2\u20134 hours. If the vital signs are worsening and haematocrit is rising \t\n\t\n\t\nrapidly, increase the rate to 5\u201310 ml/kg/hour for 1\u20132 hours. Reassess the \n \n\t\n\t\nclinical status, repeat the haematocrit and review fluid infusion rates accordingly.", "page": 46, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "35\nChapter 2: Clinical management and delivery of clinical services\nCHAPTER 2\n \n\u2022 Give the minimum intravenous fluid volume required to maintain good perfusion  \n\t\n\t\nand urine output of about 0.5 ml/kg/hr. Intravenous fluids are usually needed \t\n\t\n\t\nfor only 24\u201348 hours. Reduce intravenous fluids gradually when the rate of \t\n\t\n\t\nplasma leakage decreases towards the end of the critical phase. This is indicated \n\t\n\t\nby urine output and/or oral fluid intake that is/are adequate, or haematocrit", "page": 47, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "d intake that is/are adequate, or haematocrit \t\n\t\n\t\ndecreasing below the baseline value in a stable patient.\n \n\u2022 Patients with warning signs should be monitored by health care providers until \n\t\n\t\nthe period of risk is over. A detailed fluid balance should be maintained. \t \t\n\t\n\t\nParameters that should be monitored include vital signs and peripheral perfusion \n \n\t\n\t\n(1\u20134 hourly until the patient is out of the critical phase), urine output (4\u20136 hourly), \n\t\n\t\nhaematocrit (before and after fluid rep", "page": 47, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "rly), \n\t\n\t\nhaematocrit (before and after fluid replacement, then 6\u201312 hourly), blood \t\t\n\t\n\t\nglucose, and other organ functions (such as renal profile, liver profile, coagulation \n \n\t\n\t\nprofile, as indicated).\nIf the patient has dengue without warning signs, the action plan should be as follows:\n \n\u2022 Encourage oral fluids. If not tolerated, start intravenous fluid therapy of 0.9%  \n\t\n\t\nsaline or Ringer\u2019s lactate with or without dextrose at maintenance rate (Textbox \t\n\t\n\t\nH). For obese and overweig", "page": 47, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "nce rate (Textbox \t\n\t\n\t\nH). For obese and overweight patients, use the ideal body weight for calculation \n \n\t\n\t\nof fluid infusion (Textboxes J and K). Patients may be able to take oral fluids after \n \n\t\n\t\na few hours of intravenous fluid therapy. Thus, it is necessary to revise the fluid \t\n\t\n\t\ninfusion frequently. Give the minimum volume required to maintain good perfusion \n \n\t\n\t\nand urine output. Intravenous fluids are usually needed only for 24\u201348 hours. \n \n\u2022 Patients should be monitored by he", "page": 47, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "\u201348 hours. \n \n\u2022 Patients should be monitored by health care providers for temperature pattern,  \n\t\n\t\nvolume of fluid intake and losses, urine output (volume and frequency), warning \t\n\t\n\t\nsigns, haematocrit, and white blood cell and platelet counts (Textbox L). Other \t\n\t\n\t\nlaboratory tests (such as liver and renal functions tests) can be done, depending \n \n\t\n\t\non the clinical picture and the facilities of the hospital or health centre.\n2.3.2.3 Group C \u2013 patients who require emergency treatment an", "page": 47, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "up C \u2013 patients who require emergency treatment and urgent referral when \nthey have severe dengue\nPatients require emergency treatment and urgent referral when they are in the critical \nphase of disease, i.e. when they have:\n\t\n\t\n\u2013\t severe plasma leakage leading to dengue shock and/or fluid accumulation \t\n\t\n\t\n\t\nwith respiratory distress;\n\t\n\t\n\u2013\t severe haemorrhages;\n\t\n\t\n\u2013\t severe \norgan \nimpairment \n(hepatic \ndamage, \nrenal \nimpairment, \ncardiomyopathy, \n \n\t\n\t\n\t\nencephalopathy or encephalitis).\nAl", "page": 47, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "athy, \n \n\t\n\t\n\t\nencephalopathy or encephalitis).\nAll patients with severe dengue should be admitted to a hospital with access to \nintensive care facilities and blood transfusion. Judicious intravenous fluid resuscitation \nis the essential and usually sole intervention required. The crystalloid solution should \nbe isotonic and the volume just sufficient to maintain an effective circulation during the \nperiod of plasma leakage. Plasma losses should be replaced immediately and rapidly \nwith isotonic", "page": 47, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "be replaced immediately and rapidly \nwith isotonic crystalloid solution or, in the case of hypotensive shock, colloid solutions \n(Textbox M). If possible, obtain haematocrit levels before and after fluid resuscitation.", "page": 47, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "36\nDengue: Guidelines for diagnosis, treatment, prevention and control\nThere should be continued replacement of further plasma losses to maintain effective \ncirculation for 24\u201348 hours. For overweight or obese patients, the ideal body weight \nshould be used for calculating fluid infusion rates (textboxes J and K). A group and cross-\nmatch should be done for all shock patients. Blood transfusion should be given only in \ncases with suspected/severe bleeding.\nFluid resuscitation must be clearly sep", "page": 48, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "bleeding.\nFluid resuscitation must be clearly separated from simple fluid administration. This is a \nstrategy in which larger volumes of fluids (e.g. 10\u201320 ml boluses) are administered for \na limited period of time under close monitoring to evaluate the patient\u2019s response and \nto avoid the development of pulmonary oedema. The degree of intravascular volume \ndeficit in dengue shock varies. Input is typically much greater than output, and the input/\noutput ratio is of no utility for judging fluid", "page": 48, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "t/\noutput ratio is of no utility for judging fluid resuscitation needs during this period.\nThe goals of fluid resuscitation include improving central and peripheral circulation \n(decreasing tachycardia, improving blood pressure, pulse volume, warm and pink \nextremities, and capillary refill time <2 seconds) and improving end-organ perfusion \n\u2013 i.e. stable conscious level (more alert or less restless), urine output \u2265 0.5 ml/kg/hour, \ndecreasing metabolic acidosis.\nTreatment of shock\nThe action pl", "page": 48, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "tabolic acidosis.\nTreatment of shock\nThe action plan for treating patients with compensated shock is as follows (Textboxes D \nand N, Figure 2.2):\n \n \n\u2022 Start intravenous fluid resuscitation with isotonic crystalloid solutions at 5\u201310 \n\t\n\t\n\t\nml/kg/hour over one hour. Then reassess the patient\u2019s condition (vital signs, \t\n\t\n\t\n\t\ncapillary refill time, haematocrit, urine output). The next steps depend on the \t\n\t\n\t\n\t\nsituation.\n \n \n\u2022 If the patient\u2019s condition improves, intravenous fluids should be gr", "page": 48, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ondition improves, intravenous fluids should be gradually  \n\t\n\t\n\t\nreduced to 5\u20137 ml/kg/hr for 1\u20132 hours, then to 3\u20135 ml/kg/hr for 2\u20134 \t\n\t\n\t\n\t\nhours, then to 2\u20133 ml/kg/hr, and then further depending on haemodynamic \n \n\t\n\t\n\t\nstatus, which can be maintained for up to 24\u201348 hours. (See textboxes H \t\n\t\n\t\n\t\nand J for a more appropriate estimate of the normal maintenance requirement \n\t\n\t\n\t\nbased on ideal body weight).\n \n \n\u2022 If vital signs are still unstable (i.e. shock persists), check the haematocrit", "page": 48, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "able (i.e. shock persists), check the haematocrit after \n \n \n \nthe first bolus. If the haematocrit increases or is still high (>50%), repeat a  \n\t\n\t\n\t\nsecond bolus of crystalloid solution at 10\u201320 ml/kg/hr for one hour. After \t\n\t\n\t\n\t\nthis second bolus, if there is improvement, reduce the rate to 7\u201310 ml/\t\t\n\t\n\t\n\t\nkg/hr for 1\u20132 hours, and then continue to reduce as above. If haematocrit \t\n\t\n\t\n\t\ndecreases compared to the initial reference haematocrit (<40% in children \t\n\t\n\t\n\t\nand adult females, <45", "page": 48, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "t (<40% in children \t\n\t\n\t\n\t\nand adult females, <45% in adult males), this indicates bleeding and the need \n\t\n\t\n\t\nto cross-match and transfuse blood as soon as possible (see treatment for \t\n\t\n\t\n\t\nhaemorrhagic complications).\n \n \n\u2022 Further boluses of crystalloid or colloidal solutions may need to be given  \n\t\n\t\n\t\nduring the next 24\u201348 hours.", "page": 48, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "37\nChapter 2: Clinical management and delivery of clinical services\nCHAPTER 2\nFigure 2.2 Algorithm for fluid management in compensated shock\n\t\nCompensated shock (systolic pressure \nmaintained but has signs of reduced perfusion)\nFluid resuscitation with isotonic crystalloid \n\t\n\t\n5\u201310 ml/kg/hr over 1 hour\nIV crystalloid 5\u20137 ml/kg/hr for 1\u20132  \nhours, then: \nreduce to 3\u20135 ml/kg/hr for 2\u20134 hours; \nreduce to 2\u20133 ml/kg/hr for 2\u20134 hours.\nIf patient continues to improve, fluid can be \nfurther reduced. \nM", "page": 49, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "nues to improve, fluid can be \nfurther reduced. \nMonitor HCT 6\u20138 hourly.\nIf the patient is not stable, act according  \nto HCT levels:\nif HCT increases, consider bolus fluid \nadministration or increase fluid administration;\nif HCT decreases, consider transfusion with \nfresh whole transfusion.\nStop at 48 hours.\n\t\nNO \n\t\nYES\nHCT    or high\n\t\nHCT \nAdminister 2nd bolus of fluid\n10\u201320 ml/kg/hr for 1 hour \nConsider significant occult/overt bleed\nInitiate transfusion with fresh whole \nblood\n\t\nNO\n\t\nYES\nIf", "page": 49, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "transfusion with fresh whole \nblood\n\t\nNO\n\t\nYES\nIf patient improves, reduce to  \n7\u201310 ml/kg/hr for 1\u20132 hours\nThen reduce further\n\t\nImprovement\nCheck HCT\n\t\nImprovement\nHCT = haematocrit\nPatients with hypotensive shock should be managed more vigorously. The action plan for \ntreating patients with hypotensive shock is as follows (Textboxes D and N, Figure 2.3):\n \n\u2022 Initiate intravenous fluid resuscitation with crystalloid or colloid solution (if   \n\t\n\t\navailable) at 20 ml/kg as a bolus given over 1", "page": 49, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "available) at 20 ml/kg as a bolus given over 15 minutes to bring the patient out \n\t\n\t\nof shock as quickly as possible.\n \n\u2022 If the patient\u2019s condition improves, give a crystalloid/colloid infusion of 10 ml/ \n\t\n\t\nkg/hr for one hour. Then continue with crystalloid infusion and gradually reduce \n\t\n\t\nto 5\u20137 ml/kg/hr for 1\u20132 hours, then to 3\u20135 ml/kg/hr for 2\u20134 hours, and then", "page": 49, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "38\nDengue: Guidelines for diagnosis, treatment, prevention and control\n\t\n\t\nto 2\u20133 ml/kg/hr or less, which can be maintained for up to 24\u201348 hours \t\n\t\n\t\n\t\n(textbox H).\n \n\u2022 If vital signs are still unstable (i.e. shock persists), review the haematocrit obtained \n \n\t\n\t\nbefore the first bolus. If the haematocrit was low (<40% in children and adult \t\n\t\n\t\nfemales, <45% in adult males), this indicates bleeding and the need to cross-\t\n\t\n\t\nmatch and transfuse blood as soon as possible (see treatment for", "page": 50, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "fuse blood as soon as possible (see treatment for haemorrhagic \t\n\t\n\t\ncomplications).\n \n\u2022 If the haematocrit was high compared to the baseline value (if not available, use \n\t\n\t\npopulation baseline), change intravenous fluids to colloid solutions at 10\u201320 \t\n\t\n\t\nml/kg as a second bolus over 30 minutes to one hour. After the second bolus, \t\n\t\n\t\nreassess the patient. If the condition improves, reduce the rate to 7\u201310 ml/kg/hr \n \n\t\n\t\nfor 1\u20132 hours, then change back to crystalloid solution and reduce t", "page": 50, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "n change back to crystalloid solution and reduce the rate of \n \n\t\n\t\ninfusion as mentioned above. If the condition is still unstable, repeat the \t\n\t\n\t\n\t\nhaematocrit after the second bolus.\n \n\u2022 If the haematocrit decreases compared to the previous value (<40% in children  \n\t\n\t\nand adult females, <45% in adult males), this indicates bleeding and the need \n\t\n\t\nto cross-match and transfuse blood as soon as possible (see treatment for \n \n\t\n\t\nhaemorrhagic complications). If the haematocrit increases co", "page": 50, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ic complications). If the haematocrit increases compared to the \t\n \n \nprevious value or remains very high (>50%), continue colloid solutions at 10\u201320 \n\t\n\t\nml/kg as a third bolus over one hour. After this dose, reduce the rate to 7\u201310 \t\n\t\n\t\nml/kg/hr for 1\u20132 hours, then change back to crystalloid solution and reduce the \n \n\t\n\t\nrate of infusion as mentioned above when the patient\u2019s condition improves.\n \n\u2022 Further boluses of fluids may need to be given during the next 24 hours. The rate \n\t\n\t\nand vol", "page": 50, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "en during the next 24 hours. The rate \n\t\n\t\nand volume of each bolus infusion should be titrated to the clinical response. \t\n\t\n\t\nPatients with severe dengue should be admitted to the high-dependency or \t\n\t\n\t\n\t\nintensive care area.\nPatients with dengue shock should be frequently monitored until the danger period is \nover. A detailed fluid balance of all input and output should be maintained. \nParameters that should be monitored include vital signs and peripheral perfusion (every \n15\u201330 minutes unt", "page": 50, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "and peripheral perfusion (every \n15\u201330 minutes until the patient is out of shock, then 1\u20132 hourly). In general, the higher \nthe fluid infusion rate, the more frequently the patient should be monitored and reviewed \nin order to avoid fluid overload while ensuring adequate volume replacement. \nIf resources are available, a patient with severe dengue should have an arterial line \nplaced as soon as practical. The reason for this is that in shock states, estimation of blood \npressure using a cuff is", "page": 50, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "es, estimation of blood \npressure using a cuff is commonly inaccurate. The use of an indwelling arterial catheter \nallows for continuous and reproducible blood pressure measurements and frequent \nblood sampling on which decisions regarding therapy can be based. Monitoring of \nECG and pulse oximetry should be available in the intensive care unit. \nUrine output should be checked regularly (hourly till the patient is out of shock, then \n1\u20132 hourly). A continuous bladder catheter enables close monit", "page": 50, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "A continuous bladder catheter enables close monitoring of urine output. \nAn acceptable urine output would be about 0.5 ml/kg/hour. Haematocrit should be \nmonitored (before and after fluid boluses until stable, then 4\u20136 hourly). In addition, \nthere should be monitoring of arterial or venous blood gases, lactate, total carbon \ndioxide/bicarbonate (every 30 minutes to one hour until stable, then as indicated), \nblood glucose (before fluid resuscitation and repeat as indicated), and other organ", "page": 50, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "tion and repeat as indicated), and other organ", "page": 50, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "39\nChapter 2: Clinical management and delivery of clinical services\nCHAPTER 2\nFigure 2.3 Algorithm for fluid management in hypotensive shock\n\t\nHypotensive shock \nFluid resuscitation with 20 ml/kg isotonic crystalloid or \ncolloid over 15 minutes\nTry to obtain a HCT level before fluid resuscitation\nCrystalloid/colloid 10 ml/kg/hr for  \n1 hour, then continue with: \nIV crystalloid 5\u20137 ml/kg/hr for 1\u2013 2 hours;\nreduce to 3\u20135 ml/kg/hr for 2\u20134 hours;\nreduce to 2\u20133 ml/kg/hr for 2\u20134 hours.\nIf patient cont", "page": 51, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "uce to 2\u20133 ml/kg/hr for 2\u20134 hours.\nIf patient continues to improve, fluid can be \nfurther reduced. \nMonitor HCT 6-hourly.\nIf the patient is not stable, act according  \nto HCT levels:\nif HCT increases, consider bolus fluid \nadministration or increase fluid administration;\nif HCT decreases, consider transfusion with \nfresh whole transfusion.\nStop at 48 hours.\nNO\n\t\nYES\nHCT    or high\n\t\nHCT \nAdminister 2nd bolus fluid (colloid)\n10\u201320 ml/kg over \u00bd to 1 hour \nConsider significant occult/overt bleed\nIn", "page": 51, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "1 hour \nConsider significant occult/overt bleed\nInitiate transfusion with fresh whole \nblood\n\t\nNO\n\t\nYES\n\t\nImprovement\nReview 1st HCT\n\t\nImprovement\nHCT    or high\n\t\nHCT \nRepeat 2nd HCT\nAdminister 3rd bolus fluid (colloid)\n10\u201320 ml/kg over 1 hour \n\t\nImprovement\n\t\nNO\n\t\nYES\nRepeat 3rd HCT", "page": 51, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "40\nDengue: Guidelines for diagnosis, treatment, prevention and control\nfunctions (such as renal profile, liver profile, coagulation profile, before resuscitation \nand as indicated).\nChanges in the haematocrit are a useful guide to treatment. However, changes must \nbe interpreted in parallel with the haemodynamic status, the clinical response to fluid \ntherapy and the acid-base balance. For instance, a rising or persistently high haematocrit \ntogether with unstable vital signs (particularly narro", "page": 52, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ther with unstable vital signs (particularly narrowing of the pulse pressure) indicates \nactive plasma leakage and the need for a further bolus of fluid replacement. However, \na rising or persistently high haematocrit together with stable haemodynamic status and \nadequate urine output does not require extra intravenous fluid. In the latter case, continue \nto monitor closely and it is likely that the haematocrit will start to fall within the next 24 \nhours as the plasma leakage stops.\nA decrease", "page": 52, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "24 \nhours as the plasma leakage stops.\nA decrease in haematocrit together with unstable vital signs (particularly narrowing of \nthe pulse pressure, tachycardia, metabolic acidosis, poor urine output) indicates major \nhaemorrhage and the need for urgent blood transfusion. Yet a decrease in haematocrit \ntogether with stable haemodynamic status and adequate urine output indicates \nhaemodilution and/or reabsorption of extravasated fluids, so in this case intravenous \nfluids must be discontinued imme", "page": 52, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "case intravenous \nfluids must be discontinued immediately to avoid pulmonary oedema.\nTreatment of haemorrhagic complications\nMucosal bleeding may occur in any patient with dengue but, if the patient remains \nstable with fluid resuscitation/replacement, it should be considered as minor. The \nbleeding usually improves rapidly during the recovery phase. In patients with profound \nthrombocytopaenia, ensure strict bed rest and protect from trauma to reduce the risk \nof bleeding. Do not give intramusc", "page": 52, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "educe the risk \nof bleeding. Do not give intramuscular injections to avoid haematoma. It should be \nnoted that prophylactic platelet transfusions for severe thrombocytopaenia in otherwise \nhaemodynamically stable patients have not been shown to be effective and are not \nnecessary (14).\nIf major bleeding occurs it is usually from the gastrointestinal tract, and/or vagina in \nadult females. Internal bleeding may not become apparent for many hours until the first \nblack stool is passed. \nPatients a", "page": 52, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ntil the first \nblack stool is passed. \nPatients at risk of major bleeding are those who:\n\t\n\t\n\u2013\t have prolonged/refractory shock;\n\t\n\t\n\u2013\t have hypotensive shock and renal or liver failure and/or severe and \t\n\t\n\t\n\t\n\t\npersistent metabolic acidosis;\n\t\n\t\n\u2013\t are given non-steroidal anti-inflammatory agents;\n\t\n\t\n\u2013\t have pre-existing peptic ulcer disease;\n\t\n\t\n\u2013\t are on anticoagulant therapy;\n\t\n\t\n\u2013\t have any form of trauma, including intramuscular injection.\nPatients with haemolytic conditions are at ris", "page": 52, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "on.\nPatients with haemolytic conditions are at risk of acute haemolysis with haemoglobinuria \nand will require blood transfusion.", "page": 52, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "41\nChapter 2: Clinical management and delivery of clinical services\nCHAPTER 2\nSevere bleeding can be recognized by:\n\t\n\t\n\u2013\t persistent and/or severe overt bleeding in the presence of unstable \t\n\t\n\t\n\t\n\t\nhaemodynamic status, regardless of the haematocrit level;\n\t\n\t\n\u2013\t a decrease in haematocrit after fluid resuscitation together with unstable \t\n\t\n\t\n\t\nhaemodynamic status;\n\t\n\t\n\u2013\t refractory shock that fails to respond to consecutive fluid resuscitation of \n \n\t\n\t\n\t\n40-60 ml/kg;\n\t\n\t\n\u2013\t hypotensive shock", "page": 53, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "of \n \n\t\n\t\n\t\n40-60 ml/kg;\n\t\n\t\n\u2013\t hypotensive shock with low/normal haematocrit before fluid resuscitation;\n\t\n\t\n\u2013\t persistent or worsening metabolic acidosis \u00b1 a well-maintained systolic blood \n \n\t\n\t\n\t\npressure, especially in those with severe abdominal tenderness and \t\n\t\n\t\n\t\n\t\ndistension.\nBlood transfusion is life-saving and should be given as soon as severe bleeding is \nsuspected or recognized. However, blood transfusion must be given with care because \nof the risk of fluid overload. Do not wai", "page": 53, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "because \nof the risk of fluid overload. Do not wait for the haematocrit to drop too low before \ndeciding on blood transfusion. Note that haematocrit of <30% as a trigger for blood \ntransfusion, as recommended in the Surviving Sepsis Campaign Guideline (15), is not \napplicable to severe dengue. The reason for this is that, in dengue, bleeding usually \noccurs after a period of prolonged shock that is preceded by plasma leakage. During \nthe plasma leakage the haematocrit increases to relatively hig", "page": 53, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "eakage the haematocrit increases to relatively high values before the onset \nof severe bleeding. When bleeding occurs, haematocrit will then drop from this high \nlevel. As a result, haematocrit levels may not be as low as in the absence of plasma \nleakage.\nThe action plan for the treatment of haemorrhagic complications is as follows:\n \n\u2022 Give 5\u201310ml/kg of fresh-packed red cells or 10\u201320 ml/kg of fresh whole  \n\t\n\t\nblood at an appropriate rate and observe the clinical response. It is important tha", "page": 53, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "observe the clinical response. It is important that \n\t\n\t\nfresh whole blood or fresh red cells are given. Oxygen delivery at tissue level \n \n\t\n\t\nis optimal with high levels of 2,3 di-phosphoglycerate (2,3 DPG). Stored \t \t\n\t\n\t\nblood loses 2,3 DPG, low levels of which impede the oxygen-releasing capacity \n\t\n\t\nof  haemoglobin, resulting in functional tissue hypoxia. A good clinical response \n \n\t\n\t\nincludes improving haemodynamic status and acid-base balance.\n \n\u2022 Consider repeating the blood transfus", "page": 53, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "balance.\n \n\u2022 Consider repeating the blood transfusion if there is further blood loss or no   \n\t\n\t\nappropriate rise in haematocrit after blood transfusion. There is little evidence to \n\t\n\t\nsupport the practice of transfusing platelet concentrates and/or fresh-frozen \t\n\t\n\t\nplasma for severe bleeding. It is being practised when massive bleeding can not \n\t\n\t\nbe managed with just fresh whole blood/fresh-packed cells, but it may exacerbate \n\t\n\t\nthe fluid overload.\n \n\u2022 Great care should be taken when i", "page": 53, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "id overload.\n \n\u2022 Great care should be taken when inserting a naso-gastric tube which may cause \n\t\n\t\nsevere haemorrhage and may block the airway. A lubricated oro-gastric tube \t\n\t\n\t\nmay minimize the trauma during insertion. Insertion of central venous catheters \t\n\t\n\t\nshould be done with ultra-sound guidance or by a very experienced person.", "page": 53, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "42\nDengue: Guidelines for diagnosis, treatment, prevention and control\n2.3.3 Treatment of complications and other areas of treatment\n2.3.3.1 Fluid overload\nFluid overload with large pleural effusions and ascites is a common cause of acute \nrespiratory distress and failure in severe dengue. Other causes of respiratory distress \ninclude acute pulmonary oedema, severe metabolic acidosis from severe shock, and \nAcute Respiratory Distress Syndrome (ARDS) (refer to standard textbook of clinical care", "page": 54, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "DS) (refer to standard textbook of clinical care \nfor further guidance on management).\nCauses of fluid overload are:\n\t\n\t\n\u2013\t excessive and/or too rapid intravenous fluids;\n\t\n\t\n\u2013\t incorrect use of hypotonic rather than isotonic crystalloid solutions;\n\t\n\t\n\u2013\t inappropriate use of large volumes of intravenous fluids in patients with \t\n\t\n\t\n\t\n\t\nunrecognized severe bleeding;\n\t\n\t\n\u2013\t inappropriate transfusion of fresh-frozen plasma, platelet concentrates and \t\n\t\n\t\n\t\ncryoprecipitates;\n\t\n\t\n\u2013\t continuation o", "page": 54, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "nd \t\n\t\n\t\n\t\ncryoprecipitates;\n\t\n\t\n\u2013\t continuation of intravenous fluids after plasma leakage has resolved \n\t\n\t\n\t\n(24\u201348 hours from defervescence);\n\t\n\t\n\u2013\t co-morbid conditions such as congenital or ischaemic heart disease, chronic \n \n\t\n\t\n\t\nlung and renal diseases.\nEarly clinical features of fluid overload are:\n\t\n\t\n\u2013\t respiratory distress, difficulty in breathing;\n\t\n\t\n\u2013\t rapid breathing;\n\t\n\t\n\u2013\t chest wall in-drawing;\n\t\n\t\n\u2013\t wheezing (rather than crepitations);\n\t\n\t\n\u2013\t large pleural effusions;\n\t\n\t\n\u2013", "page": 54, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "pitations);\n\t\n\t\n\u2013\t large pleural effusions;\n\t\n\t\n\u2013\t tense ascites;\n\t\n\t\n\u2013\t increased jugular venous pressure (JVP).\nLate clinical features are:\n\t\n\t\n\u2013\t pulmonary oedema (cough with pink or frothy sputum \u00b1 crepitations, cyanosis);\n\t\n\t\n\u2013\t irreversible shock (heart failure, often in combination with ongoing \t\n\t\n\t\n\t\n\t\nhypovolaemia).\nAdditional investigations are:\n\t\n\t\n\u2013\t the chest x-ray which shows cardiomegaly, pleural effusion, upward \t\n \n\t\n\t\n\t\ndisplacement of the diaphragm by the ascites and varying", "page": 54, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ement of the diaphragm by the ascites and varying degrees of \t \t\n\t\n\t\n\t\n\u201cbat\u2019s wings\u201d appearance \u00b1 Kerley B lines suggestive of fluid overload and \t\n\t\n\t\n\t\npulmonary oedema;\n\t\n\t\n\u2013\t ECG to exclude ischaemic changes and arrhythmia;\n\t\n\t\n\u2013\t arterial blood gases;\n\t\n\t\n\u2013\t echocardiogram for assessment of left ventricular function, dimensions and \n \n\t\n\t\n\t\nregional wall dyskinesia that may suggest underlying ischaemic heart disease;\n\t\n\t\n\u2013\t cardiac enzymes.", "page": 54, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "43\nChapter 2: Clinical management and delivery of clinical services\nCHAPTER 2\nThe action plan for the treatment of fluid overload is as follows:\n \n\u2022 Oxygen therapy should be given immediately.\n \n\u2022 Stopping intravenous fluid therapy during the recovery phase will allow fluid in  \n\t\n\t\nthe pleural and peritoneal cavities to return to the intravascular compartment. \t\n\t\n\t\nThis results in diuresis and resolution of pleural effusion and ascites. Recognizing \n\t\n\t\nwhen to decrease or stop intravenous flu", "page": 55, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "zing \n\t\n\t\nwhen to decrease or stop intravenous fluids is key to preventing fluid overload. \t\n\t\n\t\nWhen the following signs are present, intravenous fluids should be discontinued \n \n\t\n\t\nor reduced to the minimum rate necessary to maintain euglycaemia:\n\t\n\t\n\u2013\t signs of cessation of plasma leakage; \n\t\n\t\n\u2013\t stable blood pressure, pulse and peripheral perfusion;\n\t\n\t\n\u2013\t haematocrit decreases in the presence of a good pulse volume;\n\t\n\t\n\u2013\t afebrile for more than 24\u201348 days (without the use of antipyretics", "page": 55, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "e than 24\u201348 days (without the use of antipyretics);\n\t\n\t\n\u2013\t resolving bowel/abdominal symptoms;\n\t\n\t\n\u2013\t improving urine output.\n \n\u2022 The management of fluid overload varies according to the phase of the disease  \n\t\n\t\nand the patient\u2019s haemodynamic status. If the patient has stable haemodynamic \n \n\t\n\t\nstatus and is out of the critical phase (more than 24\u201348 hours of defervescence), \n \n\t\n\t\nstop intravenous fluids but continue close monitoring. If necessary, give oral or \n\t\n\t\nintravenous furosemide 0", "page": 55, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "essary, give oral or \n\t\n\t\nintravenous furosemide 0.1\u20130.5 mg/kg/dose once or twice daily, or a \t\n\t\n\t\n\t\ncontinuous infusion of furosemide 0.1 mg/kg/hour. Monitor serum potassium \t\n\t\n\t\nand correct the ensuing hypokalaemia.\n \n\u2022 If the patient has stable haemodynamic status but is still within the critical phase, \n \n\t\n\t\nreduce the intravenous fluid accordingly. Avoid diuretics during the plasma \t\n\t\n\t\n\t\nleakage phase because they may lead to intravascular volume depletion.\n \n\u2022 Patients who remain in s", "page": 55, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "lar volume depletion.\n \n\u2022 Patients who remain in shock with low or normal haematocrit levels but show  \n\t\n\t\nsigns of fluid overload may have occult haemorrhage. Further infusion of large \t\n\t\n\t\nvolumes of intravenous fluids will lead only to a poor outcome. Careful fresh \t\n\t\n\t\nwhole blood transfusion should be initiated as soon as possible. If the patient \t\n\t\n\t\nremains in shock and the haematocrit is elevated, repeated small boluses of a \t\n\t\n\t\ncolloid solution may help.\n2.3.3.2 Other complication", "page": 55, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "loid solution may help.\n2.3.3.2 Other complications of dengue\nBoth hyperglycaemia and hypoglycaemia may occur, even in the absence of diabetes \nmellitus and/or hypoglycaemic agents. Electrolyte and acid-base imbalances are also \ncommon observations in severe dengue and are probably related to gastrointestinal \nlosses through vomiting and diarrhoea or to the use of hypotonic solutions for resuscitation \nand correction of dehydration. Hyponatraemia, hypokalaemia, hyperkalaemia, serum \ncalcium imba", "page": 55, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": ", hypokalaemia, hyperkalaemia, serum \ncalcium imbalances and metabolic acidosis (sodium bicarbonate for metabolic acidosis \nis not recommended for pH \u2265 7.15) can occur. One should also be alert for co-infections \nand nosocomial infections.", "page": 55, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "44\nDengue: Guidelines for diagnosis, treatment, prevention and control\n2.3.3.3 Supportive care and adjuvant therapy\nSupportive care and adjuvant therapy may be necessary in severe dengue. This may \ninclude: \n\t\n\t\n\u2013\t renal replacement therapy, with a preference to continuous veno-venous \t\n\t\n\t\n\t\nhaemodialysis (CVVH), since peritoneal dialysis has a risk of bleeding;\n\t\n\t\n\u2013\t vasopressor and inotropic therapies as temporary measures to prevent life-\t\n\t\n\t\n\t\nthreatening hypotension in dengue shock and d", "page": 56, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "threatening hypotension in dengue shock and during induction for intubation, \n \n\t\n\t\n\t\nwhile correction of intravascular volume is being vigorously carried out; \n\t\n\t\n\u2013\t further treatment of organ impairment, such as severe hepatic involvement or \n \n\t\n\t\n\t\nencephalopathy or encephalitis;\n\t\n\t\n\u2013\t further treatment of cardiac abnormalities, such as conduction abnormalities, \n \n\t\n\t\n\t\nmay occur (the latter usually not requiring interventions).\nIn this context there is little or no evidence in favou", "page": 56, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "is context there is little or no evidence in favour of the use of steroids and intravenous \nimmunoglobulins, or of recombinant Activated Factor VII.\nRefer to standard textbooks of clinical care for more detailed information regarding the \ntreatment of complications and other areas of treatment.", "page": 56, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "45\nChapter 2: Clinical management and delivery of clinical services\nCHAPTER 2\nTextbox A. Good clinical practice and bad clinical practice\n\t\n\t\nGood practice\t\nBad practice\n\t\n1\t\nAssessment and follow-up of patients with \t\nSending patients with non-severe dengue home \n\t\n\t\nnon-severe dengue and careful instruction of\t\nwith no follow-up and inadequate instructions \n\t\n\t\nwarning signs to watch out for\t\n\t\n\t\n2\t\nAdministration of paracetamol for high fever\t\nAdministration of acetylsalicylic acid  (aspirin)", "page": 57, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "Administration of acetylsalicylic acid  (aspirin)  \n\t\n\t\nif the patient is uncomfortable\t\nor ibuprofen\n\t\n3\t\nObtaining a haematocrit level before and \t\nNot knowing when haematocrit levels are taken \n\t\n\t\nafter fluid boluses\t\nwith respect to fluid therapy\n\t\n4\t\nClinical assessment of the haemodynamic\t\nNo clinical assessment of patient with respect \n\t\n\t\nstatus before and after each fluid bolus \t\nto fluid therapy\n\t\n5\t\nInterpretation of haematocrit levels in the\t\nInterpretation of haematocrit levels in", "page": 57, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ls in the\t\nInterpretation of haematocrit levels independent \n\t\n\t\ncontext of fluid administered and haemodynamic \t\nof clinical status \n\t\n\t\nassessment\n\t\n6\t\nAdministration of intravenous fluids for repeated \t\nAdministration of intravenous fluids to any patient \n\t\n\t\nvomiting or a high or rapidly rising haematocrit\t\nwith non-severe dengue\n\t\n7\t\nUse of isotonic intravenous fluids for severe\t\nUse of hypotonic intravenous fluids for severe \n\t\n\t\ndengue\t\ndengue\n\t\n8\t\nGiving intravenous fluid volume just suf", "page": 57, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ngue\n\t\n8\t\nGiving intravenous fluid volume just sufficient\t\nExcessive or prolonged intravenous fluid \n\t\n\t\nto maintain effective circulation during the \t\nadministration for severe dengue \n\t\n\t\nperiod of plasma leakage for severe dengue\n\t\n9\t\nAvoiding intramuscular injections in dengue \t\nGiving intramuscular injections to dengue patients \n\t\n\t\npatients\n\t\n10\t\nIntravenous fluid rate and frequency of monitoring \t\nFixed intravenous fluid rate and unchanged \n\t\n\t\nand haematocrit measurement adjusted\t\nfreque", "page": 57, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "and haematocrit measurement adjusted\t\nfrequency of monitoring and haematocrit  \n\t\n\t\naccording to the patient\u2019s condition\t\nmeasurement during entire hospitalization \n\t\n\t\n\t\nfor severe dengue\n\t\n11\t\nClose monitoring of blood glucose, i.e.\t\nNot monitoring blood glucose, unaware of the \n\t\n\t\ntight glycaemic control\t\nhyperglycaemic effect on osmotic diuresis and \n\t\n\t\n\t\nconfounding hypovolaemia\n\t\n12\t\nDiscontinuation or reducing fluid therapy once \t\nContinuation and no review of intravenous \n\t\n\t\nhae", "page": 57, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "Continuation and no review of intravenous \n\t\n\t\nhaemodynamic status stabilizes \t\nfluid therapy once haemodynamic status stabilizes\nANNEX", "page": 57, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "46\nDengue: Guidelines for diagnosis, treatment, prevention and control\nTextbox B. Differential diagnosis of dengue fever\n\t\nConditions that mimic the febrile phase of dengue infection\n\t\nFlu-like syndromes\t\nInfluenza, measles, Chikungunya, infectious \n\t\n\t\n\t\nmononucleosis , HIV seroconversion illness\n\t\nIllnesses with a rash\t\nRubella, measles, scarlet fever, meningococcal \t\n\t\n\t\n\t\ninfection, Chikungunya, drug reactions\n\t\nDiarrhoeal diseases\t\nRotavirus, other enteric infections\n\t\nIllnesses with neurol", "page": 58, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": ", other enteric infections\n\t\nIllnesses with neurological manifestations\t\nMeningo/encephalitis \n\t\n\t\n\t\nFebrile seizures\n\t\nConditions that mimic the critical phase of dengue infection\n\t\nInfectious \t\nAcute gastroenteritis, malaria, leptospirosis,  \n\t\n\t\n\t\ntyphoid, typhus, viral hepatitis, acute HIV \t\n\t\n\t\n\t\n\t\nseroconversion illness, bacterial sepsis, septic shock\n\t\nMalignancies\t\nAcute leukaemia and other malignancies\n\t\nOther clinical pictures\t\nAcute abdomen \n\t\n\t\n\t\n\t\n\u2013\t acute appendicitis \n\t\n\t\n\t\n\t\n\u2013\t a", "page": 58, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "domen \n\t\n\t\n\t\n\t\n\u2013\t acute appendicitis \n\t\n\t\n\t\n\t\n\u2013\t acute cholecystitis \n\t\n\t\n\t\n\t\n\u2013\t perforated viscus\n\t\n\t\n\t\nDiabetic ketoacidosis \n\t\n\t\n\t\nLactic acidosis \n\t\n\t\n\t\nLeukopenia and thrombocytopaenia \u00b1 bleeding \n\t\n\t\n\t\nPlatelet disorders \n\t\n\t\n\t\nRenal failure \n\t\n\t\n\t\nRespiratory distress (Kussmaul\u2019s breathing) \n\t\n\t\n\t\nSystemic Lupus Erythematosus\nTextbox C. Warning signs\n\t\nClinical\t\nAbdominal pain or tenderness\n\t\n\t\n\t\nPersistent vomiting\n\t\n\t\n\t\nClinical fluid accumulation\n\t\n\t\n\t\nMucosal bleed\n\t\n\t\n\t\nLethargy, res", "page": 58, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "cumulation\n\t\n\t\n\t\nMucosal bleed\n\t\n\t\n\t\nLethargy, restlessness\n \n \n \nLiver enlargement >2 cm\n\t\nLaboratory\t\nIncrease in HCT concurrent with rapid decrease in platelet count", "page": 58, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "47\nChapter 2: Clinical management and delivery of clinical services\nCHAPTER 2\nTextbox D. Haemodynamic assessment: continuum of haemodynamic changes\n\t\nParameters\t\nStable circulation\t\nCompensated shock\t\nHypotensive shock\n\t\nHypotensive shock\t\nClear and lucid \t\nClear and lucid (shock can be \t\nChange of mental state (restless,  \n\t\n\t\n\t\nmissed if you do not touch the\t\ncombative) \n\t\n\t\n\t\npatient)\n\t\nCapillary refill time\t\nBrisk (<2 sec) \nProlonged (>2 sec)  \nVery prolonged, mottled skin\n\t\nExtremities\t\nWar", "page": 59, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "Very prolonged, mottled skin\n\t\nExtremities\t\nWarm and pink \t\nCool peripheries \t\nCold, clammy extremities \n\t\n\t\nextremities\n\t\nPeripheral\t\nGood volume \t\nWeak and thready \t\nFeeble or absent \n\t\npulse volume\n\t\nHeart rate\t\nNormal for age \t\nTachycardia \t\nSevere tachycardia with \t\n\t\n\t\n\t\n\t\n\t\nbradycardia in late shock\n\t\n\t\nBlood pressure\t\nNormal for age \t\nNormal systolic pressure but \t\nNarrowed pulse pressure \t \t\n\t\n\t\nNormal pulse\t\nrising diastolic pressure\t\n(<20 mmHg) \n\t\n\t\npressure for age\t\nNarrowing puls", "page": 59, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "(<20 mmHg) \n\t\n\t\npressure for age\t\nNarrowing pulse pressure\t\nHypotension (see definition \t\t\n\t\n\t\n\t\nPostural hypotension\t\nbelow) \n\t\n\t\n\t\n\t\nUnrecordable blood pressure\n\t\n \n\t\nRespiratory rate\t\nNormal for age \t\nTachypnoea \t\nMetabolic acidosis \n\t\n\t\n\t\n\t\nhyperpnoea/ Kussmaul\u2019s \t\n\t\n\t\n\t\n\t\n\t\nbreathing\nTextbox E. Admission criteria\n\t\nWarning signs\t\nAny of the warning signs (Textbox C)\n\t\nSigns and symptoms related to hypotension \t\nDehydrated patient, unable to tolerate oral fluids\n\t\n(possible plasma leakage)", "page": 59, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "o tolerate oral fluids\n\t\n(possible plasma leakage)\t\nGiddiness or postural hypotension\n\t\n\t\n\t\nProfuse perspiration, fainting, prostration during defervescence\n\t\n\t\n\t\nHypotension or cold extremities\n\t\nBleeding\t\nSpontaneous bleeding, independent of the platelet count\n\t\nOrgan impairment\t\nRenal, hepatic, neurological or cardiac \n\t\n\t\n\t\n\t\n\u2013\t enlarged, tender liver, although not yet in shock\n\t\n\t\n\t\n\t\n\u2013\t chest pain or respiratory distress, cyanosis\n\t\nFindings through further investigations\t\nRising haematocr", "page": 59, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "s through further investigations\t\nRising haematocrit\n\t\n\t\n\t\nPleural effusion, ascites or asymptomatic gall-bladder thickening\n\t\n\t\nCo-existing conditions\t\nPregnancy\n\t\n\t\n\t\nCo-morbid conditions, such as diabetes mellitus, hypertension, \t\n\t\n\t\n\t\npeptic ulcer, haemolitic anemias and others\n\t\n\t\n\t\nOverweight or obese (rapid venous access difficult in emergency)\n\t\n\t\n\t\nInfancy or old age\n  \n\t\nSocial circumstances\t\nLiving alone\n\t\n\t\n\t\nLiving far from health facility\n\t\n\t\n\t\nWithout reliable means of transport", "page": 59, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "acility\n\t\n\t\n\t\nWithout reliable means of transport\nDefinition of hypotension:\nSystolic blood pressure of <90 mm Hg or mean arterial pressure <70 mm Hg in adults or a systolic blood pressure decrease of  \n>40 mm Hg or <2 SD below normal for age.\nIn children up to 10 years of age, the 5th centile for systolic blood pressure can be determined by the formula: 70 + (age in years x 2) mm Hg.", "page": 59, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "48\nDengue: Guidelines for diagnosis, treatment, prevention and control\nTextbox F. Discharge criteria (all of the following conditions must be present)\n\t\nClinical\t\nNo fever for 48 hours. \n\t\n\t\n\t\nImprovement in clinical status (general well-being, appetite, haemodynamic \t\n\t\n\t\n\t\nstatus, urine output, no respiratory distress).\n\t\nLaboratory\t\nIncreasing trend of platelet count.\n\t\n\t\n\t\nStable haematocrit without intravenous fluids.\nTextbox G. Home care card for dengue\n\t\nHome care card for dengue (please", "page": 60, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "rd for dengue\n\t\nHome care card for dengue (please take this card to your health facility for each visit)\n\t\nWhat should be done?\n \n\u2022 \nAdequate bed rest\n \n\u2022 \nAdequate fluid intake (>5 glasses for average-sized adults or accordingly in children) \n\t\n\t\n-\t\nMilk, fruit juice (caution with diabetes patient) and isotonic electrolyte solution (ORS) and  \n\t\n\t\n\t\nbarley/rice water. \n\t\n\t\n-\t\nPlain water alone may cause electrolyte imbalance. \n \n\u2022 \nTake paracetamol (not more than 4 grams per day for adults and", "page": 60, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "mol (not more than 4 grams per day for adults and accordingly in children)\n \n\u2022 \nTepid sponging\n \n\u2022 \nLook for mosquito breeding places in and around the home and eliminate them\n\t\nWhat should be avoided?\n \n\u2022 \nDo not take acetylsalicylic acid (aspirin), mefenemic acid (ponstan), ibuprofen or other non-steroidal  \n\t\n\t\nanti-inflammatory agents (NSAIDs), or steroids. If you are already taking these medications please consult \t\n\t\n\t\nyour doctor.\n \n\u2022 \nAntibiotics are not necessary.\n\t\nIf any of following", "page": 60, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ibiotics are not necessary.\n\t\nIf any of following is observed, take the patient immediately to the nearest hospital. These are warning signs  \n\t\nfor danger:\n \n\u2022 \nBleeding: \n\t\n\t\n-\t\nred spots or patches on the skin \n\t\n\t\n-\t\nbleeding from nose or gums \n\t\n\t\n-\t\nvomiting blood \n\t\n\t\n-\t\nblack-coloured stools \n\t\n\t\n-\t\nheavy menstruation/vaginal bleeding\n \n\u2022 \nFrequent vomiting\n \n\u2022 \nSevere abdominal pain\n \n\u2022 \nDrowsiness, mental confusion or seizures\n \n\u2022 \nPale, cold or clammy hands and feet\n \n\u2022 \nDifficulty in", "page": 60, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": ", cold or clammy hands and feet\n \n\u2022 \nDifficulty in breathing\n\t\nLaboratory results monitoring\n\t\n\t\n1st Visit\t\n\t\nDate\t\n\t\n\t\nHaematocrit\t\n\t\n\t\nWhite cell count\t\n\t\n\t\nPlatelet count", "page": 60, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "49\nChapter 2: Clinical management and delivery of clinical services\nCHAPTER 2\nTextbox H. Calculations for normal maintenance of intravenous fluid infusion\n\t\nNormal maintenance fluid per hour can be calculated on the basis of the following formula*  \n\t\n(equivalent to Holliday-Segar formula):\n \t\n\t\n\t\n4 mL/kg/h for first 10 kg body weight\n \t\n\t\n\t\n+ 2 mL/kg/h for next 10 kg body weight\n \t\n\t\n\t\n+ 1 mL/kg/h for subsequent kg body weight\n\t\n*For overweight/obese patients calculate normal maintenance fluid", "page": 61, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "obese patients calculate normal maintenance fluid based on ideal body weight (IBW) \n\t\n(Adapted from reference 16)\n\t\nIBW for overweight/obese adults can be estimated on the basis of the following formula \n\t\n\t\nFemale: 45.5 kg + 0.91(height -152.4) cm\n\t\n\t\nMale: 50.0 kg + 0.91(height -152.4) cm \n\t\n\t\n(17)\nTextbox J. Hourly maintenance fluid regime for overweight or obese patients\n\t Estimated ideal body \t Normal maintenance\t\nFluid regime based on \t\nFluid regime based on  \n\t weight, or IBW (kg)\t\nfluid", "page": 61, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "id regime based on  \n\t weight, or IBW (kg)\t\nfluid (ml/hour) based on \t\n2\u20133 ml/kg /hour (ml/hour)\t 1.5 \u20132 ml/kg/hour (ml/hour)\n\t \t\nHolliday-Segar formula\n\t\n5\t\n10\t\n10\u201315\t\n\t\n10\t\n20\t\n20\u201330\t\n\t\n15\t\n30\t\n30\u201345\t\n\t\n20\t\n60\t\n40\u201360\t\n\t\n25\t\n65\t\n50\u201375\t\n\t\n30\t\n70\t\n60\u201390\t\n\t\n35\t\n75\t\n70\u2013105\t\n\t\n40\t\n80\t\n80\u2013120\t\n\t\n50\t\n90\t\n100\u2013150 \t\n\t\n60\t\n100\t\n\t\n90\u2013120\n\t\n70\t\n110\t\n\t\n105\u2013140\n\t\n80\t\n120\t\n\t\n120\u2013150\nNotes:\nFor adults with IBW >50 kg, 1.5\u20132 ml/kg can be used for quick calculation of hourly maintenance fluid regime.\nFor adults", "page": 61, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "on of hourly maintenance fluid regime.\nFor adults with IBW\u226450 kg, 2\u20133 ml/kg can be used for quick calculation of hourly maintenance fluid regime.\nTextbox K. Estimated ideal body weight for overweight or obese adults\n\t Height (cm)\t   Estimated, IBW (kg) for adult males\t\nEstimated IBW (kg) for adult females\n\t 150\t\n50\t\n45.5\n\t 160\t\n57\t\n52\n\t 170\t\n66\t\n61.5\n\t 180\t\n75\t\n70", "page": 61, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "50\nDengue: Guidelines for diagnosis, treatment, prevention and control\nTextbox L. Example of a monitoring chart for dengue\n\t \t\n\t\n\t\n\t\nTime and date\n\tParameters\n\tBody temperature\n\tRespiratory rate\n\tHeart rate\n\tBlood pressure\n\tPulse pressure/volume\n\tCapillary refill time\n\tTemperature of \n\textremities\n\tAbdominal pain\n\tVomiting\n\tBleeding\nTextbox M. Choice of intravenous fluids for resuscitation\nBased on the three randomized controlled trials comparing the different types of fluid resuscitation regime", "page": 62, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "the different types of fluid resuscitation regime in \ndengue shock in children, there is no clear advantage to the use of colloids over crystalloids in terms of the overall \noutcome. However, colloids may be the preferred choice if the blood pressure has to be restored urgently, i.e. in \nthose with pulse pressure less than 10 mm Hg. Colloids have been shown to restore the cardiac index and reduce \nthe level of haematocrit faster than crystalloids in patients with intractable shock (18\u201320). \nAn", "page": 62, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "s in patients with intractable shock (18\u201320). \nAn ideal physiological fluid is one that resembles the extracellular and intracellular fluids compartments closely. \nHowever, the available fluids have their own limitations when used in large quantities. Therefore it is advisable to \nunderstand the limitations of these solutions to avoid their respective complications.\n\t\nCrystalloids\n0.9% saline (\u201cnormal\u201d saline)\nNormal plasma chloride ranges from 95 to 105 mmol/L. 0.9% Saline is a suitable option", "page": 62, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "5 to 105 mmol/L. 0.9% Saline is a suitable option for initial fluid \nresuscitation, but repeated large volumes of 0.9% saline may lead to hyperchloraemic acidosis. Hyperchloraemic \nacidosis may aggravate or be confused with lactic acidosis from prolonged shock. Monitoring the chloride \nand lactate levels will help to identify this problem. When serum chloride level exceeds the normal range, it is \nadvisable to change to other alternatives such as Ringer\u2019s Lactate.\n\t\nRinger\u2019s Lactate\nRinger\u2019s Lac", "page": 62, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "Ringer\u2019s Lactate.\n\t\nRinger\u2019s Lactate\nRinger\u2019s Lactate has lower sodium (131 mmol/L) and chloride (115 mmol/L) contents and an osmolality of  \n273 mOsm/L. It may not be suitable for resuscitation of patients with severe hyponatremia. However, it is a \nsuitable solution after 0.9 Saline has been given and the serum chloride level has exceeded the normal range. \nRinger\u2019s Lactate should probably be avoided in liver failure and in patients taking metformin where lactate \nmetabolism may be impaired.", "page": 62, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "formin where lactate \nmetabolism may be impaired.\n\t\nColloids\nThe types of colloids are gelatin-based, dextran-based and starch-based solutions. One of the biggest concerns \nregarding their use is their impact on coagulation. Theoretically, dextrans bind to von Willebrand factor/Factor VIII \ncomplex and impair coagulation the most. However, this was not observed to have clinical significance in fluid \nresuscitation in dengue shock. Of all the colloids, gelatine has the least effect on coagulation", "page": 62, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "oids, gelatine has the least effect on coagulation but the highest risk \nof allergic reactions. Allergic reactions such as fever, chills and rigors have also been observed in Dextran 70. \nDextran 40 can potentially cause an osmotic renal injury in hypovolaemic patients.", "page": 62, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "51\nChapter 2: Clinical management and delivery of clinical services\nCHAPTER 2", "page": 63, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "PRESUMPTIVE DIAGNOSIS\nLive in/travel to dengue endemic area. \nFever and two of the following criteria:\n\u2022 Anorexia and nausea\n\u2022 Rash\n\u2022 Aches and pains\n\u2022 Warning signs\n\u2022 Leukopenia\n\u2022 Tourniquet test positive\nWARNING SIGNS*\n\u2022 Abdominal pain or tenderness\n\u2022 Persistent vomiting\n\u2022 Clinical fluid accumulation\n\u2022 Mucosal bleed\n\u2022 Lethargy, restlessness\n\u2022 Liver enlargment >2 cm\n\u2022 Laboratory: increase in HCT concurrent \n\t with rapid decrease in platelet count\n*(requiring strict observation and medical inter", "page": 64, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "t\n*(requiring strict observation and medical intervention)\n DENGUE WITHOUT WARNING SIGNS\nASSESSMENT\nLaboratory confirmed dengue\n(important when no sign of plasma leakage)\nCLASSIFICATION\nMANAGEMENT\nNEGATIVE\nDENGUE WITH WARNING SIGNS\nGroup A\n(May be sent home)\nGroup criteria\nPatients who do not have warning signs     \nAND  \nwho are able:\n\u2022 to tolerate adequate volumes of oral  \n\t\nfluids\n\u2022 to pass urine at least once every  \n\t\n6 hours\nLaboratory tests\n\u2022 full blood count (FBC)\n\u2022 haematocrit (HCT)\nTr", "page": 64, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ts\n\u2022 full blood count (FBC)\n\u2022 haematocrit (HCT)\nTreatment\nAdvice for:\n\u2022 adequate bed rest\n\u2022 adequate fluid intake\n\u2022 Paracetamol, 4 gram maximum per  \n\t\nday in adults and accordingly in \t\t\n\t\nchildren.\nPatients with stable HCT can be sent home.\nMonitoring\nDaily review for disease progression:\n\u2022 decreasing white blood cell count \n\u2022 defervescence\n\u2022 warning signs (until out of critical period).\nAdvice for immediate return to hospital if \ndevelopment of any warning signs, and\n\u2022 written advice for mana", "page": 64, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "f any warning signs, and\n\u2022 written advice for management (e.g.  \n\t\nhome care card for dengue).\nGroup criteria\nPatients with any of the following features:\n\u2022 co-existing conditions such as  \n \n\t\npregnancy, infancy, old age, diabetes \t\n\t\nmellitus, renal failure\n\u2022 social circumstances such as living  \n\t\nalone, living far from hospital \nLaboratory tests\n\u2022 full blood count (FBC)\n\u2022 haematocrit (HCT)\nTreatment\n\u2022 Encouragement for oral fluids. If not \n\t\ntolerated, start intravenous fluid \t \t\n\t\ntherapy 0", "page": 64, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "tolerated, start intravenous fluid \t \t\n\t\ntherapy 0,9% saline or Ringer\u2019s Lactate \t\n\t\nat maintenance rate.\nMonitoring\nMonitor:\n\u2022 temperature pattern\n\u2022 volume of fluid intake and losses\n\u2022 urine output (volume and frequency)\n\u2022 warning signs\n\u2022 HCT, white blood cell and platelet  \n\t\ncounts.\nGroup B\n(Referred for in-hospital care)\nOR: Existing warning signs                 \n \nLaboratory tests\n\u2022 full blood count (FBC)\n\u2022 haematocrit (HCT)\nTreatment\nObtain reference HCT before fluid therapy.\nGive isotoni", "page": 64, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "n reference HCT before fluid therapy.\nGive isotonic solutions such as 0.9 % saline, \nRinger\u2019s Lactate. Start with 5\u20137 ml/kg/hr for \n1\u20132 hours, then reduce to 3\u20135 ml/kg/hr for \n2\u20134 hr, and then reduce to 2\u20133 ml/kg/hr \nor less according to clinical response.\nReassess clinical status and repeat HCT:\n\u2022 if HCT remains the same or rises only  \n \nminimally -> continue with 2\u20133 ml/kg/ \n\t\nhr for another 2\u20134 hours;\n\u2022 if worsening of vital signs and rapidly  \n \nrising HCT -> increase rate to 5\u201310  \n\t\nml/kg", "page": 64, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "rising HCT -> increase rate to 5\u201310  \n\t\nml/kg/hr for 1\u20132 hours.\nReassess clinical status, repeat HCT and \nreview fluid infusion rates accordingly:\n\u2022 reduce intravenous fluids gradually when  \n\t\nthe rate of plasma leakage decreases \t\n\t\ntowards the end of the critical phase. \nThis is indicated by:\n\u2022 adequate urine output and/or fluid  \n\t\nintake\n\u2022 HCT deceases below the baseline value  \n\t\nin a stable patient.\nMonitoring\nMonitor:\n\u2022 vital signs and peripheral perfusion (1\u20134  \n\t\nhourly until pati", "page": 64, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "nd peripheral perfusion (1\u20134  \n\t\nhourly until patient is out of critical phase\n\u2022 urine output (4\u20136 hourly)\n\u2022 HCT (before and after fluid replacement,  \n\t\nthen 6\u201312 hourly)\n\u2022 blood glucose \n\u2022 other organ functions (renal profile, liver  \n\t\nprofile, coagulation profile, as indicated).\nPOSITIVE\nDENGUE CASE \nCo-existing conditions\nSocial circumstances\nNEGATIVE", "page": 64, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "POSITIVE\nSEVERE DENGUE\nGroup C\n(Require emergency treatment)\nGroup criteria\nPatients with any of the following features:\n\u2022 severe plasma leakage with shock and/or fl\n uid accumulation with respiratory distress\n\u2022 severe bleeding\n\u2022 severe organ impairment\nLaboratory tests\n\u2022 full blood count (FBC)\n\u2022 haematocrit (HCT)\n\u2022 other organ function tests as indicated\nTreatment of compensated shock\nStart IV fl\n uid resuscitation with isotonic crystalloid solutions at 5\u201310 ml/kg/hr over 1 hour. Reassess patie", "page": 65, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "tions at 5\u201310 ml/kg/hr over 1 hour. Reassess patients\u2019 condition.\nIf patient improves:\n\u2022 IV fl\n uids should be reduced gradually to 5\u20137 ml/kg/hr for 1\u20132 hours, then to 3\u20135 ml/kg/hr for 2\u20134 hours, \n \nthen to 2-3 ml/kg/hr for 2\u20134 hours and then reduced further depending on haemodynamic status;\n\u2022 IV fl\n uids can be maintained for up to 24\u201348 hours.\nIf patient is still unstable: \n\u2022 check HCT after fi\n rst bolus;\n\u2022 if HCT increases/still high (>50%), repeat a second bolus of crystalloid solution at 1", "page": 65, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "repeat a second bolus of crystalloid solution at 10\u201320 ml/kg/hr for 1 hour;\n\u2022 if there is improvement after second bolus, reduce rate to 7\u201310 ml/kg/hr for 1\u20132 hours and continue to reduce as above;\n\u2022 if HCT decreases, this indicates bleeding and need to cross-match and transfuse blood as soon as possible.\nTreatment of hypotensive shock\nInitiate IV fl\n uid resuscitation with crystalloid or colloid solution at 20 ml/kg as a bolus for 15 minutes.\nIf patient improves:\n\u2022 give a crystalloid/colloid so", "page": 65, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "patient improves:\n\u2022 give a crystalloid/colloid solution of 10 ml/kg/hr for 1 hour, then reduce gradually as above.\nIf patient is still unstable:\n\u2022 review the HCT taken before the fi\n rst bolus;\n\u2022 if HCT was low (<40% in children and adult females, <45% in adult males) this indicates bleeding, \n \nthe need to cross-match and transfuse (see above);\n\u2022 if HCT was high compared to baseline value, change to IV colloids at 10\u201320 ml/kg as a second bolus over 30 minutes to 1 hour; \n \nreassess after secon", "page": 65, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "over 30 minutes to 1 hour; \n \nreassess after second bolus.\n\u2022 If patient is improving reduce the rate to 7\u201310ml/kg/hr for 1\u20132 hours, then back to IV cystalloids and reduce rates as above;\n\u2022 if patient\u2019s condition is still unstable, repeat HCT after second bolus.\n\u2022 If HCT decreases, this indicates bleeding (see above); \n\u2022 if HCT increases/remains high (>50%), continue colloid infusion at 10\u201320 ml/kg as a third bolus over 1 hour, \n \nthen reduce to 7\u201310 ml/kg/h 1\u20132 hours, then change back to crystal", "page": 65, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "\u201310 ml/kg/h 1\u20132 hours, then change back to crystalloid solution and reduce rate as above.\nTreatment of haemorrhagic complications\nGive 5\u201310 ml/kg of fresh packed red cells or 10\u201320 ml/kg of fresh whole blood.\nDays of illness\nTemperature\nPotential clinical issues\nLaboratory changes\nSerology and virology\nDehydration            Shock            Reabsorption\n                            bleeding         Fluid overload\n        1     2     3     4     5     6     7     8     9     10\nOrgan impairment\nH", "page": 65, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "6     7     8     9     10\nOrgan impairment\nHematocrit\nPlatelet\nViraemia\nIgM/IgG\nFebrile                 Critical               Recovery phases\nCourse of dengue illness:\n40\u00b0\nMANAGEMENT", "page": 65, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "54\nDengue: Guidelines for diagnosis, treatment, prevention and control\n2.4 References\n1. Rigau-Perez JG et al. Dengue and dengue haemorrhagic fever. Lancet, 1998, \n352:971\u2013977.\n2. Yip WCL. Dengue haemorrhagic fever: current approaches to management. Medical \nProgress, October 1980.\n3. Kalayanarooj S et al. Early clinical and laboratory indicators of acute dengue illness. \n \nJournal of Infectious Diseases, 1997, 176:313\u2013321. \n4. Phuong CXT et al. Evaluation of the World Health Organization standa", "page": 66, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "Evaluation of the World Health Organization standard tourniquet \ntest in the diagnosis of dengue infection in Vietnam. Tropical Medicine and International \nHealth, 2002, 7:125\u2013132.\n5. Balmaseda A et al. Assessment of the World Health Organization scheme for \nclassification of dengue severity in Nicaragua. American Journal of Tropical Medicine \nand Hygiene, 2005, 73:1059\u20131062.\n6. Srikiatkhachorn A et al. Natural history of plasma leakage in dengue hemorrhagic \nfever: a serial ultrasonic study. Pe", "page": 66, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "hemorrhagic \nfever: a serial ultrasonic study. Pediatric Infectious Disease Journal, 2007, 26(4):283\u2013\n290. \n7. Nimmannitya S et al. Dengue and chikungunya virus infection in man in Thailand, \n1962\u201364. Observations on hospitalized patients with haemorrhagic fever. American \nJournal of Tropical Medicine and Hygiene, 1969, 18(6):954\u2013971.\n8. Martinez-Torres E, Polanco-Anaya AC, Pleites-Sandoval EB. Why and how children \nwith dengue die? Revista cubana de medicina tropical, 2008, 60(1):40\u201347.\n9. Nim", "page": 66, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "na de medicina tropical, 2008, 60(1):40\u201347.\n9. Nimmannitya S. Clinical spectrum and management of dengue haemorrhagic fever. \nSoutheast Asian Journal of Tropical Medicine and Public Health, 1987, 18(3):392\u2013\n397.\n10. Martinez E. A Organizacao de Assistencia Medica durante uma epidemia de \nFHD-SCD. In: Dengue. Rio de Janeiro, Editorial Fiocruz, 2005 (pp 222\u2013229).\n11. Lemus ER, Estevez G, Velazquez JC. Campana por la Esparanza. La Lucha contra \nel Dengue (El Salvador, 2000). La Habana, Editors Poli", "page": 66, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "engue (El Salvador, 2000). La Habana, Editors Politica, 2002.\n12. Martinez E. Preventing deaths from dengue: a space and challenge for primary \nhealth care. Pan American Journal of Public Health, 2006, 20:60\u201374.\n13. Harris E et al. Fluid intake and decreased risk for hospitalization for dengue fever, \nNicaragua. Emerging Infectious Diseases, 2003, 9:1003\u20131006.\n14. Lum L et al. Preventive transfusion in dengue shock syndrome \u2013 is it necessary? \nJournal of Pediatrics, 2003, 143:682\u2013684.", "page": 66, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "urnal of Pediatrics, 2003, 143:682\u2013684.", "page": 66, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "55\nChapter 3: Vector management and delivery of vector control services\nCHAPTER 3\n15. Dellinger RP, Levy MM, Carlet JM. Surviving Sepsis Campaign: international \nguidelines for management of severe sepsis and septic shock: 2008. Critical Care \nMedicine, 2008, 36:296\u2013327.\n16. WHO. Dengue haemorrhagic fever: diagnosis, treatment, prevention and control, \n2nd edition. Geneva, World Health Organization, 1997.\n17. Gilbert DN et al. The Sanford guide to antimicrobial therapy 2007, 37th ed. \nSperryvill", "page": 67, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "o antimicrobial therapy 2007, 37th ed. \nSperryville, VA, Antimicrobial Therapy, Inc., 2007 (p 87).\n18. Dung NM, Day NP, Tam DT. Fluid replacement in dengue shock syndrome: a \nrandomized, double-blind comparison of four intravenous-fluid regimens. Clinical \nInfectious Diseases, 1999, 29:787\u2013794.\n19. Ngo NT, Cao XT, Kneen R. Acute management of dengue shock syndrome: a \nrandomized double-blind comparison of 4 intravenous fluid regimens in the first hour. \nClinical Infectious Diseases, 2001, 32:204", "page": 67, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "hour. \nClinical Infectious Diseases, 2001, 32:204\u2013213.\n20. Wills BA et al. Comparison of three fluid solutions for resuscitation in dengue shock \nsyndrome. New England Journal of Medicine, 2005, 353:877\u2013889.", "page": 67, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "56\nDengue: Guidelines for diagnosis, treatment, prevention and control", "page": 68, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "57\nChapter 3: Vector management and delivery of vector control services\nCHAPTER 3\nChapter 3\n \nVector management and  \ndelivery of vector control services", "page": 69, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "58\nDengue: Guidelines for diagnosis, treatment, prevention and control", "page": 70, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "59\nChapter 3: Vector management and delivery of vector control services\nCHAPTER 3\nChapter 3.Vector management and delivery of vector \ncontrol services\n3.1  OVERVIEW\nPreventing or reducing dengue virus transmission depends entirely on control of the \nmosquito vectors or interruption of human\u2013vector contact.\nActivities to control transmission should target Ae. aegypti (the main vector) in the habitats \nof its immature and adult stages in the household and immediate vicinity, as well as other \nsett", "page": 71, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "old and immediate vicinity, as well as other \nsettings where human\u2013vector contact occurs (e.g. schools, hospitals and workplaces), \nunless there is sound evidence that Ae. albopictus or other mosquito species are the \nlocal vectors of dengue. Ae. aegypti proliferates in many purposely-filled household \ncontainers such as those used for domestic water storage and for decorative plants, \nas well as in a multiplicity of rain-filled habitats \u2013 including used tyres, discarded food \nand beverage conta", "page": 71, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ing used tyres, discarded food \nand beverage containers, blocked gutters and buildings under construction. Typically, \nthese mosquitoes do not fly far, the majority remaining within 100 metres of where they \nemerged. They feed almost entirely on humans, mainly during daylight hours, and both \nindoors and outdoors. \nIntegrated vector management (IVM) is the strategic approach to vector control \npromoted by WHO (1) and includes control of the vectors of dengue. Defined as \u201ca \nrational decision-mak", "page": 71, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "rs of dengue. Defined as \u201ca \nrational decision-making process for the optimal use of resources for vector control\u201d, IVM \nconsiders five key elements in the management process, namely: \n \n\u2022 advocacy, social mobilization and legislation \u2013 the promotion of these \t\n\t\n\t\n\t\nprinciples in development policies of all relevant agencies, organizations and \t\n\t\n\t\ncivil society; the establishment or strengthening of regulatory and legislative \t\n\t\n\t\ncontrols for public health; and the empowerment of communitie", "page": 71, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "r public health; and the empowerment of communities; \n \n\u2022 collaboration within the health sector and with other sectors \u2013  the consideration \n \n\t\n\t\nof all options for collaboration within and between public and private sectors; \t\n\t\n\t\nplanning and decision-making delegated to the lowest possible administrative \t\n\t\n\t\nlevel; and strengthening communication among policy-makers, managers of \t\n\t\n\t\nprogrammes for the control of vector-borne diseases, and other key partners; \n \n\u2022 integrated approach to", "page": 71, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "d other key partners; \n \n\u2022 integrated approach to disease control \u2013 ensuring the rational use of available \t\n\t\n\t\nresources through the application of a multi-disease control approach; integration \n \n\t\n\t\nof non-chemical and chemical vector control methods; and integration with other \n\t\n\t\ndisease control measures; \n \n\u2022 evidence-based decision-making \u2013 adaptation of strategies and interventions to \n \n\t\n\t\nlocal vector ecology, epidemiology and resources, guided by operational \t\t\n\t\n\t\nresearch and sub", "page": 71, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ces, guided by operational \t\t\n\t\n\t\nresearch and subject to routine monitoring and evaluation;\n \n\u2022 capacity-building \u2013 the development of essential infrastructure, financial resources \n\t\n\t\nand adequate human resources at national and local levels to manage IVM \t\n\t\n\t\nprogrammes, based on a situation analysis.\nControl of Ae. aegypti is mainly achieved by eliminating container habitats that are \nfavourable oviposition sites and which permit the development of the aquatic stages.", "page": 71, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "pment of the aquatic stages.", "page": 71, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "60\nDengue: Guidelines for diagnosis, treatment, prevention and control\nThe habitats are eliminated by preventing access by mosquitoes to these containers \nor by frequently emptying and cleaning them, by removing the developing stages \nusing insecticides or biological control agents, by killing the adult mosquitoes using \ninsecticides, or by combinations of these methods. \nHistorically, efforts to control dengue vectors in the WHO Region of the Americas resulted \nin the elimination of Ae. aegypti", "page": 72, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ericas resulted \nin the elimination of Ae. aegypti populations from much of the neotropics by the 1970s. \nHowever, re-introductions followed, leading to the re-establishment of vector populations. \nToday, therefore, the main aim of most programmes is to reduce the densities of vector \npopulations as much as possible and to maintain them at low levels. Where feasible, \nefforts may also be made to reduce the longevity of adult female mosquitoes by the use \nof insecticidal methods in order to lesse", "page": 72, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "the use \nof insecticidal methods in order to lessen the risk of virus transmission.\n \nIn selecting the most appropriate vector control method, or combination of methods, \nconsideration should be given to the local ecology and behaviour of the target species, the \nresources available for implementation, the cultural context in which control interventions \nare carried out, the feasibility of applying them in a timely manner, and the adequacy \nof coverage. Methods of vector control include the elim", "page": 72, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "verage. Methods of vector control include the elimination or management of larval \nhabitats, larviciding with insecticides, the use of biological agents and the application \nof adulticides. \n3.2 Methods of vector control\nAe. aegypti uses a wide range of confined larval habitats, both man-made and natural. \nHowever, it may not be feasible or cost-effective to attempt to control the immature stages \nin all such habitats in a community. Some man-made container habitats produce large \nnumbers of adu", "page": 72, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "e container habitats produce large \nnumbers of adult mosquitoes, whereas others are less productive. Consequently, control \nefforts should target the habitats that are most productive and hence epidemiologically \nmore important rather than all types of container, especially when there are major resource \nconstraints. Such targeted strategies require a thorough understanding of the local vector \necology and the attitudes and habits of residents pertaining to the containers.\n3.2.1 \tEnvironmental m", "page": 72, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "rtaining to the containers.\n3.2.1 \tEnvironmental management\nEnvironmental management seeks to change the environment in order to prevent or \nminimize vector propagation and human contact with the vector-pathogen by destroying, \naltering, removing or recycling non-essential containers that provide larval habitats. Such \nactions should be the mainstay of dengue vector control. Three types of environmental \nmanagement are defined:\n \n\u2022 Environmental modification \u2013 long-lasting physical transformatio", "page": 72, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "modification \u2013 long-lasting physical transformations to reduce vector \n \n\t\n\t\nlarval habitats, such as installation of a reliable piped water supply to communities, \n\t\n\t\nincluding household connections.\n \n\u2022 Environmental manipulation \u2013 temporary changes to vector habitats involving \t\n\t\n\t\nthe management of \u201cessential\u201d containers, such as frequent emptying and cleaning \n \n\t\n\t\nby scrubbing of water-storage vessels, flower vases and desert room coolers; \t\n\t\n\t\ncleaning of gutters; sheltering stored ty", "page": 72, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "s; \t\n\t\n\t\ncleaning of gutters; sheltering stored tyres from rainfall; recycling or proper \t\t\n\t\n\t\ndisposal of discarded containers and tyres; management or removal from the", "page": 72, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "61\nChapter 3: Vector management and delivery of vector control services\nCHAPTER 3\n\t\n\t\nvicinity of homes of plants such as ornamental or wild bromeliads that collect \t\n\t\n\t\nwater in the leaf axils.\n \n\u2022 Changes to human habitation or behaviour \u2013 actions to reduce human\u2013vector \t\n\t\n\t\ncontact, such as installing mosquito screening on windows, doors and other \t\n\t\n\t\nentry points, and using mosquito nets while sleeping during daytime. \nThe choice of approach should be effective, practicable and appropria", "page": 73, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ach should be effective, practicable and appropriate to local \ncircumstances. Actual or potentially important container types that cannot be removed \nfrom the area should be dealt with in situ. Table 3.1 summarizes the main actions used \nto control immature Aedes larval habitats.\nTable 3.1 Environmental management actions to control immature stages of Aedes aegyptia\nLarval  \t\nEmpty,clean\t\nMosquito-\t Store  \t\nModify design,\t\nUse expanded\t Fill (with sand, \t\nCollect,\t\nPuncture \nhabitat\t\nand scrub", "page": 73, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "th sand, \t\nCollect,\t\nPuncture \nhabitat\t\nand scrub\t\nproof \t\nunder \t\nand/or repair\t\npolystyrene \t\nsoil or concrete)\t recycle and\t\nor drain \n\t\nweekly\t\ncover   \t\nroof\t\nand clean \t\nbeads\t\n\t\ndispose of\nWater-storage \t\n\t\n+\t\n\t\n+\t\n+ \ntank or cistern\nDrums \t\n\t\n+\t\n+\t\n\t\n+\n(150\u2013200 litres)\nFlower vase filled \t\n+\t\n\t\n\t\n\t\n\t\n+ \nwith water\nPotted plants\t\n+\t\n\t\n\t\n+ \nwith saucers\nRoof gutter\t\n\t\n\t\n\t\n+\nAnimal water\t\n+ \ncontainer\nDiscarded food and \t\n\t\n\t\n\t\n\t\n\t\n\t\n+ \ndrink containers\nHollow fence posts\t\n\t\n\t\n\t\n+\t\n\t\n+\nUsed", "page": 73, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "k containers\nHollow fence posts\t\n\t\n\t\n\t\n+\t\n\t\n+\nUsed tyres\t\t\n\t\n\t\n+\t\n\t\n\t\n+\t\n+\nDiscarded large \t\n\t\n\t\n\t\n\t\n\t\n\t\n+ \nappliances\nDiscarded buckets \t\n\t\n\t\n+\t\n\t\n\t\n\t\n+\t\n+ \n(<20 litres)\nTree holes\t\t\n\t\n\t\n\t\n\t\n\t\n+\nRock holes\t\t\n\t\n\t\n\t\n\t\n\t\n+\na Adapted from Dengue and dengue haemorrhagic fever in the Americas: guidelines for prevention and control (2)", "page": 73, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "62\nDengue: Guidelines for diagnosis, treatment, prevention and control\nImprovements in, and maintenance of, urban infrastructure and basic services contribute \nto the reduction in available larval habitats since large Ae. aegypti populations are \noften associated with poor water supply and inadequate sanitation and waste disposal \nservices. \n3.2.1.1 Improvement of water supply and water-storage systems\n\t\nImproving water supplies is a fundamental method of controlling Aedes vectors, \nespecially A", "page": 74, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "method of controlling Aedes vectors, \nespecially Ae. aegypti. Water piped to households is preferable to water drawn from \nwells, communal standpipes, rooftop catchments and other water-storage systems. \nHowever, potable water must be supplied reliably so that water-storage containers that \nserve as larval habitats  \u2013 such as drums, overhead or ground tanks and concrete jars \n\u2013 are not necessary. In urban areas the use of cost-recovery mechanisms such as the \nintroduction of metered water may ac", "page": 74, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "such as the \nintroduction of metered water may actually encourage household collection and storage \nof roof catchment rainwater that can be harvested at no cost, resulting in the continued \nuse of storage containers. Traditional water storage practices may also persist even \nwhen reliable supplies are available. The installation of reliable piped water supplies in \nhouses should therefore be accompanied by a communication strategy that discourages \ntraditional storage practices.\n3.2.1.2\t Mosqui", "page": 74, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "es \ntraditional storage practices.\n3.2.1.2\t Mosquito-proofing of water-storage containers\n\t\n\t\nWater-storage containers can be designed to prevent access by mosquitoes for \noviposition. Containers can be fitted with tight lids or, if rain-filled, tightly-fitted mesh \nscreens can allow for rainwater to be harvested from roofs while keeping mosquitoes \nout. Removable covers should be replaced every time water is removed and should be \nwell maintained to prevent damage that permits mosquitoes to get", "page": 74, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "d to prevent damage that permits mosquitoes to get in and out. \nExpanded polystyrene beads used on the surface of water provide a physical barrier \nthat inhibits oviposition in storage containers from which water is drawn from below via \na pipe and from which there is no risk of overflow. These beads can also be placed in \nseptic tanks, which Ae. aegypti sometimes exploits.\n3.2.1.3 Solid waste management \n\t\nIn the context of dengue vector control, \u201csolid waste\u201d refers mainly to non-biodegradable", "page": 74, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": ", \u201csolid waste\u201d refers mainly to non-biodegradable \nitems of household, community and industrial waste. The benefits of reducing the \namount of solid waste in urban environments extend beyond those of vector control, \nand applying many of the basic principles can contribute substantially to reducing \nthe availability of Ae. aegypti larval habitats. Proper storage, collection and disposal \nof waste are essential for protecting public health. The basic rule of \u201creduce, reuse, \nrecycle\u201d is highly a", "page": 74, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "asic rule of \u201creduce, reuse, \nrecycle\u201d is highly applicable. Efforts to reduce solid waste should be directed against \ndiscarded or non-essential containers, particularly if they have been identified in the \ncommunity as important mosquito-producing containers.\nSolid waste should be collected in plastic sacks and disposed of regularly. The frequency \nof collection is important: twice per week is recommended for housefly and rodent \ncontrol in warm climates. Integration of Ae. aegypti control wit", "page": 74, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "m climates. Integration of Ae. aegypti control with waste management \nservices is possible and should be encouraged.", "page": 74, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "63\nChapter 3: Vector management and delivery of vector control services\nCHAPTER 3\nIt is also important to provide information on these activities to encourage and promote \nthem. Globally, recycling is on the increase. This practice places value on many items \npreviously classified as waste products, leading to growth in the recycling market \nand profit for both small and large-scale businesses as a consequence. But although \nrecycling can contribute to significant economic improvements, the recy", "page": 75, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ute to significant economic improvements, the recycling market \ncan potentially impact dengue vector populations. For there to be an impact, however, \ncontainers of importance must have value in the marketplace, be it real (e.g. plastics or \ntyres for recycling) or created (e.g. beverage container deposit laws), and advertising \nand promotion must be sustained.\nUsed tyres are common and sometimes highly productive larval habitats that may \nwarrant special attention in urban areas. Discarded tyre", "page": 75, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "t special attention in urban areas. Discarded tyres should be collected, recycled \nor disposed of by proper incineration in waste transformation facilities (e.g. incinerators, \nenergy-production plants, or lime kilns fitted with emission control devices). Regulation of \nthe sale of new tyres mandating the payment of an additional deposit and return charge \nmay also be an incentive for better management and disposal of old tyres. Tyres can be \nrecycled in a variety of ways, including for use as s", "page": 75, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ycled in a variety of ways, including for use as shoe soles, flooring, industrial rubber \ngaskets or household hardware (e.g. buckets, rubbish bins). Industrially shredded tyres \ncan be incorporated into road surfacing materials. Sanitary regulations may require \nthat whole tyres are buried in a separate area of a landfill to avoid their rising upwards \nunder compaction and disrupting soil cover.\n3.2.1.4 Street cleansing\nA reliable and regular street cleansing system that removes discarded water", "page": 75, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "reet cleansing system that removes discarded water-bearing \ncontainers and cleans drains to ensure they do not become stagnant and breed \nmosquitoes will both help to reduce larval habitats of Ae. aegypti and remove the origin \nof other urban pests.\n3.2.1.5 Building structures\t\nDuring the planning and construction of buildings and other infrastructure, including urban \nrenewal schemes, and through legislation and regulation, opportunities arise to modify \nor reduce potential larval habitats of u", "page": 75, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "o modify \nor reduce potential larval habitats of urban disease vectors, including Ae. aegypti, \nCulex quinquefasciatus and An. stephensi. For example, under revised legislation in \nSingapore, roof gutters are not permitted on buildings in new developments because they \nare difficult to access and maintain. Moreover, property owners are required to remove \nexisting gutters on their premises if they are unable to maintain them satisfactorily.\n3.2.2 \tChemical control: larvicides\nAlthough chemicals", "page": 75, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "Chemical control: larvicides\nAlthough chemicals are widely used to treat Ae. aegypti larval habitats, larviciding \nshould be considered as complementary to environmental management and \u2013 except \nin emergencies \u2013 should be restricted to containers that cannot otherwise be eliminated \nor managed. Larvicides may be impractical to apply in hard-to-reach natural sites such \nas leaf axils and tree holes, which are common habitats of Ae. albopictus, or in deep \nwells. The difficulty of accessing indo", "page": 75, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "r in deep \nwells. The difficulty of accessing indoor larval habitats of Ae. aegypti (e.g. water-\nstorage containers, plant vases, saucers) to apply larvicides is a major limitation in many \nurban contexts.", "page": 75, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "64\nDengue: Guidelines for diagnosis, treatment, prevention and control\nAs Ae. aegypti often deposits eggs in water-storage containers, the larvicides should \nhave low toxicity to other species and should not significantly change the taste, odour \nor colour of the water. \nThe International Programme on Chemical Safety (IPCS) has assessed the toxicity of \nthe active ingredients methoprene, pyriproxyfen and temephos and those in Bacillus \nthuringiensis serovar israelensis (Bti) to determine their s", "page": 76, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "sis serovar israelensis (Bti) to determine their safety for use as mosquito larvicides \nin drinking-water at dosages that are effective against Aedes larvae. However, the \nsafety of the active ingredients in the final formulation varies from product to product and \nrequires further study, as does the possible microbiological contaminants in formulations \nof Bti. WHO\u2019s Guidelines for drinking-water quality (3) provide authoritative guidance \non the use of pesticides in drinking-water. Understanda", "page": 76, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "e use of pesticides in drinking-water. Understandably, placing chemicals in \ndomestic water, particularly drinking-water, is often viewed with suspicion and may be \nunacceptable in some communities. \n3.2.2.1 Target area\nProductive larval habitats should be treated with chemicals only if environmental \nmanagement methods or other non-chemical methods cannot be easily applied or \nare too costly. Perifocal treatment involves the use of hand-held or power-operated \nequipment to spray, for example, w", "page": 76, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "power-operated \nequipment to spray, for example, wettable powder or emulsifiable-concentrate \nformulations of insecticide on larval habitats and peripheral surfaces. This will destroy \nexisting and subsequent larval infestations in containers of non-potable water, and will \nkill the adult mosquitoes that frequent these sites. Perifocal treatment can be used to treat \ncontainers, irrespective of whether they hold water or are dry at the time of application. \nThe internal and external walls of con", "page": 76, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "plication. \nThe internal and external walls of containers are sprayed until they are covered by a \nfilm of insecticide, and spraying is also extended to cover any wall within 60 cm of \nthe container. Perifocal treatment thus has both larviciding and residual adulticiding \ncharacteristics. This method is suitable only for collections of non-potable water (such as \nin large piles of tyres or discarded food and beverage containers).\n3.2.2.2 Insecticides\n\t\nTable 3.2 lists the mosquito larvicides tha", "page": 76, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ides\n\t\nTable 3.2 lists the mosquito larvicides that are suitable for application to non-potable \nwater containers. For treatment of drinking-water, temephos and methoprene can \nbe applied at dosages of up to 1 mg of active ingredient (a.i.) per litre (1 ppm); \npyriproxyfen can be applied at dosages up to 0.01 mg a.i. per litre (0.01 ppm) and \nBti at1\u20135mg per litre\n3.2.2.3 Application procedures\nHand-operated compression sprayers are suitable for applying liquid insecticides to \nlarger larval hab", "page": 76, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "applying liquid insecticides to \nlarger larval habitats. Knapsack sprayers are also suitable, especially for delivering \nwettable powder formulations. A syringe or pipette can be used for treating indoor \nflower vases and ant traps. Granule and certain other solid formulations are applied \ndirectly by (protected) hand to confined larval habitats or by a convenient standard \nmeasure (e.g. a dessert spoon or teaspoon). When treating containers of drinking-\nwater, sufficient insecticide should be a", "page": 76, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "rinking-\nwater, sufficient insecticide should be added for the volume of the container even if the \ncontainer is not full of water (e.g. 1 g of 1% temephos granules for 10 litres of container \nvolume).", "page": 76, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "65\nChapter 3: Vector management and delivery of vector control services\nCHAPTER 3\n3.2.2.4 Treatment cycle\t\n\t\nThe treatment cycle will depend on the species of mosquito, seasonality of transmission, \npatterns of rainfall, duration of efficacy of the larvicide and types of larval habitat. \nTwo or three application rounds carried out annually in a timely manner with proper \nmonitoring of efficacy may suffice, especially in areas where the main transmission \nseason is short. \n3.2.2.5 Precautions\n\t\nE", "page": 77, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "mission \nseason is short. \n3.2.2.5 Precautions\n\t\nExtreme care must be taken when treating drinking-water to avoid dosages that are toxic \nfor humans. Label instructions must always be followed when using insecticides.\nTable 3.2 \t WHO-recommended compounds and formulations for control of mosquito larvae in \n\t\n\t\n\t\ncontainer habitatsa\n\t\nInsecticide\t\nFormulationb\t\nDosagec\t\nWHO hazard classification  \n\t\n\t\n\t\n\t\nof active ingredientd\n\t\nOrganophosphates\n\t\nPirimiphos-methyl\t\nEC\t\n1\t\nIII\n\t\nTemephos\t\nEC, GR", "page": 77, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "Pirimiphos-methyl\t\nEC\t\n1\t\nIII\n\t\nTemephos\t\nEC, GR\t\n1\t\nU\n\t\nInsect growth regulators\n\t\nDiflubenzuron\t\nDT, GR, WP\t\n0.02\u20130.25\t\nU\n\t\nrs-methoprenee\t\nEC\t\n1\t\nU\n\t\nNovaluron\t\nEC\t\n0.01\u20130.05\t\nNA\n\t\nPyriproxyfene\t\nGR\t\n0.01\t\nU\n\t\nBiopesticides\n\t\nBacillus thuringiensis israelensise\t\nWG\t\n1\u20135 mg/L\t\nU\n\t\nSpinosad\t\nDT, GR, SC\t\n0.1-0.5\t\nU\na\t WHO recommendations on the use of pesticides in public health are valid only if linked to WHO specifications for their quality \t\n\t control. WHO specifications for public health pe", "page": 77, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "control. WHO specifications for public health pesticides are available at http://www.who.int/whopes/quality/en/. Label \t\n\t\n\t instructions must always be followed when using insecticides.\nb \tDT = tablet for direct application; GR = granule; EC = emulsifiable concentrate; WG = water-dispersible granule; WP = wettable \t\n\t powder; SC = suspension concentrate.\nc \tmg/L of active ingredient for control of container-breeding mosquitoes.\nd \tClass II = moderately hazardous; Class III = slightly hazardou", "page": 77, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "oderately hazardous; Class III = slightly hazardous; Class U = unlikely to pose an acute hazard in normal use; NA = not \t\n\t available.\ne \tCan be used at recommended dosages in potable water.\n3.2.3 \tChemical control: adulticides\nMethods of chemical control that target adult vectors are intended to impact on mosquito \ndensities, longevity and other transmission parameters. Adulticides are applied either as \nresidual surface treatments or as space treatments.", "page": 77, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "reatments.", "page": 77, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "66\nDengue: Guidelines for diagnosis, treatment, prevention and control\n3.2.3.1 Residual treatment\nPerifocal treatment, as described above, has both adulticiding and larviciding effects. \nSuitable insecticides can be applied with hand-operated compression sprayers. Power \nsprayers can be used to treat large accumulations of discarded containers (e.g. tyre \ndumps) rapidly. Care must be taken not to treat containers used to store potable water.\n3.2.3.2 Space sprays and their application \nSpace spra", "page": 78, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "3.2 Space sprays and their application \nSpace spraying is recommended for control only in emergency situations to suppress \nan ongoing epidemic or to prevent an incipient one. The objective of space spraying is \nthe massive, rapid destruction of the adult vector population. However, there has been \nconsiderable controversy about the efficacy of aerosol insecticide applications during \nepidemics of dengue and yellow fever. Any control method that reduces the number \nof infective adult mosquitoes,", "page": 78, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "reduces the number \nof infective adult mosquitoes, even for a short time, should reduce virus transmission \nduring that time, but it remains unclear whether the transient impact of space treatments \nis epidemiologically significant in the long run. There is no well-documented example \nof the effectiveness of this approach in interrupting an epidemic. Nevertheless, if space \nspraying is used early in an epidemic and on a sufficiently large scale, the intensity of \ntransmission may be reduced, whi", "page": 78, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "the intensity of \ntransmission may be reduced, which would give time for the application of other vector \ncontrol measures that provide longer-term control, including larviciding and community-\nbased source reduction. Thus, if disease surveillance is sensitive enough to detect cases \nin the early stages of an epidemic, and if the resources are available, emergency space \nspraying can be initiated at the same time as source reduction measures and larviciding \nare intensified. \nNot only  insectici", "page": 78, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "larviciding \nare intensified. \nNot only  insecticide susceptibility but also droplet size, application rate and indoor \npenetration of the insecticide are all crucial to the efficacy of this method for controlling \nAe. aegypti. Indoor penetration of an insecticide depends on the structure of the \nbuilding, whether doors and windows are left open during spraying and, when applied \nfrom vehicle-mounted equipment, residential block configuration, the route of the spray \nvehicle and meteorological c", "page": 78, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "e route of the spray \nvehicle and meteorological conditions. Where indoor penetration of droplets is likely to \nbe poor, indoor application with portable equipment will be more effective against Ae. \naegypti. However, rates of coverage are much lower and accessibility may be difficult, \nparticularly in large cities.\nVector populations can be suppressed over large areas by the use of space sprays \nreleased from low-flying aircraft, especially where access with ground equipment is \ndifficult and e", "page": 78, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "e access with ground equipment is \ndifficult and extensive areas must be treated rapidly. Indoor penetration of insecticide \ndroplets is again a critical factor for efficacy. In applying space sprays from the air, \ncareful consideration must be given to meteorological conditions, especially wind speed \nat spray height and at ground level, and to the droplet size spectrum obtained at \nthe flying speed of the aircraft. For all aerial spraying operations, clearance must be \nobtained from the civil", "page": 78, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "tions, clearance must be \nobtained from the civil aviation authority. For safety reasons, populated areas must \nusually be sprayed from twin-engined aircraft. Modern aircraft are fitted with global \npositioning systems so the exact position of the aircraft while the insecticide is being \napplied can be accurately recorded.", "page": 78, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "67\nChapter 3: Vector management and delivery of vector control services\nCHAPTER 3\nTarget area\nSince total coverage can rarely be achieved during ground applications, space spraying \nshould focus on areas where people congregate (e.g. high-density housing, schools, \nhospitals) and where dengue cases have been reported or vectors are abundant. \nSelective space treatment up to 400 metres from houses in which dengue cases have \nbeen reported is commonly practised (and is sometimes also referred to a", "page": 79, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "nly practised (and is sometimes also referred to as \u201cperifocal \nspraying\u201d). However, by the time a case is detected and a response mounted, the \ninfection is likely to have spread to a wider area. Thorough planning is required to \nensure that adequate resources (equipment, insecticide, human and financial resources) \ncan be deployed in a timely manner to ensure proper coverage. Only if resources permit \nshould area-wide treatment be considered.\nInsecticides\nTable 3.3 lists the insecticides that", "page": 79, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "nsecticides\nTable 3.3 lists the insecticides that are suitable for space spraying as cold aerosols or \nthermal fogs. The choice of insecticide formulation for space spraying in and around \ndwellings should be based on its immediate environmental impact and the compliance \nof the community. Only insecticide products with high flash-points should be used for \nthermal fogging. Space-spraying formulations are usually oil-based, as the oil carrier \ninhibits evaporation of small fog droplets. Diesel f", "page": 79, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "hibits evaporation of small fog droplets. Diesel fuel has been used as a carrier for \nthermal fogging agents, but it creates thick smoke, has a strong smell and creates oily \ndeposits, which may lead the community to reject its use. Water-based formulations are \nalso available, some of which contain substances that prevent rapid evaporation. Label \ninstructions should always be followed when using insecticides.\nApplication procedures\nSpace sprays can be applied either as thermal fogs at 10\u201350 l/", "page": 79, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "can be applied either as thermal fogs at 10\u201350 l/ha or as ultra-low-\nvolume applications of undiluted or slightly diluted technical-grade insecticide in the \nform of a cold aerosol of droplets of controlled size (15\u201325 \u00b5m) at a rate of 0.5\u2013\n2.0 l/ha. Portable or vehicle-mounted thermal or cold-fog generators can be used \nfor ground application. If the target area exceeds 1000 ha or cannot be covered \nby ground equipment within 10 days, aerial cold fog application is sometimes used. \nHowever, se", "page": 79, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ld fog application is sometimes used. \nHowever, several factors must first be considered \u2013 including safety, timeliness, cost, \nmeteorological conditions, vector behaviour, biological effectiveness and availability of \nequipment, operational sites, and highly skilled air and ground crews. The difficulties \nof ensuring penetration of insecticide droplets into the resting sites of the target species \nare similar to those for aerosols dispensed from road vehicles. For ground applications, \nmaps of", "page": 79, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "road vehicles. For ground applications, \nmaps of the areas to be sprayed showing all passable roads are helpful in planning \nroutes. The development of Geographic Information Systems (GIS) may also be helpful. \nA communication plan should be prepared to inform the population, encouraging them \nto open their doors and windows in order to improve the effectiveness of the spraying \nprogramme. \nApplication rates vary with the susceptibility of the target species and environmental \nconsiderations. W", "page": 79, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "arget species and environmental \nconsiderations. Wind speed has a strong effect on droplet distribution and contact \nwith insects. In most situations, a wind speed of 1\u20134 metres per second (approximately", "page": 79, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "68\nDengue: Guidelines for diagnosis, treatment, prevention and control\n3.6\u201315 km/h) is needed to drift droplets downwind from the line of travel. Furthermore, \nspace sprays should be applied when there are temperature inversions \u2013 i.e. colder \nair closer to the ground \u2013 which occur early in the morning or in the evening when \nthe ground temperature begins to fall. Space spray applications should correspond to \nthe activity of the target species. Ae. aegypti and Ae. albopictus are active during t", "page": 80, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "Ae. aegypti and Ae. albopictus are active during the \nday, with peak flight activity in the morning and afternoon. For these species, spraying \noutdoors is therefore usually carried out in the early morning or late afternoon. Indoor \ntreatments with portable cold or thermal fog generators are particularly effective against \nAe. aegypti because its resting behaviour is mainly indoors. Indoor treatments are the \nonly choice where there is no access for vehicles. \nFor application from vehicle-mount", "page": 80, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "for vehicles. \nFor application from vehicle-mounted equipment in areas with narrow roads and houses \nclose to the roadside, the spray should be directed backwards from the vehicle. In areas \nwith wide roads and buildings far from the roadside, the vehicle should be driven close \nto the side of the road and the spray should be directed at a right angle (downwind) to \nthe road rather than directly behind the vehicle. More detailed information on operational \nguidelines for space spraying is avail", "page": 80, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "perational \nguidelines for space spraying is available in the WHO manual on this subject (5). \nCold fog applications from large fixed-wing aircraft are made at approximately 240 \nkm/h and 60 m above the ground, with swath spacing of 180 m. Smaller, fixed-wing \naircraft are flown at slower speeds and usually lower altitudes (approximately 160 \nkm/h, 30 m above the ground, with a swath width of 50\u2013100 m). In emergencies, \nagricultural spraying aircraft can be used so long as they are fitted with r", "page": 80, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "raft can be used so long as they are fitted with rotary atomizers \nor other suitable nozzles calibrated for the insecticide, its formulation and the desired \napplication rate. \nTreatment cycle\nWhen a rapid reduction in vector density is essential, such as in emergencies, space \ntreatment should ideally be carried out every 2\u20133 days for 10 days. Further applications \nshould then be made once or twice a week to sustain suppression of the adult vector \npopulation. Continuous entomological and epide", "page": 80, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "or \npopulation. Continuous entomological and epidemiological surveillance should be \nconducted, however, to determine the appropriate application schedule and the \neffectiveness of the control strategy.\nPrecautions\nOperators who carry out house-to-house space spraying using portable equipment \nshould wear face masks in addition to normal protective clothing and should operate \nthe equipment for short periods only. Fogging with vehicle-mounted equipment in urban \nareas can be a traffic hazard, an", "page": 80, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ipment in urban \nareas can be a traffic hazard, and spotting of vehicle paintwork may result, particularly \nwhen large droplets are used. Ultra-low-volume aerial applications should be made only \nby highly skilled pilots trained to undertake spraying at the proper speeds and heights. \nClearance from the local civil aviation authority must be sought. Ground reconnaissance \nshould be made before treatment and the public advised to safeguard non-target animals \nand beehives.", "page": 80, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "get animals \nand beehives.", "page": 80, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "69\nChapter 3: Vector management and delivery of vector control services\nCHAPTER 3\nTable 3.3\t Selected insecticides for cold aerosol or thermal fog application against mosquitoesa\n\t\nInsecticide\t\nChemical\t\nDosage of active ingredient (g/ha)\t\nWHO hazard \t \t\n\t\n\t\n\t\n\t\n\t\nclassification  \n\t\n\t\n\t\nCold aerosols\t\nThermal fogsb\t\nof active ingredientc\n\t\nFenitrothion\t\nOrganophosphate\t\n250\u2013300\t\n250\u2013300\t\nII\n\t\nMalathion\t\nOrganophosphate\t\n112\u2013600\t\n500\u2013600\t\nIII\n\t\nPirimiphos-methyl\t\nOrganophosphate\t\n230\u2013330\t\n180\u2013200", "page": 81, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "rimiphos-methyl\t\nOrganophosphate\t\n230\u2013330\t\n180\u2013200\t\nIII\n\t\nBioresmethrin\t\nPyrethroid\t\n5\t\n10\t\nU\n\t\nCyfluthrin\t\nPyrethroid\t\n1\u20132\t\n1\u20132\t\nII\n\t\nCypermethrin\t\nPyrethroid\t\n1\u20133\t\n\u2013\t\nII\n\t\nCyphenothrin\t\nPyrethroid\t\n2\u20135\t\n5\u201310\t\nII\n\t\nd,d-trans-Cyphenothrin\t Pyrethroid\t\n1\u20132\t\n2.5\u20135\t\nNA\n\t\nDeltamethrin\t\nPyrethroid\t\n0.5\u20131.0\t\n0.5 \u2013 1.0\t\nII\n\t\nD-Phenothrin\t\nPyrethroid\t\n5\u201320\t\n\u2013\t\nU\n\t\nEtofenprox\t\nPyrethroid\t\n10\u201320\t\n10\u201320\t\nU\n\t\n\u03bb-Cyhalothrin\t\nPyrethroid\t\n1.0\t\n1.0\t\nII\n\t\nPermethrin\t\nPyrethroid\t\n5\t\n10\t\nII\n\t\nResmethrin\t\nPyrethroi", "page": 81, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "rin\t\nPyrethroid\t\n5\t\n10\t\nII\n\t\nResmethrin\t\nPyrethroid\t\n2\u20134\t\n4\t\nIII\na\t Adapted from: Pesticides and their application for the control of vectors and pests of public health importance (6). Label instructions \t\n\t must always be followed when using insecticides.\nb \tThe strength of the finished formulation when applied depends on the performance of the spraying equipment used.\nc \tClass II = moderately hazardous; class III = slightly hazardous; class U = unlikely to pose an acute hazard in normal use;", "page": 81, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "unlikely to pose an acute hazard in normal use;  \n\t NA = not available.\n3.2.4 \tSafe use of insecticides\nAll pesticides are toxic to some degree. Safety precautions for their use \u2013 including \ncare in the handling of pesticides, safe work practices for those who apply them, \nand appropriate field application \u2013 should be followed. A safety plan for insecticide \napplication can be organized along the following lines:\n \n\u2022 Instructions on pesticide labels should be followed carefully.\n \n\u2022 Spray opera", "page": 81, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "bels should be followed carefully.\n \n\u2022 Spray operators should be provided with at least two uniforms to allow for   \n\t\n\t\nfrequent changes.\n \n\u2022 Safety gloves, goggles and masks should be used for high-exposure activities  \n\t\n\t\nsuch as machine calibration.\n \n\u2022 Changing and washing facilities should be available.\n \n\u2022 All work clothes should be removed at the end of each day\u2019s operations and a  \n\t\n\t\nshower or bath taken.\n \n\u2022 Work clothes should be washed regularly, preferably daily.\n \n\u2022 Particular a", "page": 81, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "shed regularly, preferably daily.\n \n\u2022 Particular attention should be given to washing gloves, as wearing contaminated \n \n\t\n\t\ngloves can be dangerous.\n \n\u2022 Spray operators should wash their hands and face before eating and should not \n\t\n\t\nsmoke during work hours.\n \n\u2022 Spray operators should not be exposed to toxic material for periods that are  \n\t\n\t\nlonger than recommended.\n \n\u2022 Care must be taken in disposing of used insecticide containers.\n \n\u2022 After each day\u2019s operation, any unused liquid larvicid", "page": 81, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "r each day\u2019s operation, any unused liquid larvicide should be disposed of  \n\t\n\t\nsafely.", "page": 81, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "70\nDengue: Guidelines for diagnosis, treatment, prevention and control\n \n\u2022 Blood cholinesterase levels should be monitored if organophosphate insecticides \n\t\n\t\nare used.\n \n\u2022 Operator supervision by a well-trained individual is essential.\n \n\u2022 During and immediately after indoor space spray operations, householders and  \n\t\n\t\npets must remain outside the dwelling.\nWHO has published specific guidelines on use of insecticides and safety procedures \n(3\u20137).\n3.2.5 \tMonitoring of insecticide susceptibili", "page": 82, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "\u20137).\n3.2.5 \tMonitoring of insecticide susceptibility\nInsecticides have been used widely for dengue vector control since their development. \nAs a result, insecticide-resistant populations of Ae. aegypti have been detected in a \nnumber of countries. Operationally significant levels of resistance to organophosphates, \npyrethroids, carbamates and organochlorines have been documented. \nInsecticide resistance must be considered as a potentially serious threat to effective \ndengue vector control. Routi", "page": 82, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "threat to effective \ndengue vector control. Routine monitoring of insecticide susceptibility should be integral \nto any programme. \nIn countries with a history of extensive DDT use, resistance may be widespread. Also, \nDDT resistance may predispose to pyrethroid resistance, since both insecticides have \nthe same target site (the voltage gated sodium channel) and both have been associated \nwith mutations in the kdr gene in Ae. aegypti. Consequently, in countries such as \nThailand where pyrethroi", "page": 82, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ly, in countries such as \nThailand where pyrethroids \u2013 including deltamethrin, cypermethrin and permethrin \u2013 are \nincreasingly being used in favour of organophosphates for space spraying, pyrethroid \nresistance is likely to occur sooner in mosquito populations that already have this mutation. \nThis phenomenon reinforces the importance of carrying out routine susceptibility testing \nat regular intervals during any control programme. \nWHO kits for testing the susceptibility of adult and larval mos", "page": 82, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "testing the susceptibility of adult and larval mosquitoes remain the standard \nmethods for determining the susceptibility status of Aedes populations. Instructions on \ntesting and for purchasing kits, test papers and solutions are available to order from \nWHO1.  \n3.2.6 \tIndividual and household protection\nClothing that minimizes skin exposure during daylight hours when mosquitoes are most \nactive affords some protection from the bites of dengue vectors and is encouraged \nparticularly during outb", "page": 82, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ectors and is encouraged \nparticularly during outbreaks. Repellents may be applied to exposed skin or to clothing. \nRepellents should contain DEET (N, N-diethyl- 3-methylbenzamide), IR3535 (3-[N-\nacetyl-N-butyl]-aminopropionic acid ethyl ester) or Icaridin (1-piperidinecarboxylic acid, \n2-(2-hydroxyethyl)-1-methylpropylester). The use of repellents must be in strict accordance \nwith label instructions. Insecticide-treated mosquito nets afford good protection for those \nwho sleep during the day (", "page": 82, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "d protection for those \nwho sleep during the day (e.g. infants, the bedridden and night-shift workers). \nWhere indoor biting occurs, household insecticide aerosol products, mosquito coils or \nother insecticide vaporizers may also reduce biting activity. Household fixtures such as \nwindow and door screens and air-conditioning can also reduce biting.\nSupplies for monitoring insecticide resistance in disease vectors: procedures and conditions. Geneva, World Health \nOrganization, 2002. Accessible at", "page": 82, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "a, World Health \nOrganization, 2002. Accessible at: http://www.who.int/whopes/resistance/en/WHO_CDS_CPE_PVC_2001.2.pdf", "page": 82, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "71\nChapter 3: Vector management and delivery of vector control services\nCHAPTER 3\n3.2.7 \tBiological control\nBiological control is based on the introduction of organisms that prey upon, parasitize, \ncompete with or otherwise reduce populations of the target species. Against Aedes \nvectors of dengue, only certain species of larvivorous fish and predatory copepods \n(Copepoda: Cyclopoidea) \u2013 small freshwater crustaceans \u2013 have proved effective in \noperational contexts in specific container habitats,", "page": 83, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "erational contexts in specific container habitats, and even then seldom on a large \nscale. While biological control avoids chemical contamination of the environment, there \nmay be operational limitations \u2013 such as the expense and task of rearing the organisms \non a large scale, difficulty in applying them and their limited utility in aquatic sites \nwhere temperature, pH and organic pollution may exceed the narrow requirements of \nthe organism. Biological control methods are effective only agains", "page": 83, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ological control methods are effective only against the immature stages \nof vector mosquitoes in the larval habitat where they are introduced. Importantly, the \nbiological control organisms are not resistant to desiccation, so their utility is mainly \nrestricted to container habitats that are seldom emptied or cleaned, such as large \nconcrete or glazed clay water-storage containers or wells. The willingness of local \ncommunities to accept the introduction of organisms into water containers is es", "page": 83, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "roduction of organisms into water containers is essential; \ncommunity involvement is desirable in distributing the fish or copepods, and monitoring \nand restocking containers when necessary. \n3.2.7.1 Fish\nA variety of fish species have been used to eliminate mosquitoes from larger containers \nused to store potable water in many countries, and in open freshwater wells, concrete \nirrigation ditches and industrial tanks. The viviparous species Poecilia reticulata adapts \nwell to these types of conf", "page": 83, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "lia reticulata adapts \nwell to these types of confined water bodies and has been most commonly used. Only \nnative larvivorous fish should be used because exotic species may escape into natural \nhabitats and threaten the indigenous fauna. WHO has published further information on \nthe use of fish for mosquito control (8).\n3.2.7.2 Predatory copepods\nVarious predatory copepod species have also proved effective against dengue vectors \nin operational settings. However, although copepod populations can", "page": 83, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ettings. However, although copepod populations can survive for long \nperiods, as with fish, reintroductions may be necessary for sustained control. A vector \ncontrol programme in northern Viet Nam using copepods in large water-storage tanks, \ncombined with source reduction, successfully eliminated Ae. aegypti in many communes \nand has prevented dengue transmission for a number of years. To date, these successes \nhave not been replicated in other countries.\n3.2.8 \tTowards improved tools for vecto", "page": 83, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "countries.\n3.2.8 \tTowards improved tools for vector control\nSome promising new dengue vector control tools are the subject of operational research \nbut have not been sufficiently well field-tested under programmatic conditions for \nrecommendations to be made for their use as public health interventions. In 2006, \na WHO/TDR Scientific Working Group identified major streams of recommended \nresearch on dengue, including in the area of vector control (9).", "page": 83, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "(9).", "page": 83, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "72\nDengue: Guidelines for diagnosis, treatment, prevention and control\n3.2.8.1 Insecticide-treated materials\nInsecticide-treated materials (ITMs), typically deployed as insecticide-treated bednets, \nhave proved highly effective in preventing diseases transmitted by nocturnally active \nmosquitoes. Research on the efficacy of ITMs in controlling diurnally active Ae. aegypti \nis being encouraged. There is accumulating evidence that insecticide-treated window \ncurtains (net curtains hung in windows,", "page": 84, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ed window \ncurtains (net curtains hung in windows, over any existing curtains if necessary) and \nlong-lasting insecticidal fabric covers for domestic water-storage containers can reduce \ndengue vector densities to low levels in some communities \u2013 with prospects for reducing \ndengue transmission risk. Curtains also provide personal protection in the home. \nAlthough more studies are needed to confirm that transmission can be reduced by this \ntype of intervention, ITMs appear to hold promise for de", "page": 84, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "f intervention, ITMs appear to hold promise for dengue prevention and control. In \nstudies in Mexico and Venezuela, ITMs (particularly curtains) were well accepted by the \ncommunities as their efficacy was reinforced by the reduction of other biting insects as \nwell as cockroaches, houseflies and other pests (10).\nThe location or type of ITM need not be limited to those described or tested to date. \nWindow curtains, screens, and doorway or wardrobe curtains, etc. all appear to \nwarrant investiga", "page": 84, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "be curtains, etc. all appear to \nwarrant investigation in different settings. If the application of these interventions is \nshown to be efficacious and cost-effective, it may offer additional prospects for dengue \nvector control in the home, workplace, schools, hospitals and other locations, and allow \nfor the selection of the most appropriate ITMs by the communities that will use them.\n3.2.8.2 Lethal ovitraps\nThe ovitrap or oviposition trap used for surveillance of Aedes vectors can be modified", "page": 84, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "for surveillance of Aedes vectors can be modified \nto render it lethal to immature or adult populations of Ae. aegypti. Lethal ovitraps (which \nincorporate an insecticide on the oviposition substrate), autocidal ovitraps (which allow \noviposition but prevent adult emergence), and sticky ovitraps (which trap the mosquito \nwhen it lands) have been used on a limited basis. Studies have shown that population \ndensities can be reduced with sufficiently large numbers of frequently-serviced traps. Lif", "page": 84, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ly large numbers of frequently-serviced traps. Life \nexpectancy of the vector may also potentially be shortened, thus reducing the number of \nvectors that become infective. In Singapore, ovitraps used as a control device reportedly \neliminated Ae. aegypti from the international airport, but this level of success has not \nbeen repeated elsewhere (11). In Brazil, lethal ovitraps with deltamethrin-treated ovistrips \nsubstantially reduced adult densities of Ae. aegypti and produced almost 100% larva", "page": 84, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ties of Ae. aegypti and produced almost 100% larval \nmortality during a one-month field trial (12). The potential advantages of lethal ovitraps \nfor controlling Aedes vectors include their simplicity, their specificity for and effectiveness \nagainst container breeders such as Ae. aegypti, and the prospect of their integration \nwith other chemical or biological control methodologies.\n3.3 Delivery of vector control interventions\nWhereas section 3.1 describes the main methods used in dengue vector", "page": 84, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "describes the main methods used in dengue vector control, section \n3.2 focuses on the management approaches to their delivery, including intrasectoral \nas well as intersectoral collaboration. Table 3.4 summarizes vector surveillance and \ncontrol activities and their purposes. Further details of entomological surveillance and \nemergency vector control are described in Chapter 5.", "page": 84, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "73\nChapter 3: Vector management and delivery of vector control services\nCHAPTER 3\n3.3.1 Links to epidemiological services\nVector control services should be closely linked to epidemiological services that capture \nand analyse the occurrence of dengue cases (temporal and spatial information). \nThe epidemiological surveillance system should be able to differentiate between \ntransient and seasonal increases in disease incidence and increases observed at the \nbeginning of a dengue outbreak. One such", "page": 85, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "at the \nbeginning of a dengue outbreak. One such approach is to track the occurrence of \ncurrent (probable) cases and compare them with the average number of cases by week \n(or month) of the preceding 5\u20137 years, with confidence intervals set at two standard \ndeviations above and below the average (\u00b12 SD). This is sometimes referred to as the \n\u201cendemic channel\u201d. If the number of cases reported exceeds 2 SDs above the \u201cendemic \nchannel\u201d in weekly or monthly reporting, an outbreak alert is trigger", "page": 85, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "or monthly reporting, an outbreak alert is triggered. Figure 3.1 is an \nexample from the surveillance system in Puerto Rico in 2007\u20132008. Such an approach \nis epidemiologically far more meaningful than year-to-year comparisons of cumulative \ntotals of reported cases. \nFigure 3.1 Surveillance data for dengue outbreak alerts, Puerto Rico, 2007\u20132008a\na Reproduced by kind permission of Centers for Disease Control and Prevention (CDC), Division of Vector-Borne Infectious Diseases,  \nSan Juan, Puerto", "page": 85, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "tor-Borne Infectious Diseases,  \nSan Juan, Puerto Rico.\nNotified cases\n1\t\n6\t\n11\t\n16\t\n21\t\n26\t\n31\t\n36\t\n41\t\n46\t\n51\t\nWeek of first symptom\n0\t\n200\t\n600\n2007\n2008\nHistorical average\nEpidemic threshold", "page": 85, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "74\nDengue: Guidelines for diagnosis, treatment, prevention and control\nTable 3.4\t Vector control services: activities and purpose\n\t Area of activity\t\nSpecific activity\t\nPurpose\n\t Entomology\t\n\t\n\t Entomological surveillance\t\n1. Presence/absence of larvae and/or pupae\t\nTo describe levels of infestation and ecology of immature development stages\n\t \t\n\t\nTo monitor impact of vector control \n\t \t\n2. Number of pupae\t\nTo describe levels of infestation and to identify the most adult-productive \t\t\n\t \t\n\t\ncont", "page": 86, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "o identify the most adult-productive \t\t\n\t \t\n\t\ncontainer categories\n\t \t\n\t\nTo focus vector control activities on the most epidemiologically important \t\n\t\n\t \t\n\t\ncontainer categories to contribute to the estimation of transmission risk\n\t \t\n3. Relative adult abundance over time\t\nTo measure impact of vector control activities, seasonal and diel activity\n\t \t\n4. Insecticide susceptibility (larvae and adults)\t\nTo monitor for insecticide resistance and its management\n\t Routine vector control \t\n1. Controll", "page": 86, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "management\n\t Routine vector control \t\n1. Controlling the immature stages\t\nTo reduce the vector population to levels at which transmission of virus is \t\n\t\n\t operations\t\n\t\nlowered or prevented\n\t \t\n2. Controlling adults\t\nTo reduce adult survival to lower vectorial capacity (for transmission of virus)\n\t Emergency vector control \t\n1. Controlling the immature stages\t\nTo rapidly reduce vector population to slow/contain/interrupt transmission, \t\n\t operations\t\n2. Controlling adults\t\nor prevent incipient", "page": 86, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "tions\t\n2. Controlling adults\t\nor prevent incipient outbreak\n\t \t\n\t Collaboration \t\n\t\n\t Communication and social \t\nDesign communication strategies and tools to inform and mobilize \t\nTo increase awareness and collaboration with recommended actions \n\t mobilization\t\ncommunities and other partners/sectors for vector control, personal  \n\t \t\nprotection, and case management.\n\t Epidemiological surveillance\t\n1. Passive surveillance data\t\n- describe trends and burden of disease\n\t \t\n- clinical reporting of d", "page": 86, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "nd burden of disease\n\t \t\n- clinical reporting of dengue cases (probable or confirmed dengue \t\n- detect areas of transmission  \n\t \t\nand severe dengue)\t\n- outbreak detection/prediction\n\t \t\n- laboratory reporting on confirmed dengue cases/ serotypes.\t\n- guide epidemiological stratification\n\t \t\n2. Active surveillance data\n\t \t\n- case report verification\n\t \t\n- active case-finding\n\t \t\n- specific studies.\n\t Support \t\n\t\n\t Interagency coordination\t\nCoordination between different national and international", "page": 86, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ation between different national and international agencies  \t\nTo increase coordination between different players \n\t \t\ninvolved in dengue control\t\nTo reduce overlap of interventions and wastage of resources\n\t Innovation\t\nAssessment of novel techniques for use in the national context\t\nTo increase the uptake of novel techniques\n\t Capacity-training\t\nRolling programme of training in techniques for vector control services\t\nTo ensure appropriate training and retraining of personnel\n\t Monitoring and ev", "page": 86, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ng and retraining of personnel\n\t Monitoring and evaluation\t\nContinuous monitoring and evaluation of vector control services according \t\nTo ensure that programmes achieve what they should  \n\t \t\nto established programme criteria and indicators\n\t Logistics\t\nSupport of vector control services \t\nTo ensure appropriate logistical support\n\t Administration and finances\t\nSupport of vector control services\t\nTo ensure appropriate administrative and financial support", "page": 86, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "support", "page": 86, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "75\nChapter 3: Vector management and delivery of vector control services\nCHAPTER 3\nThe spatial patterning of health events and disease outcomes has a long history. \nThe development of GIS has facilitated the inclusion of a spatial component in \nepidemiological, entomological and environmental studies. A GIS is a collection of \ncomputer hardware, software and geographical data used for capturing, managing, \nanalysing and displaying all forms of geographically referenced information. It allows \nuse", "page": 87, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "graphically referenced information. It allows \nusers to choose different layers of information and to combine them according to what \nquestions need to be answered or what data need to be analysed. Figure 3.2 describes \nthe workings of a GIS.\nIn setting up a GIS to support vector control services, data are organized in different \nlayers to describe features such as streets, residences, buildings, train stations, schools, \nconstruction sites, shopping centres, medical clinics and electoral divisi", "page": 87, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ping centres, medical clinics and electoral divisions. Above these \nbase layers can be added entomological data, case data, virus serotype, enforcement \ndata, demographics, weather data and so on. \nFigure 3.3 shows a snapshot of a GIS map with eight layers of data used to support \nvector control operations in Singapore.\nFigure 3.2 Geographical information system (GIS), Singaporea\na Reproduced by kind permission of ESRI South Asia Pte Ltd, Singapore.\nPoints\nPolygons\nLines\nGIS allows the layering", "page": 87, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "re.\nPoints\nPolygons\nLines\nGIS allows the layering of health, demographic and environmental data sources to be analysed by their \nlocation on earth\u2019s surface.", "page": 87, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "76\nDengue: Guidelines for diagnosis, treatment, prevention and control\nGIS are widely used in public health to map diseases with different pathologies, to \nanalyse the distribution of disease data in space and space-time, to identify risk factors \nand to map areas of risk. Typically, each case is located at either the residential or \nwork address, and these locations are integrated into a GIS for mapping and analysis. \nBecause a GIS allows epidemiologists to map environmental risk factors associ", "page": 88, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "iologists to map environmental risk factors associated \nwith disease vectors \u2013 such as construction sites, derelict or uninhabited premises and \nareas of congregation \u2013 it is especially relevant for the surveillance of vector-borne \ndiseases such as dengue and malaria. For dengue, such mapping (epidemiological, \nentomological and environmental stratification) can serve to identify areas where \ntransmission repeatedly occurs and which may warrant intensified or targeted control \nactivities, or to", "page": 88, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "intensified or targeted control \nactivities, or to stratify areas based on characteristics of larval habitats. The availability \nof such information in a timely manner could determine the outcome of vector control \noperations and even help to reduce the intensity of outbreaks. GIS technology has \nbeen found particularly useful for planning vector control operations, for managing and \ndeploying resources for dengue control, and for presenting the dengue situation of any \nlocality. \nFree-access co", "page": 88, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "dengue situation of any \nlocality. \nFree-access computer software programs are available; some software packages and \nmaps can be downloaded from the Internet. Some dengue control programmes use \nhand-held global positioning system (GPS) devices and other hand-operated computer \nequipment to record data that are uploaded to a central database.\nFigure 3.3 \t\nSnapshot of geographical information system (GIS) mapping, Singaporea\na Reproduced by kind permission of the National Environment Agency, Sin", "page": 88, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "permission of the National Environment Agency, Singapore.", "page": 88, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "77\nChapter 3: Vector management and delivery of vector control services\nCHAPTER 3\nWhere such resources are unavailable, commercial or hand-drawn maps may be used, \nwith pins or labels indicating reported data.\n3.3.2\t Advocacy, social mobilization and legislation\nAdvocacy is a process through which groups of stakeholders can be influenced to \ngain support for and reduce barriers to specific initiatives or programmes. Multiple \nstrategies, often used simultaneously, are key to the success of any a", "page": 89, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ed simultaneously, are key to the success of any advocacy effort. \nStrategies may include social mobilization and administrative, legislative, regulatory, \nlegal and media advocacy (13). While there may be different target audiences and \neven different objectives for the strategies, it is the coordination of actions that leads to \nthe achievement of the overarching goal of the strategic advocacy effort. Some actions \nmay have a longer time frame \u2013 such as legislative and regulatory advocacy to a", "page": 89, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "\u2013 such as legislative and regulatory advocacy to address \ntyre disposal at national level \u2013 while others such as mobilizing local authorities and \nresidents to carry out specific actions before the start of the rainy season may be time-\nlimited. \nA strategic advocacy plan usually includes one or more of the following types of \nadvocacy (Table 3.5 shows examples of advocacy efforts in Asia and Latin America):\n \n\u2022 Social mobilization \u2013 brings people together to achieve a common goal with a \t\n\t\n\t\ns", "page": 89, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "e together to achieve a common goal with a \t\n\t\n\t\nshared interpretation and direction. \n \n\u2022 Administrative advocacy \u2013 informs authorities, decision-makers and opinion \t\n\t\n\t\nleaders of the importance of the programme, the costs and benefits of its activities \n\t\n\t\nand programme needs in order to enlist their support and cooperation. \n \n\u2022 Legislative advocacy \u2013 uses federal/state/provincial/departmental/local \t\t\n\t\n\t\nlegislative processes to promote legislation that addresses issues beyond the", "page": 89, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "egislation that addresses issues beyond the \t\n\t\n\t\nresponsibility of any one governmental entity (e.g. legislation to address tyre \t\n\t\n\t\ndisposal at national or regional level, the establishment of sanitary landfills, or \t\n\t\n\t\nthe modification of housing designs or water catchment and storage systems). \n \n\u2022 Regulatory advocacy \u2013 creates rules through which legislation is implemented \t\n\t\n\t\n(e.g. efforts to implement or modernize existing sanitary laws).\n \n\u2022 Legal advocacy \u2013 uses the judicial syste", "page": 89, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "aws).\n \n\u2022 Legal advocacy \u2013 uses the judicial system to enforce sanitary legislation and \t\n\t\n\t\nregulations (e.g. fines on contractors whose building construction sites persistently \n\t\n\t\nharbour aquatic foci of dengue vectors, or on householders and estates that fail \t\n\t\n\t\nto prevent mosquito breeding on their premises).\n \n\u2022 Media advocacy \u2013 systematically engages the media to place issues of community \n \n\t\n\t\ninterest on the social agenda, with a view to influencing public agendas. One \t\n\t\n\t\nsuch", "page": 89, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "iew to influencing public agendas. One \t\n\t\n\t\nsuch example, although not dengue-specific, is the PAHO Caribbean Media \t\n\t\n\t\nAwards for Health Journalism, an annual prize-giving event involving all mass \t\n\t\n\t\nmedia communication channels in the subregion.", "page": 89, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "78\nDengue: Guidelines for diagnosis, treatment, prevention and control\n3.3.3 Social mobilization and communication\nUnlike chronic or sexually transmitted infections, vector-borne diseases require more than \nindividual behaviour change in order to influence disease transmission. Behavioural \nchange is required at both individual and community levels in order to reduce vector \nlarval habitats successfully, and in turn to reduce the number of adult mosquitoes \navailable to transmit disease. This ha", "page": 90, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "mosquitoes \navailable to transmit disease. This has led to greater emphasis on social mobilization \nand communication activities which are fully integrated into dengue prevention and \ncontrol efforts (14). \nIn order to develop an appropriate communication strategy, it is necessary to understand \nthat communication is not just the dissemination of messages through various channels \nTable 3.5\t Examples of advocacy efforts in Asia and Latin America\n\t Type of advocacy\t\nAsia\t\nLatin America\t\n\t\n\t\n\t Soc", "page": 90, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "Type of advocacy\t\nAsia\t\nLatin America\t\n\t\n\t\n\t Social mobilization\t Malaysia. Large-scale social mobilization \t\nBrazil. D-Day, a large-scale, coordinated \n\t \t\nstarted out \u201clocally\u201d in Johor Bahru.\t\nsocial mobilization and media advocacy\n\t \t\nSingapore. Social mobilization involves \t\neffort started out \u201clocally\u201d in Rio de Janeiro. \n\t \t\nthe creation of  \u201cdengue prevention  \n\t \t\nvolunteer groups\u201d among local grassroots  \n\t \t\norganizations in the community.\n\t Administrative\t\nMalaysia. Through adminis", "page": 90, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "unity.\n\t Administrative\t\nMalaysia. Through administrative advocacy, \t\nBrazil. Through administrative advocacy \n\t advocacy\t\nactivities have expanded to several \t\nD-Day is now nationwide. \n\t \t\nother states. \t\nNicaragua. After the elections, programme \t\n\t \t\n\t\npersonnel initiated administrative advocacy \t\n\t \t\n\t\nto engage new personnel and elected\t\t\n\t \t\n\t\nofficials in the COMBI process.\n\t Legislative\t\nIndia. Mumbai implements legislative\t\nBrazil. Through the national tyre recycling \n\t advocacy\t\nmeasu", "page": 90, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ugh the national tyre recycling \n\t advocacy\t\nmeasures to prevent mosquito breeding \t\nprogramme, regional tyre collection and \n\t \t\non premises. Several municipalities of \t\nprocessing centres were created. \n\t \t\nGujarat State have framed by-laws to \t\nEl Salvador. The first tyre recycling \n\t \t\nimplement similar measures. In Goa State, \t\ncentre was modelled on the Brazil  \n\t \t\nmodified by-laws require householders to \t\nprogramme. \n\t \t\ninstall mosquito-proof lids on their water  \n\t \t\ntanks, and buildi", "page": 90, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "-proof lids on their water  \n\t \t\ntanks, and building construction site  \n\t \t\nmanagers are required to prevent mosquito  \n\t \t\nbreeding. \n\t \t\nSingapore. The law requires all construction  \n\t \t\nsites to have a full-time or part-time  \n\t \t\n\u201cenvironmental control officer\u201d to take care  \n\t \t\nof sanitation, hygiene and vector control issues  \n\t \t\nof the site.\n\t Legal\t\nIndia. Fines are imposed on house owners on\t\nCuba. Fines are universally imposed  \n\t advocacy\t\ndetection of mosquito breeding in cities", "page": 90, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "dvocacy\t\ndetection of mosquito breeding in cities such \t\non house owners and businesses \n\t \t\nas Ahmedabad, Delhi, Mumbai and Surat.\t\nwhen Aedes breeding is found. \n\t \t\nSingapore. House owners who create  \n\t \t\nconditions favourable for mosquito breeding  \n\t \t\nare penalized. Legislation exists to regulate  \n\t \t\nsanitation.\n\t Media advocacy\t\nMalaysia. Media advocacy and social \t\nBrazil. Media advocacy and social  \n\t \t\nmobilization are two key components \t\nmobilization are two key components of", "page": 90, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ents \t\nmobilization are two key components of  \n\t \t\nof the dengue programme.\t\nD-Day.", "page": 90, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "79\nChapter 3: Vector management and delivery of vector control services\nCHAPTER 3\nsuch as interpersonal communication or the mass media. Communication is a two-way \ninteractive process through which two or more participants (individuals or groups) create \nand share information in order to reach a common understanding and to identify areas \nof mutual agreement. This in turn allows for collective actions such as advocacy and \nsocial mobilization to be implemented. Once collective actions have been", "page": 91, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "be implemented. Once collective actions have been identified, \nsocial mobilization can be used to engage people\u2019s participation in achieving a specific \ngoal through their own efforts (15). Social mobilization is not just a single activity; it \ninvolves all relevant segments of society (i.e. decision-makers and policy-makers, opinion \nleaders, bureaucrats and technocrats, professional groups, religious groups, commerce \nand industry, communities and individuals). It also takes into account the", "page": 91, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "and individuals). It also takes into account the perceived \nneeds of the people, embraces the critical principle of community involvement, and \nseeks to empower individuals and groups for action.\nTo date, most dengue-related communication (including more traditional information, \neducation and communication (or IEC) efforts) and social mobilization activities have \ntargeted individuals and communities generally defined by geographical boundaries \n\u2013 such as neighbourhoods, schools, and houses th", "page": 91, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "\u2013 such as neighbourhoods, schools, and houses that fall within the radius of a confirmed \ndengue case. Little attention has been given to creating and sustaining a dialogue \nat policy level in order to address the underlying causes of increasing availability of \nvector larval habitats, such as ineffective refuse disposal services or an inconsistent \nor poor-quality water supply. Policy efforts require different communication strategies \nin order to engage the diverse target audience, which may", "page": 91, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "r to engage the diverse target audience, which may include representatives \nfrom ministries of natural resources and the environment (water and sanitation), urban \nplanning, finance and tourism, as well as municipal authorities. While many countries \nhave a national dengue committee that may be activated during outbreaks or epidemics, \nthese committees generally do not address the broader issues that lead to the ongoing \npropagation of the mosquito vectors of dengue fever. \nCommunication plans a", "page": 91, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "to vectors of dengue fever. \nCommunication plans and strategies are often lacking, resulting in short-term information \ncampaigns and ad hoc activities in reaction to outbreaks. In 2004, WHO published \nPlanning social mobilization and communication for dengue prevention and control: \na step-by-step guide (16) to assist programme managers in developing effective \nmobilization and communication strategies to promote behavioural change as part of \nroutine vector control programming. The guide uses", "page": 91, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "outine vector control programming. The guide uses the COMBI (communication-for-\nbehavioural-impact) planning methodology to focus communication and mobilization \nefforts on promoting and measuring changes in behaviour, and not just changes in \nknowledge and attitudes. This focus on behaviour rather than knowledge builds on \nmany years of IEC efforts to increase community knowledge of dengue, the mosquito \nvector(s) and their larval habitats. Understanding the precise steps needed to carry out a", "page": 91, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "rstanding the precise steps needed to carry out a \nrecommended behaviour will help programmes to shift from the use of general messages \nthat are often ignored by the target audience to messages that promote and encourage \nthe process of behavioural change (17). \n3.3.4\t Collaboration within the health sector and with other sectors\nIntersectoral collaboration among partners is a key strategy of IVM. Networking \nfacilitates a more coordinated approach than the individual and independent efforts of", "page": 91, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ach than the individual and independent efforts of \ndifferent sectors, and provides a platform for partners to resolve cross-agency issues and \nto share best practices while reducing duplication of efforts. Networking for dengue", "page": 91, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "80\nDengue: Guidelines for diagnosis, treatment, prevention and control\ncontrol also helps to leverage the strengths of partners and to synergize their efforts, \nthereby enhancing the effectiveness and efficiency of actions for dengue prevention \nand control. \n3.3.4.1 Collaboration within the health sector\nControl measures can be integrated with strong local health systems by transferring \nresponsibility, authority, resources and knowledge from central to local level. However, \nit is critically i", "page": 92, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ntral to local level. However, \nit is critically important for the transfer of responsibility to be accompanied by the transfer \nof financial and technical resources. Transfer can be accomplished by offering, for \ninstance, capacity-strengthening workshops or training courses in vector biology and \ncontrol, epidemiology, and communication among other topics at the local level. At \nall administrative levels of government (state, provincial, departmental and local), \nthe dengue control programme i", "page": 92, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "mental and local), \nthe dengue control programme is usually part of the local health system, wherein lies \nthe responsibility for planning, implementing, monitoring and evaluating the local \nprogramme.\n \nContacts, liaison and cooperative activities should be promoted within the different \ndivisions of the health sector. This cooperation with the dengue programme is necessary \nsince the prevention and control of dengue is not the responsibility of a single department. \nRegardless of whether the p", "page": 92, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "a single department. \nRegardless of whether the programme is led by the Ministry of Health, collaboration \nwithin this ministry is essential among those departments responsible for vector control \nand surveillance, epidemiological surveillance, clinical diagnosis and management, \nmaternal and child health (e.g. the programme on integrated management of childhood \nillnesses), health education, community participation and environmental health. Entities \nsuch as national health institutes and scho", "page": 92, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ities \nsuch as national health institutes and schools of public health and medicine can also \ncontribute by carrying out activities for which the Ministry of Health may not have \nresources, such as training and research projects.\n3.3.4.2 Collaboration with other sectors and with the community\nDengue prevention and control necessitates an effective intersectoral approach, requiring \ncoordination between the lead ministry, usually the Ministry of Health, and other ministries \nand government agenci", "page": 92, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ealth, and other ministries \nand government agencies, the private sector (including private health providers), \nnongovernmental organizations (NGOs) and local communities. Resource-sharing is an \nimportant aspect of this (Table 3.6). Such cooperation is critical in emergency situations \nwhen scarce or widely dispersed human and material resources must be mobilized \nrapidly and their use coordinated to mitigate the effects of an epidemic. The process \ncan be facilitated by policy adjustment.\n \nPo", "page": 92, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ess \ncan be facilitated by policy adjustment.\n \nPolicy adjustment\nThe Ministry of Health and the programme manager should seek mutual agreement \nwith other ministries, sectors or municipal governments \u2013 and even the adjustment of \nexisting policies and practices \u2013 to place public health centrally among the goals of \nthose bodies (administrative advocacy). For instance, the public works sector could be \nencouraged to give priority to improvements in water supply for those communities at \nhighest", "page": 92, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "in water supply for those communities at \nhighest risk of dengue.", "page": 92, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "81\nChapter 3: Vector management and delivery of vector control services\nCHAPTER 3\nTable 3.6\t Selected examples of potential intersectoral actions\n\t Sector\t\nIssue\t\nRationale\t\n\t\n\t Public sector\t\n\t Ministry of the\t\nSolid waste management, water supply,\t\nDiscarded containers and household water-\t\n\t\n\t Environment\t\npromotion of healthy public policies\t\nstorage containers are larval habitats.\n\t Ministry of\t\nIncorporation of environmental health\t\nEmpowerment of children with knowledge \n\t Education\t\nissu", "page": 93, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ment of children with knowledge \n\t Education\t\nissues and activities in school curricula\t\nof health risks and skills to carry out actions to\t\n\t \t\n\t\nmanage the environment. This is often an entry\t\n\t \t\n\t\npoint for community action.\n\t Municipal \t\nUrban infrastructure and planning, \t\nUrban development and infrastructure can be \n\t authority\t\nincluding water and sanitation services\t\ndesigned and managed to avoid creation of \t\n\t \t\n\t\nlarval habitats (e.g. sufficient resources  \n\t \t\n\t\ndedicated to the col", "page": 93, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "sufficient resources  \n\t \t\n\t\ndedicated to the collection and disposal of \t\n\t \t\n\t\nrefuse, and to a reliable and good quality  \n\t \t\n\t\nwater system).\n\t Ministry of \t\nStreet stormwater drainage systems, \t\nDesign of water run-off drainage systems and \n\t Public Works\t\nunderground service units for telephones, \t\nmanholes that do not create underground \n\t \t\netc.\t\nmosquito larval habitats.\n\t \t\nHousing structure and water-storage \t\nDesign structures that avoid the creation of \t\t\n\t \t\ncontainers.\t\nmosquito", "page": 93, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "avoid the creation of \t\t\n\t \t\ncontainers.\t\nmosquito larval habitats (e.g. roofing design, \t\n\t \t\n\t\nwater run-off and catchment systems).\n\t Ministry of \t\nReduction of economic losses associated\t\nInvolvement of the hospitality sector in routine \n\t Tourism\t\nwith dengue outbreaks\t\nvector control actions and environmental \t \t\n\t \t\n\t\nmanagement.\n\t Ministry of \t\nLegislative framework\t\nProvision of the legislative and regulatory \n\t Finance and \t\n\t\nframework to support environmental \n\t Planning\t\n  \t\nmanagem", "page": 93, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "to support environmental \n\t Planning\t\n  \t\nmanagement actions and sound use of \t\n\t\n\t \t\n\t\ninsecticides.\n\t Private sector\t\nStewardship, particularly in industrial and \t\nConsumer packaging and petrochemical \n\t \t\nmanufacturing sectors\t\nindustries, and manufacturers of tyres and water-\t\n\t \t\n\t\nstorage tanks are examples of how the private \t\n\t \t\n\t\nsector may contribute \u2013 indirectly or directly \u2013 to \n\t \t\n\t\nlarval habitats and to potential solutions,  \n\t \t\n\t\nespecially in the context of \u201csocial or", "page": 93, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "especially in the context of \u201csocial or \t\n\t\n\t \t\n\t\nenvironmental responsibility\u201d. Small-scale tyre \t\n\t \t\n\t\nbusinesses may have limited means to protect \t\n\t \t\n\t\nused tyres stored on the premises.\n\t Nongovernmental \t Mobilization of community action\t\nNGOs are able to mobilize resources and \n\t organizations\t\n\t\nactions at community level on issues of common \t\n\t \t\n\t\ninterest.\nPotential roles of government ministries\nPublic works. The ministry responsible for public works and its municipal counterp", "page": 93, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "nsible for public works and its municipal counterparts \nare responsible for providing dependable water supply, sanitation and solid waste \nmanagement services to all planned communities. The dimensions and quality of those \nservices have a direct bearing on the availability of larval habitats. Additionally, through \nthe adoption and enforcement of housing and building codes (legislative and regulatory \nadvocacy), a municipality may mandate the provision of utilities such as piped water or", "page": 93, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ovision of utilities such as piped water or", "page": 93, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "82\nDengue: Guidelines for diagnosis, treatment, prevention and control\nsewerage connections for individual households and rainwater run-off control for new \nhousing developments, or it may prohibit the construction of open groundwater wells. \nSuch opportunities are prescient when planning urban redevelopment schemes and \nbecause of the benefits of reduced risk of dengue and of mosquitoes and other pests.\nEducation. The Ministry of Education should be a key partner as it is responsible not only", "page": 94, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "d be a key partner as it is responsible not only \nfor educating children and young people but also for inculcating social norms which \ninclude appropriate hygiene behaviours. Where dengue prevention and control involve \na health communication component targeted at schoolchildren, the Ministry of Health \ncan work closely with the Ministry of Education to develop, communicate and impart \nappropriate messages and skills for behaviour change. Such messages and skills should \nideally be integrated in", "page": 94, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ssages and skills should \nideally be integrated into existing curricula to ensure long-term continuity (18).\nHealth education models can be jointly developed, tested and evaluated for different \nage groups. Research programmes in universities and colleges can be encouraged to \ninclude components that generate information of direct importance (e.g. vector biology \nand control, case management) or of indirect importance (e.g. improved water supplies, \npromotion of community sanitation, waste chara", "page": 94, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "s, \npromotion of community sanitation, waste characterization studies, analysis of cost and \ncost-effectiveness of interventions) to aid evidence-based decision-making.\nTourism. Coordination with the Ministry of Tourism can facilitate the timely communication \nof outbreak or epidemic alert messages to tourists and to the hotel industry so that actions \ncan be taken to reduce the risk of exposure to infection.\nEnvironment. The ministry responsible for the environment can help the Ministry of Heal", "page": 94, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "for the environment can help the Ministry of Health \nto gather information on ecosystems and habitats in and around cities and smaller \ncommunities at high risk of dengue so as to aid in programme planning. In at least one \ncountry (Singapore), the Ministry of the Environment has direct responsibility for dengue \nvector control and promotes healthy public policies that include sound management of \npublic health pesticides.\nCollaboration with nongovernmental organizations\nNGOs can play important", "page": 94, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "governmental organizations\nNGOs can play important roles in promoting and implementing environmental \nmanagement for dengue vector control, most often involving health communication on \nreduction of sources and improvement of housing. Community NGOs \u2013 which may \nbe informal neighbourhood groups such as private volunteer organizations, religious \ngroups and environmental and social action groups \u2013 should be identified as potential \npartners.\nWith appropriate orientation and guidance, particularly", "page": 94, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "appropriate orientation and guidance, particularly on source reduction methods, \nNGOs can collect discarded containers (e.g. tyres, food and drink containers), or can \nclean drains and culverts, remove abandoned vehicles and roadside litter, and fill tree \nand rock holes. During outbreaks NGOs may be influential in mobilizing householders \nand other community members to eliminate important larval habitats of the vector or \nto manage the containers in ways that do not allow mosquito emergence (e.", "page": 94, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "s in ways that do not allow mosquito emergence (e.g. by \nemptying and cleaning water-storage containers at weekly intervals). NGOs may \nalso encourage public cooperation and acceptance of space spraying and larvicide \napplication measures.", "page": 94, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "83\nChapter 3: Vector management and delivery of vector control services\nCHAPTER 3\nCommunities organize themselves in many ways, so there is no prescribed formula \nfor interaction. However, social mobilization initiatives must be socially and culturally \nsensitive and should be developed between partners in a spirit of mutual respect. There \nare many examples of voluntary organizations and women\u2019s associations taking the \nlead in providing money, advertising and political support to successful co", "page": 95, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "advertising and political support to successful community-\nbased campaigns for source reduction or in organizing regular household activities to \nreduce mosquito populations.\nCollaboration with industry and the private sector\nCollaboration with industry and the private sector can advance the manufacture and \nutilization of mosquito-proof designs of water-storage containers and room-coolers, \nand can promote the collection and recycling of used tyres, plastic, aluminium, glass \nand other containe", "page": 95, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "res, plastic, aluminium, glass \nand other containers. In the construction industry, architects\u2019 associations can help to \npromote the design and building of mosquito-proof and otherwise healthy houses and \nworkplaces.\n3.3.5\t Integrated approaches to control\nInstead of targeting only the vector or vectors of dengue, there may be opportunities to \nintegrate Aedes control with control of pests or vectors of other diseases. Addressing \ntwo or more public health problems simultaneously may improve co", "page": 95, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "blic health problems simultaneously may improve cost-effectiveness \nand may help promote public acceptance and involvement in the programme. For \nexample, control of Ae. aegypti in some urban areas can be combined with control \nof Culex quinquefasciatus, the latter species usually being a much greater nuisance to \nthe public and an important vector of lymphatic filariasis in many tropical environments. \nCollection of solid waste as an environmental management component of Aedes control \nprogramm", "page": 95, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "al management component of Aedes control \nprogrammes need not be restricted just to the container sources of Aedes production but \ncan also include items that are associated with filth flies and rodents. Moreover, given \nthat urban yellow fever and chikungunya viruses are also transmitted by Ae. aegypti, \nand chikungunya by Ae. albopictus as well, their control is an effective way of reducing \nthe risk of outbreaks of these diseases in addition to dengue. In many cities in India, Ae. \naegypti an", "page": 95, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "o dengue. In many cities in India, Ae. \naegypti and the malaria vector Anopheles stephensi share common larval habitats and \ncan be targeted simultaneously.\n3.3.6\t Strengthening capacity\nIn vector control, as in other areas of public health, staffing levels and capacity-\nstrengthening are important. In particular, public health entomologists, vector control \npersonnel, environmental specialists, social scientists and communication specialists \nplay pivotal roles.\n3.3.6.1 Social scientists and co", "page": 95, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ay pivotal roles.\n3.3.6.1 Social scientists and communication specialists\nBecause social mobilization and communication are often the least planned and most \nunder-funded elements of the dengue prevention and control programme, it is even \nmore important to use resources in a targeted and cost-effective manner. This can be \naccomplished by working with social scientists who have expertise in using behavioural \nchange theories in programme development, and with communication specialists who", "page": 95, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ment, and with communication specialists who", "page": 95, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "84\nDengue: Guidelines for diagnosis, treatment, prevention and control\nhave a background preferably in health communication (i.e. the use of communication \nstrategies to inform and influence individual and community decisions that enhance \nhealth). This will require that the dengue programme includes in its annual budget an \nallocation for social mobilization and communication activities in order to integrate \nthese specialists into routine programme planning.\nMost ministries of health have heal", "page": 96, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "amme planning.\nMost ministries of health have health promotion or health education departments, and it is \nincreasingly common to find communication included in them. However, communication \nis frequently viewed as use of the mass media, and therefore the communication \nspecialists may be individuals with backgrounds in public relations, journalism or mass \nmedia who have limited knowledge of the principles of health promotion or behavioural \nchange. In this case it is even more important to inv", "page": 96, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "nge. In this case it is even more important to involve a health promotion specialist \nor a social scientist to ensure that the messages focus on appropriate and feasible \nbehaviours that target the principal vector larval habitats, and that the impact of the social \nmobilization and communication activities are evaluated for changes in behaviour and \nnot just for changes in knowledge or attitudes. Health promotion and health education \npersonnel can generally be found at the central and state or", "page": 96, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "can generally be found at the central and state or provincial levels, while at \nthe local level this role may be filled by a nurse or social worker if a person qualified in \ncommunication is not part of the health clinic staffing. \nOngoing training and practice in communication at all levels is critical for ensuring \nappropriate and effective interpersonal communication between vector control staff and \nhouseholders, between the dengue programme manager and vector control staff, and \nbetween the", "page": 96, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "manager and vector control staff, and \nbetween the dengue programme manager and partners within and outside the health \nsector. When and how to use the mass media at national, regional and local levels can \nbe determined in collaboration with the communications specialist. Using the media may \nentail training sessions in public speaking for key spokespersons within the programme \nas well as for epidemiologists and medical personnel who may also be required to \nspeak to the media. Training in how", "page": 96, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "e required to \nspeak to the media. Training in how to work with the media, particularly during an \noutbreak or epidemic, is vital to ensure that accurate and useful information is shared \nwith the broader community through the media, to avoid sending mixed messages about \nwhat is expected of the community during the outbreak and to reduce the chance of \nmisinterpretation or sensationalization of information (particularly the number of cases \nof dengue).\n3.3.6.2 Public health entomologists and ve", "page": 96, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "engue).\n3.3.6.2 Public health entomologists and vector control and environmental management \npersonnel\nThe skills for managing, implementing, monitoring and evaluating the programme must \nbe determined in accordance with availability of resources, programme objectives and \nintervention strategies. Training activities, including in-service training, should be tailored \nto the needs of the various groups of personnel. WHO has published guidance on \nneeds assessment for all components of the dengue", "page": 96, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "needs assessment for all components of the dengue control programme (19).\nWhether or not vector control activities are aligned with centralized or decentralized \nhealth systems, and whether they are distinct from or integrated with other health sector", "page": 96, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "85\nChapter 3: Vector management and delivery of vector control services\nCHAPTER 3\nactivities, the available skills at any given level of administrative responsibility should \nbe commensurate with those responsibilities. This is equally important for the purposes \nof financial and operational planning \u2013 including workforce planning and strategic, \ntechnical guidance \u2013 as well as for essential physical infrastructure.\n3.3.7\t Operational research\nOperational research should be oriented to the prior", "page": 97, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "erational research should be oriented to the priority needs of the programme in order \nto generate the evidence base for adaptation of strategies and interventions. This may \ninclude, for example, studies on the ecology of the vector, the efficacy, effectiveness \nand cost-effectiveness of existing and promising new vector control methods, formative \nresearch on relevant cultural practices, and guidance for engaging communities in \nprogramme activities. \n3.3.8 Monitoring and evaluation\nRegular mo", "page": 97, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ities. \n3.3.8 Monitoring and evaluation\nRegular monitoring of the delivery of dengue prevention and control services and \nevaluation of the impact of interventions are important activities for effective programme \nmanagement. Suitable indicators should be identified to measure the progress of \nimplementation, as well as output and outcome indicators. Table 3.7 gives examples of \ngood and bad practice in dengue prevention and control.\nTable 3.7 \t Dengue prevention and control: examples of good an", "page": 97, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "Dengue prevention and control: examples of good and bad practice\n\t Activity\t\nGood practice\t\nBad practice\t\n\t\n\t\n\t Environmental \t\nDetermining local ecology of immature\t\nInvesting disproportionately in chemical control \n\t management\t\nstages as a basis for choosing the most\t\nmethods when affordable and more sustainable  \n\t \t\nappropriate interventions\t\nenvironmental management solutions are \t \t\n\t \t\n\t\navailable.\n\t \t\nIntegrating dengue control with sanitation, \t\nResponding primarily to outbreaks and no", "page": 97, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "tation, \t\nResponding primarily to outbreaks and not \n\t \t\nsolid waste disposal, water supply services, \t investing in sustained vector control measures. \n\t \t\nand other vector and pest control  \n\t \t\nprogrammes\n\t Chemical control\t\nUsing insecticides judiciously\t\nUsing chemical control methods without \t\n\t\n\t \t\n\t\nevaluating efficacy and cost-effectiveness, and \t\n\t \t\n\t\nwithout monitoring local vector susceptibility.\n\t Municipal services\t Intersectoral collaboration on urban \t\nSocial marketing of larvic", "page": 97, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ollaboration on urban \t\nSocial marketing of larvicides for water-storage \n\t \t\ndevelopment or renewal to minimize \t\ncontainers, with consequent low coverage  \n\t \t\navailability of larval habitats of dengue \t\nrates. \n\t \t\nvectors and vectors of other diseases\n\t Entomological \t\nMonitoring of vector populations to target\t\nGenerating routine entomological surveillance  \n\t monitoring and\t\ncontrol in time and space, and to provide\t\ndata that are not analysed or utilized in a timely\n\t surveillance\t\nfeedba", "page": 97, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "sed or utilized in a timely\n\t surveillance\t\nfeedback for programme adjustment\t\nand efficient manner for management decision-\t\n\t \t\n\t\nmaking.", "page": 97, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "86\nDengue: Guidelines for diagnosis, treatment, prevention and control\n3.4 REFERENCES\n1. WHO. Global strategic framework for integrated vector management. Geneva, World \nHealth Organization, 2004 (Document WHO/CDS/CPE/2004.10, available at: \nhttp://whqlibdoc.who.int/hq/2004/WHO_CDS_CPE_PVC_2004_10.pdf; accessed \nOctober 2008).\n2. PAHO. Dengue and dengue hemorrhagic fever in the Americas: guidelines for \nprevention and control. Washington, DC, Pan American Health Organization, 1994 \n(Scientific p", "page": 98, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "American Health Organization, 1994 \n(Scientific publication, No. 548).\n3. WHO. Guidelines for drinking-water quality, 3rd ed., incorporating first addendum. \nGeneva, World Health Organization, 2006 (available at:\nhttp://www.who.int/water_sanitation_health/dwq/gdwq3rev/en/index.html; \naccessed October 2008).\n4. WHO. WHOPES guidelines for insecticide resistance.  Available at: http://www.\nwho.int/whopes/guidelines/en/; accessed October 2008.\n5. WHO. Space spray application of insecticides for vec", "page": 98, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "O. Space spray application of insecticides for vector and pest control: a \npractitioner\u2019s guide. Geneva, World Health Organization, 2003 (Document WHO/\nCDS/WHOPES/GCDPP/2003.5).\n6. WHO. Pesticides and their application for the control of vectors and pests of public \nhealth importance. Geneva, World Health Organization, 2006 (Document WHO/\nCDS/WHOPES/GCDPP/2006.1; available at:\nhttp://whqlibdoc.who.int/hq/2006/WHO_CDS_NTD_WHOPES_GCDPP_\n2006.1_eng.pdf).\n7. WHO. Safe use of pesticides. Fourteenth r", "page": 98, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "pdf).\n7. WHO. Safe use of pesticides. Fourteenth report of the WHO Expert Committee \non Vector Biology and Control. Geneva, World Health Organization, 1991 (WHO \nTechnical Report Series, No. 813).\n8. WHO/EMRO. Use of fish for mosquito control. Cairo, World Health Organization \nRegional Office for the Eastern Mediterranean, 2003 (Document WHO/EM/\nMAL/289/E/G). \n9.  WHO/TDR. Report of the Scientific Working Group on Dengue (TDR/SWG/08). \nGeneva, World Health Organization, Special Programme for Res", "page": 98, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "rld Health Organization, Special Programme for Research and Training \nin Tropical Diseases, 2006 (available at: http://www.who.int/tdr/publications/\npublications/swg_dengue_2.htm; accessed October 2008).\n10. Kroeger A et al. Effective control of dengue vectors with curtains and water container \ncovers treated with insecticide in Mexico and Venezuela: cluster randomized trials. \nBritish Medical Journal, 2006, 332:1247\u20131252.", "page": 98, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "87\nChapter 3: Vector management and delivery of vector control services\nCHAPTER 3\n11. The eradication of Aedes aegypti at the Singapore Paya Lebar International Airport. \nIn: Chan YC, Chan KL, Ho BC, eds. Vector control in South-East Asia. Proceedings of \nthe First SEAMEO-TROPMED Workshop, Singapore, 1972. Bangkok, SEAMEO, 1973 \n(pp 85\u201388).\n12.  Perich M et al. Field evaluation of a lethal ovitrap against dengue vectors in Brazil. \nMedical and Veterinary Entomology, 2003, 17:205\u2013210.\n13. Loue S,", "page": 99, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "terinary Entomology, 2003, 17:205\u2013210.\n13. Loue S, Lloyd LS, O\u2019Shea DJ. Community health advocacy. New York, NY, Kluwer \nAcademic/Plenum Press, 2003.\n14. Lloyd LS. Best practices for dengue prevention and control in the Americas. \nWashington, DC, Environmental Health Project, 2003 (Strategic Report No. 7).\n15. UNICEF\n.Communication handbook for polio eradication and routine EPI. New \nYork, NY, United Nations Children\u2019s Fund, 2000. \n16. Parks W, Lloyd LS. Planning social mobilization and communic", "page": 99, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "loyd LS. Planning social mobilization and communication for dengue \nfever prevention and control: a step-by-step guide. Geneva, World Health Organization, \n2004 \n(available \nat: \nhttp://www.who.int/tdr/publications/publications/pdf/planning_\ndengue.pdf; accessed October 2008).\n17. Renganathan E et al. Communication-for-Behavioural-Impact (COMBI): a review \nof WHO\u2019s experiences with strategic social mobilization and communication in the \nprevention and control of communicable diseases. In: Haider", "page": 99, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "n and control of communicable diseases. In: Haider M, ed. Global public \nhealth communication: challenges, perspectives, and strategies. Sudbury, MA, Jones \nand Bartlett Publishers, Inc., 2005 (pp 305\u2013320).\n18. Nathan MB, Lloyd L, Wiltshire A. Community participation in environmental \nmanagement for dengue vector control: experiences from the English-speaking \nCaribbean. Dengue Bulletin, 2004, 28(Suppl):13\u201316.\n19. WHO. Guidelines for conducting a review of a national dengue prevention and \ncontr", "page": 99, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "review of a national dengue prevention and \ncontrol programme. Geneva, World Health Organization, 2005 (Document WHO/\nCDS/CPE/PVC/2005.13).", "page": 99, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "88\nDengue: Guidelines for diagnosis, treatment, prevention and control", "page": 100, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "89\nChapter 4: Laboratory diagnosis and diagnostic tests\nCHAPTER 4\nChapter 4\n \nLaboratory diagnosis and  \ndiagnostic tests", "page": 101, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "90\nDengue: Guidelines for diagnosis, treatment, prevention and control", "page": 102, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "91\nChapter 4: Laboratory diagnosis and diagnostic tests\nCHAPTER 4\nChapter 4. Laboratory diagnosis and diagnostic tests\n4.1 Overview\nEfficient and accurate diagnosis of dengue is of primary importance for clinical care (i.e. \nearly detection of severe cases, case confirmation and differential diagnosis with other \ninfectious diseases), surveillance activities, outbreak control, pathogenesis, academic \nresearch, vaccine development, and clinical trials. \nLaboratory diagnosis methods for confirming", "page": 103, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ials. \nLaboratory diagnosis methods for confirming dengue virus infection may involve \ndetection of the virus, viral nucleic acid, antigens or antibodies, or a combination of \nthese techniques. After the onset of illness, the virus can be detected in serum, plasma, \ncirculating blood cells and other tissues for 4\u20135 days. During the early stages of the \ndisease, virus isolation, nucleic acid or antigen detection can be used to diagnose the \ninfection. At the end of the acute phase of infection, s", "page": 103, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ion. At the end of the acute phase of infection, serology is the method of choice \nfor diagnosis.\nAntibody response to infection differs according to the immune status of the host (1). \nWhen dengue infection occurs in persons who have not previously been infected with \na flavivirus or immunized with a flavivirus vaccine (e.g. for yellow fever, Japanese \nencephalitis, tick-borne encephalitis), the patients develop a primary antibody response \ncharacterized by a slow increase of specific antibodie", "page": 103, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "acterized by a slow increase of specific antibodies. IgM antibodies are the first \nimmunoglobulin isotype to appear. These antibodies are detectable in 50% of patients \nby days 3-5 after onset of illness, increasing to 80% by day 5 and 99% by day 10 \n(Figure 4.1). IgM levels peak about two weeks after the onset of symptoms and then \ndecline generally to undetectable levels over 2\u20133 months. Anti-dengue serum IgG is \ngenerally detectable at low titres at the end of the first week of illness, incre", "page": 103, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "res at the end of the first week of illness, increasing slowly \nthereafter, with serum IgG still detectable after several months, and probably even for \nlife (2\u20134) .\nDuring a secondary dengue infection (a dengue infection in a host that has previously \nbeen infected by a dengue virus, or sometimes after non-dengue flavivirus vaccination \nor infection), antibody titres rise rapidly and react broadly against many flaviviruses. The \ndominant immunoglobulin isotype is IgG which is detectable at high", "page": 103, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "lobulin isotype is IgG which is detectable at high levels, even in the \nacute phase, and persists for periods lasting from 10 months to life. Early convalescent \nstage IgM levels are significantly lower in secondary infections than in primary ones \nand may be undetectable in some cases, depending on the test used (5). To distinguish \nprimary and secondary dengue infections, IgM/IgG antibody ratios are now more \ncommonly used than the haemagglutination-inhibition test (HI) (6\u20138).\nA range of labor", "page": 103, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ation-inhibition test (HI) (6\u20138).\nA range of laboratory diagnostic methods has been developed to support patient \nmanagement and disease control. The choice of diagnostic method depends on the \npurpose for which the testing is done (e.g. clinical diagnosis, epidemiological survey, \nvaccine development), the type of laboratory facilities and technical expertise available, \ncosts, and the time of sample collection.", "page": 103, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "92\nDengue: Guidelines for diagnosis, treatment, prevention and control\nFigure 4.1\tApproximate time-line of primary and secondary dengue virus infections and the diagnostic \n \n\t\n\t\n\t\nmethods that can be used to detect infection\n\t\n-2\t\n-1\t\n0\t 1\t 2 \t 3 \t 4 \t 5 \t 6  \t7 \t8 \t9\t10\t\t\n11 12   13   14   15   16-20    21-40   41-60    61-80    90     >90  Days\t\nNS1 detection\t\nVirus isolation\nRNA detection\t\nViraemia\t\n IgM primary\t\n IgM secondary\t\n IgG secondary\t\n IgG secondary infection\t\nO.D\nO.D\nOnset of symp", "page": 104, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "y\t\n IgG secondary infection\t\nO.D\nO.D\nOnset of symptoms (days)\t\n\u226525\n60\n80\n0\nIn general, tests with high sensitivity and specificity require more complex technologies \nand technical expertise, while rapid tests may compromise sensitivity and specificity for \nthe ease of performance and speed. Virus isolation and nucleic acid detection are more \nlabour-intensive and costly but are also more specific than antibody detection using \nserologic methods. Figure 4.2 shows a general inverse relationship be", "page": 104, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "Figure 4.2 shows a general inverse relationship between the ease of \nuse or accessibility of a diagnostic method and the confidence in the results of the test. \nFigure 4.2 Comparison of diagnostic tests according to their accessibility and confidence\nNS1 \ndetection\t\n  ACCESSIBILITY\t\nGenome \ndetection\t\nVirus\nisolation\t\nSerology\n    IgM\t\nSerology\n    IgG\t\n   CONFIDENCE\t\n  DIRECT METHODS\t\n  INDIRECT METHODS", "page": 104, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "93\nChapter 4: Laboratory diagnosis and diagnostic tests\nCHAPTER 4\n4.2\t\nConsiderations in the choice of diagnostic methods\n4.2.1 \tClinical management\nDengue virus infection produces a broad spectrum of symptoms, many of which are \nnon-specific. Thus, a diagnosis based only on clinical symptoms is unreliable. Early \nlaboratory confirmation of clinical diagnosis may be valuable because some patients \nprogress over a short period from mild to severe disease and sometimes to death. Early \ninterventio", "page": 105, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "disease and sometimes to death. Early \nintervention may be life-saving. \nBefore day 5 of illness, during the febrile period, dengue infections may be diagnosed \nby virus isolation in cell culture, by detection of viral RNA by nucleic acid amplification \ntests (NAAT), or by detection of viral antigens by ELISA or rapid tests. Virus isolation in \ncell culture is usually performed only in laboratories with the necessary infrastructure \nand technical expertise. For virus culture, it is important to", "page": 105, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "expertise. For virus culture, it is important to keep blood samples cooled \nor frozen to preserve the viability of the virus during transport from the patient to the \nlaboratory. The isolation and identification of dengue viruses in cell cultures usually takes \nseveral days. Nucleic acid detection assays with excellent performance characteristics \nmay identify dengue viral RNA within 24\u201348 hours. However, these tests require \nexpensive equipment and reagents and, in order to avoid contamination", "page": 105, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "and reagents and, in order to avoid contamination, tests must \nobserve quality control procedures and must be performed by experienced technicians. \nNS1 antigen detection kits now becoming commercially available can be used in \nlaboratories with limited equipment and yield results within a few hours. Rapid dengue \nantigen detection tests can be used in field settings and provide results in less than \nan hour. Currently, these assays are not type-specific, are expensive and are under \nevaluation", "page": 105, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "-specific, are expensive and are under \nevaluation for diagnostic accuracy and cost-effectiveness in multiple settings. Table 4.1 \nsummarizes various dengue diagnostic methods and their costs.\nTable 4.1 Summary of operating characteristics and comparative costs of dengue diagnostic methods (9)\n\tDiagnostic\t\nDiagnosis\t\nTime to\t\nSpecimen\t\nTime of collection \t\nFacilities\t\nCost \n\tmethods\t\nof acute \t\nresults  \t\n\t\nafter onset of \n\t\t\ninfection\t\n\t\n\t\nsymptoms\t\n\t\n\t\n\t\n\tViral isolation\t\nConfirmed \t\n1\u20132 weeks", "page": 105, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "oms\t\n\t\n\t\n\t\n\tViral isolation\t\nConfirmed \t\n1\u20132 weeks\t\nWhole blood, \t\n1\u20135 days\t\nMosquito or cell culture facilities,\t $$$ \n\tand serotype \t\n\t\n\t\nserum, tissues\t\n\t\nBSL-2/BSL-3\na  laboratory,  \n\tidentification\t\n \t\n\t\n  \t\n\t\nfluorescence microscope or  \n\t\t\n\t\n\t\n\t\n\t\nmolecular biology equipment\n\tNucleic acid \t\nConfirmed \t\n1 or 2 days\t\nTissues, whole  \t\n1\u20135 days \t\nBSL-2 laboratory, equipment\t\n$$$ \n\tdetection\t\n\t\n\t\nblood, serum,\t\n\t\nfor molecular biology\t\n\t\n\t\n\t\t\n\t\n\t\nplasma\n\tAntigen\t\nNot yet \t\n1 day\t\nSerum\t\n1\u20136 d", "page": 105, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "plasma\n\tAntigen\t\nNot yet \t\n1 day\t\nSerum\t\n1\u20136 days \t\nELISA facilities\t\n$$ \n\tdetection \t\ndetermined\n  \nConfirmed  \n>1 day \nTissue for \nNA \nFacilities for histology \n$$$ \n\t\t\n\t\n\t\nimmuno-chemistry\n\tIgM ELISA \t\nProbable \t\n1\u20132 days\t\nSerum, plasma,\t\nAfter 5 days \t\nELISA facilities\t\n$\n\tIgM rapid test\t\n\t\n30 minutes\t\nwhole blood\t\n\t\nNo additional supplies\n\tIgG (paired\t\nConfirmed\t\n7 days \t\nSerum, plasma,\t\nAcute sera,\t\nELISA facilities\t\n$\n\tsera) by ELISA, HI\t\n\t\nor more\t\nwhole blood\t\n1\u20135 days; \t\nBSL-2 labo", "page": 105, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "HI\t\n\t\nor more\t\nwhole blood\t\n1\u20135 days; \t\nBSL-2 laboratory \n\tor neutralization\t\n\t\n\t\n\t\nconvalescent \t\nfor neutralization assay \n\ttest \t\n\t\n\t\n\t\nafter 15 days\na Requirements may vary according to each country\u2019s national policies.", "page": 105, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "94\nDengue: Guidelines for diagnosis, treatment, prevention and control\nAfter day 5, dengue viruses and antigens disappear from the blood coincident with the \nappearance of specific antibodies. NS1 antigen may be detected in some patients for \na few days after defervescence. Dengue serologic tests are more available in dengue-\nendemic countries than are virological tests. Specimen transport is not a problem as \nimmunoglobulins are stable at tropical room temperatures. \nFor serology, the time of s", "page": 106, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "al room temperatures. \nFor serology, the time of specimen collection is more flexible than that for virus isolation \nor RNA detection because an antibody response can be measured by comparing a \nsample collected during the acute stage of illness with samples collected weeks or months \nlater. Low levels of a detectable dengue IgM response \u2013 or the absence of it \u2013 in some \nsecondary infections reduces the diagnostic accuracy of IgM ELISA tests. Results of rapid \ntests may be available within less", "page": 106, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ults of rapid \ntests may be available within less than one hour. Reliance on rapid tests to diagnose \ndengue infections should be approached with caution, however, since the performance \nof all commercial tests has not yet been evaluated by reference laboratories (10). \nA four-fold or greater increase in antibody levels measured by IgG ELISA or by \nhaemagglutination inhibition (HI) test in paired sera indicates an acute or recent flavivirus \ninfection. However, waiting for the convalescent serum", "page": 106, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ction. However, waiting for the convalescent serum collected at the time of patient \ndischarge is not very useful for diagnosis and clinical management and provides only \na retrospective result. \n \n4.2.1.1 Differential diagnosis\nDengue fever can easily be confused with non-dengue illnesses, particularly in non-\nepidemic situations. Depending on the geographical origin of the patient, other \netiologies \u2013 including non-dengue flavivirus infections \u2013 should be ruled out. These \ninclude yellow fever", "page": 106, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "\u2013 should be ruled out. These \ninclude yellow fever, Japanese encephalitis, St Louis encephalitis, Zika, and West \nNile, alphaviruses (such as Sinbis and chikungunya), and other causes of fever \nsuch as malaria, leptospirosis, typhoid, Rickettsial diseases (Rickettsia prowazeki, R. \nmooseri, R. conori, R. rickettsi, Orientia tsutsugamushi, Coxiella burneti, etc.), measles, \nenteroviruses, influenza and influenza-like illnesses, haemorrhagic fevers (Arenaviridae: \nJunin, etc.; Filoviridae: Marburg", "page": 106, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "(Arenaviridae: \nJunin, etc.; Filoviridae: Marburg, Ebola; Bunyaviridae: hantaviruses, Crimean-Congo \nhaemorrhagic fever, etc.).\nBoth the identification of virus/viral RNA/viral antigen and the detection of an antibody \nresponse are preferable for dengue diagnosis to either approach alone (see Table \n4.2).\nTable 4.2 Interpretation of dengue diagnostic tests [adapted from Dengue and Control (DENCO) study]\n\t Highly suggestive\t\nConfirmed\t\n\t\n\t\n\t One of the following:\t\nOne of the following:\n\t 1.\tIgM", "page": 106, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "of the following:\t\nOne of the following:\n\t 1.\tIgM + in a single serum sample\t\n1.\tPCR +\n\t 2.\tIgG + in a single serum sample with a \t\n2.\tVirus culture + \n\t \t\nHI titre of 1280 or greater\t\n3.\tIgM seroconversion in paired sera\n\t \t\n\t\n4.\tIgG seroconversion in paired sera or fourfold  \n\t \t\n\t\n\t\nIgG titer increase in paired sera", "page": 106, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "95\nChapter 4: Laboratory diagnosis and diagnostic tests\nCHAPTER 4\nUnfortunately, an ideal diagnostic test that permits early and rapid diagnosis, is affordable \nfor different health systems, is easy to perform, and has a robust performance, is not yet \navailable.\n4.2.2 \tOutbreak investigations\nDuring outbreaks some patients may be seen presenting with fever with or without rash \nduring the acute illness stage; some others may present with signs of plasma leakage or \nshock, and others with signs", "page": 107, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "f plasma leakage or \nshock, and others with signs of haemorrhages, while still others may be observed during \nthe convalescent phase. \nOne of the priorities in a suspected outbreak is to identify the causative agent so that \nappropriate public health measures can be taken and physicians can be encouraged to \ninitiate appropriate acute illness management. In such cases, the rapidity and specificity \nof diagnostic tests is more important than test sensitivity. Samples collected from febrile \npatie", "page": 107, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "sensitivity. Samples collected from febrile \npatients could be tested by nucleic acid methods in a well-equipped laboratory or a \nbroader spectrum of laboratories using an ELISA-based dengue antigen detection kit. \nIf specimens are collected after day 5 of illness, commercial IgM ELISA or sensitive \ndengue IgM rapid tests may suggest a dengue outbreak, but results are preferably \nconfirmed with reliable serological tests performed in a reference laboratory with broad \narbovirus diagnostic capabi", "page": 107, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "laboratory with broad \narbovirus diagnostic capability. Serological assays may be used to determine the extent \nof outbreaks.\n4.2.3 Surveillance\nDengue surveillance systems aim to detect the circulation of specific viruses in the human \nor mosquito populations. The diagnostic tools used should be sensitive, specific and \naffordable for the country. Laboratories responsible for surveillance are usually national \nand/or reference laboratories capable of performing diagnostic tests as described \nab", "page": 107, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "le of performing diagnostic tests as described \nabove for dengue and for a broad range of other etiologies. \n4.2.4\t Vaccine trials\nVaccine trials are performed in order to measure vaccine safety and efficacy in vaccinated \npersons. The plaque reduction and neutralization test (PRNT) and the microneutralization \nassays are commonly used to measure protection correlates.\nFollowing primary infections in non-flavivirus immunes, neutralizing antibodies as \nmeasured by PRNT may be relatively or comple", "page": 107, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "s as \nmeasured by PRNT may be relatively or completely specific to the infecting virus type \n(11,12). This assay is the most reliable means of measuring the titre of neutralizing \nantibodies in the serum of an infected individual as a measure of the level of protection \nagainst an infecting virus. The assay is based on the principle that neutralizing antibodies \ninactivate the virus so that it is no longer able to infect and replicate in target cells. \nAfter a second dengue virus infection, high", "page": 107, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ells. \nAfter a second dengue virus infection, high-titre neutralizing antibodies are produced \nagainst at least two, and often all four, dengue viruses as well as against non-dengue \nflaviviruses. This cross reactivity results from memory B-cells which produce antibodies \ndirected at virion epitopes shared by dengue viruses. During the early convalescent stage \nfollowing sequential dengue infections, the highest neutralizing antibody titre is often \ndirected against the first infecting virus and", "page": 107, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "en \ndirected against the first infecting virus and not the most recent one. This phenomenon is \nreferred to as \u201coriginal antigenic sin\u201d (13).", "page": 107, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "96\nDengue: Guidelines for diagnosis, treatment, prevention and control\nThe disadvantages of PRNT are that it is labour-intensive. A number of laboratories \nrecently developed high through-put neutralization tests that can be used in large-scale \nsurveillance studies and vaccine trials. Variable results have been observed in PRNTs \nperformed in different laboratories. Variations can be minimized if tests are performed \non standard cell lines using the same virus strains and the same temperature a", "page": 108, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "the same virus strains and the same temperature and time \nfor incubation of virus with antibody. Input virus should be carefully calculated to avoid \nplaque overlap. Cell lines of mammalian origin, such as VERO cells, are recommended \nfor the production of seed viruses for use in PRNT. \nThe microneutralization assay is based on the same principle as PRNT. Variable methods \nexist. In one, instead of counting the number of plaques per well, viral antigen is stained \nusing a labelled antibody and", "page": 108, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "antigen is stained \nusing a labelled antibody and the quantity of antigen measured colorimetrically. The \ntest may measure nucleic acid using PCR. The microneutralization assay was designed \nto use smaller amounts of reagents and for testing larger numbers of samples. In viral \nantigen detection tests the spread of virus throughout the cells is not limited because, \nin PRNTs using semisolid overlays, the time after infection must be standardized to \navoid measuring growth after many cycles of re", "page": 108, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "to \navoid measuring growth after many cycles of replication. Since not all viruses grow \nat the same rate, the incubation periods are virus-specific. As with standard PRNTs, \nantibodies measured by micromethods from individuals with secondary infections may \nreact broadly with all four dengue viruses. \nTable 4.3 Advantages and limitations of dengue diagnostic methods (9)\n\tIndications \t\nDiagnostic Tests\t\nAdvantages\t\nLimitations\t\n\t\n\t\n\t\n Diagnosis of  \nNucleic acid detection \n\u2022Most sensitive and sp", "page": 108, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "f  \nNucleic acid detection \n\u2022Most sensitive and specific \n\u2022Potential false positive due to  \n acute dengue \n \n\u2022Possible to identify serotype \n contamination\n infection \n \n\u2022Early appearance (pre-antibody), \n\u2022Expensive \n  \n \n so opportunity to impact on patient  \n\u2022Needs expertise and expensive laboratory  \n \n\t\t\n\t\n \tmanagement\t\n\t equipment\t\n  \n \n  \n\u2022Not possible to differentiate between \n\t\t\n\t\n\t \t\n\t primary and secondary infection\n  \nIsolation in cell culture  \n\u2022Specific \n\u2022Need expertise and facilit", "page": 108, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "l culture  \n\u2022Specific \n\u2022Need expertise and facility  \n  \nand identification using  \n\u2022Possible to identify \n for cell culture and fluorescent microscopy \n  \nimmuno-fluorescence  \n serotype by using specific antibodies \n\u2022Takes more than 1 week\n  \n \n  \n\u2022Not possible to differentiate between  \n \n\t\t\n\t\n\t \t\n\t primary and secondary infection\n  \n \nAntigen detection  \n\u2022Easy to perform \n\u2022Not as sensitive as virus isolation or \n  \nin clinical specimens  \n\u2022Opportunity for early diagnosis may  \n RNA detection", "page": 108, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "portunity for early diagnosis may  \n RNA detection \n\t\t\n\t\n\t impact on patient treatment\n  \nSerologic tests: \n\u2022Useful for confirmation of acute infection \n\u2022May miss cases because IgM levels may \n  \nIgM tests \n\u2022Least expensive \n  be low or undetectable in some secondary \n  \nSeroconversion: 4-fold  \n\u2022Easy to perform  \n infections \n  \nrise in HI or ELISA IgG \n\u2022Can distinguish between primary \n\u2022Need two samples\n  \ntitres between acute  \n  and secondary infection \n\u2022Delay in confirming diagnosis \n\t\t\nand", "page": 108, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "infection \n\u2022Delay in confirming diagnosis \n\t\t\nand convalescent samples\t\n Surveillance  \nIgM detection  \n\u2022Identify probable dengue cases  \n\u2022May miss cases because IgM levels may \n and outbreak  \n \n\u2022Easy to perform for case detection in  \n be low in secondary infections \n\tidentification;\t\n\t\n\t sentinel laboratories  \n\tMonitor \t\n\t\n \n effectiveness  \nViral isolation and  \n\u2022Confirm cases \n\u2022Can be performed only in reference  \n \n of interventions  RNA detection \n\u2022Identify serotypes \n laboratories", "page": 108, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "detection \n\u2022Identify serotypes \n laboratories \n  \n \n  \n\u2022Need acute samples", "page": 108, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "97\nChapter 4: Laboratory diagnosis and diagnostic tests\nCHAPTER 4\nIn drug trials, patients should have confirmed etiological diagnosis (see Table 4.2 for \nhighly suggestive and confirmed diagnosis).\nTable 4.3 summarizes the advantages and limitations of each of the diagnostic methods \nfor each purpose.\n4.3\t\nCurrent dengue diagnostic methods\n4.3.1\t Virus isolation\nSpecimens for virus isolation should be collected early in the course of the infection, \nduring the period of viraemia (usually before", "page": 109, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "on, \nduring the period of viraemia (usually before day 5). Virus may be recovered from \nserum, plasma and peripheral blood mononuclear cells and attempts may be made \nfrom tissues collected at autopsy (e.g. liver, lung, lymph nodes, thymus, bone marrow). \nBecause dengue virus is heat-labile, specimens awaiting transport to the laboratory \nshould be kept in a refrigerator or packed in wet ice. For storage up to 24 hours, \nspecimens should be kept at between +4 \u00b0C and +8 \u00b0C. For longer storage, sp", "page": 109, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "at between +4 \u00b0C and +8 \u00b0C. For longer storage, specimens \nshould be frozen at -70 \u00b0C in a deep-freezer or stored in a liquid nitrogen container. \nStorage even for short periods at \u201320 \u00b0C is not recommended.\nCell culture is the most widely used method for dengue virus isolation. The mosquito cell \nline C6/36 (cloned from Ae. albopictus) or AP61 (cell line from Ae. pseudoscutellaris) \nare the host cells of choice for routine isolation of dengue virus. Since not all wild type \ndengue viruses induc", "page": 109, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "rus. Since not all wild type \ndengue viruses induce a cytopathic effect in mosquito cell lines, cell cultures must be \nscreened for specific evidence of infection by an antigen detection immunofluorescence \nassay using serotype-specific monoclonal antibodies and flavivirus group-reactive or \ndengue complex-reactive monoclonal antibodies. Several mammalian cell cultures, \nsuch as Vero, LLCMK2, and BHK21, may also be used but are less efficient. Virus \nisolation followed by an immunofluorescence a", "page": 109, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "rus \nisolation followed by an immunofluorescence assay for confirmation generally requires \n1\u20132 weeks and is possible only if the specimen is properly transported and stored to \npreserve the viability of the virus in it.\nWhen no other methods are available, clinical specimens may also be inoculated by \nintracranial route in suckling mice or intrathoracic inoculation of mosquitoes. Newborn \nanimals can develop encephalitis symptoms but with some dengue strains mice may \nexhibit no signs of illnes", "page": 109, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "engue strains mice may \nexhibit no signs of illness. Virus antigen is detected in mouse brain or mosquito head \nsquashes by staining with anti-dengue antibodies.\n4.3.2 Nucleic acid detection\nRNA is heat-labile and therefore specimens for nucleic acid detection must be handled \nand stored according to the procedures described for virus isolation.\n4.3.2.1 RT-PCR\nSince the 1990s, several reverse transcriptase-polymerase chain reaction (RT-PCR) \nassays have been developed. They offer better sensitiv", "page": 109, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ys have been developed. They offer better sensitivity compared to virus isolation", "page": 109, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "98\nDengue: Guidelines for diagnosis, treatment, prevention and control\nwith a much more rapid turnaround time. In situ RT-PCR offers the ability to detect dengue \nRNA in paraffin-embedded tissues.\nAll nucleic acid detection assays involve three basic steps: nucleic acid extraction and \npurification, amplification of the nucleic acid, and detection and characterization of the \namplified product. Extraction and purification of viral RNA from the specimen can be \ndone by traditional liquid phase se", "page": 110, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ecimen can be \ndone by traditional liquid phase separation methods (e.g. phenol, chloroform) but has \nbeen gradually replaced by silica-based commercial kits (beads or columns) that are \nmore reproducible and faster, especially since they can be automated using robotics \nsystems. Many laboratories utilize a nested RT-PCR assay, using universal dengue \nprimers targeting the C/prM region of the genome for an initial reverse transcription and \namplification step, followed by a nested PCR amplificat", "page": 110, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "fication step, followed by a nested PCR amplification that is serotype-specific (14). \nA combination of the four serotype-specific oligonucleotide primers in a single reaction \ntube (one-step multiplex RT-PCR) is an interesting alternative to the nested RT-PCR (15). \nThe products of these reactions are separated by electrophoresis on an agarose gel, \nand the amplification products are visualized as bands of different molecular weights in \nthe agarose gel using ethidium bromide dye, and compared", "page": 110, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "rose gel using ethidium bromide dye, and compared with standard molecular \nweight markers. In this assay design, dengue serotypes are identified by the size of their \nbands. \nCompared to virus isolation, the sensitivity of the RT-PCR methods varies from 80% to \n100% and depends on the region of the genome targeted by the primers, the approach \nused to amplify or detect the PCR products (e.g. one-step RT-PCR versus two-step RT-\nPCR), and the method employed for subtyping (e.g. nested PCR, blot hy", "page": 110, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "d employed for subtyping (e.g. nested PCR, blot hybridization with \nspecific DNA probes, restriction site-specific PCR, sequence analysis, etc.). To avoid \nfalse positive results due to non-specific amplification, it is important to target regions of \nthe genome that are specific to dengue and not conserved among flavi- or other related \nviruses. False-positive results may also occur as a result of contamination by amplicons \nfrom previous amplifications. This can be prevented by physical separa", "page": 110, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ications. This can be prevented by physical separation of different \nsteps of the procedure and by adhering to stringent protocols for decontamination. \n4.3.2.2 Real-time RT-PCR\nThe real-time RT-PCR assay is a one step assay system used to quantitate viral RNA \nand using primer pairs and probes that are specific to each dengue serotype. The use \nof a fluorescent probe enables the detection of the reaction products in real time, in a \nspecialized PCR machine, without the need for electrophoresis.", "page": 110, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "PCR machine, without the need for electrophoresis. Many real-time RT-PCR \nassays have been developed employing TaqMan or SYBR Green technologies. The \nTaqMan real-time PCR is highly specific due to the sequence-specific hybridization of \nthe probe. Nevertheless, primers and probes reported in publications may not be able \nto detect all dengue virus strains: the sensitivity of the primers and probes depends on \ntheir homology with the targeted gene sequence of the particular virus analyzed. The", "page": 110, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "e sequence of the particular virus analyzed. The \nSYBR green real-time RT-PCR has the advantage of simplicity in primer design and uses \nuniversal RT-PCR protocols but is theoretically less specific. \nReal-time RT-PCR assays are either \u201csingleplex\u201d (i.e. detecting only one serotype at \na time) or \u201cmultiplex\u201d (i.e. able to identify all four serotypes from a single sample). \nThe multiplex assays have the advantage that a single reaction can determine all four \nserotypes without the potential for i", "page": 110, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ne all four \nserotypes without the potential for introduction of contamination during manipulation of \nthe sample. However the multiplex real-time RT-PCR assays, although faster, are currently \nless sensitive than nested RT-PCR assays. An advantage of this method is the ability to", "page": 110, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "99\nChapter 4: Laboratory diagnosis and diagnostic tests\nCHAPTER 4\ndetermine viral titre in a clinical sample, which may be used to study the pathogenesis \nof dengue disease (16).\n4.3.2.3 Isothermal amplification methods\nThe NASBA (nucleic  acid sequence based amplification) assay is an isothermal RNA-\nspecific amplification assay that does not require thermal cycling instrumentation. The \ninitial stage is a reverse transcription in which the single-stranded RNA target is copied \ninto a double-st", "page": 111, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "le-stranded RNA target is copied \ninto a double-stranded DNA molecule that serves as a template for RNA transcription. \nDetection of the amplified RNA is accomplished either by electrochemiluminescence or in \nreal-time with fluorescent-labelled molecular beacon probes. NASBA has been adapted \nto dengue virus detection with sensitivity near that of virus isolation in cell cultures and \nmay be a useful method for studying dengue infections in field studies (17).\nLoop mediated amplification methods", "page": 111, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "studies (17).\nLoop mediated amplification methods have also been described but their performance \ncompared to other nucleic acid amplification methods are not known (18).\n4.3.3 Detection of antigens\nUntil recently, detection of dengue antigens in acute-phase serum was rare in patients \nwith secondary infections because such patients had pre-existing virus-IgG antibody \nimmunocomplexes. New developments in ELISA and dot blot assays directed to the \nenvelop/membrane (E/M) antigen and the non-stru", "page": 111, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "e \nenvelop/membrane (E/M) antigen and the non-structural protein 1 (NS1) demonstrated \nthat high concentrations of these antigens in the form of immune complexes could be \ndetected in patients with both primary and secondary dengue infections up to nine days \nafter the onset of illness. \nThe NS1 glycoprotein is produced by all flaviviruses and is secreted from mammalian \ncells. NS1 produces a very strong humoral response. Many studies have been directed \nat using the detection of NS1 to make an", "page": 111, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "irected \nat using the detection of NS1 to make an early diagnosis of dengue virus infection. \nCommercial kits for the detection of NS1 antigen are now available, though they do \nnot differentiate between dengue serotypes. Their performance and utility are currently \nbeing evaluated by laboratories worldwide, including the WHO/TDR/PDVI laboratory \nnetwork. \nFluorescent antibody, immunoperoxidase and avidin-biotin enzyme assays allow \ndetection of dengue virus antigen in acetone-fixed leucocytes a", "page": 111, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "dengue virus antigen in acetone-fixed leucocytes and in snap-frozen or \nformalin-fixed tissues collected at autopsy.\n4.3.4 \tSerological tests\n4.3.4.1 MAC-ELISA\nFor the IgM antibody-capture enzyme-linked immunosorbent assay (MAC-ELISA) total IgM \nin patients\u2019 sera is captured by anti-\u00b5 chain specific antibodies (specific to human IgM) \ncoated onto a microplate. Dengue-specific antigens, from one to four serotypes (DEN-1, \n-2, -3, and -4), are bound to the captured anti-dengue IgM antibodies and a", "page": 111, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "d to the captured anti-dengue IgM antibodies and are detected \nby monoclonal or polyclonal dengue antibodies directly or indirectly conjugated with an", "page": 111, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "100\nDengue: Guidelines for diagnosis, treatment, prevention and control\nenzyme that will transform a non-coloured substrate into coloured products. The optical \ndensity is measured by spectrophotometer. \nSerum, blood on fi\n lter paper and saliva, but not urine, can be used for detection of IgM if \nsamples are taken within the appropriate time frame (fi\n ve days or more after the onset of \nfever). Serum specimens may be tested at a single dilution or at multiple dilutions. Most \nof the antigens u", "page": 112, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "or at multiple dilutions. Most \nof the antigens used for this assay are derived from the dengue virus envelope protein \n(usually virus-infected cell culture supernatants or suckling mouse brain preparations). \nMAC-ELISA has good sensitivity and specifi\n city but only when used fi\n ve or more days \nafter the onset of fever. Different commercial kits (ELISA or rapid tests) are available but \nhave variable sensitivity and specifi\n city. A WHO/TDR/PDVI laboratory network recently \nevaluated selecte", "page": 112, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "DVI laboratory network recently \nevaluated selected commercial ELISAs and fi\n rst-generation rapid diagnostic tests, fi\n nding \nthat ELISAs generally performed better than rapid tests.\nCross-reactivity with other circulating fl\n aviviruses such as Japanese encephalitis, St Louis \nencephalitis and yellow fever, does not seem to be a problem but some false positives \nwere obtained in sera from patients with malaria, leptospirosis and past dengue infection \n(10). These limitations have to be taken", "page": 112, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "fection \n(10). These limitations have to be taken into account when using the tests in regions \nwhere these pathogens co-circulate. It is recommended that tests be evaluated against \na panel of sera from relevant diseases in a particular region before being released to \nthe market. It is not possible to use IgM assays to identify dengue serotypes as these \nantibodies are broadly cross-reactive even following primary infections. Recently, some \nauthors have described MAC-ELISA (Figure 4.3) that c", "page": 112, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "thors have described MAC-ELISA (Figure 4.3) that could allow serotype determination \nbut further evaluations are required (19).\n4.3.4.2 IgG ELISA\nThe IgG ELISA is used for the detection of recent or past dengue infections (if paired sera \nare collected within the correct time frame). This assay uses the same antigens as the \nFigure 4.3 Principle of a MAC-ELISA test\nColoured\n substrate \nNon-coloured\n    substrate \nMicroplate \nAnti-\u00b5 chain\nPatient\u2019s IgM \nDEN antigen \nAnti-dengue\nAb conjugated\n  wi", "page": 112, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "s IgM \nDEN antigen \nAnti-dengue\nAb conjugated\n  with enzyme \nSpectrophotometer \nNon dengue-specifi\n c \nIgM", "page": 112, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "101\nChapter 4: Laboratory diagnosis and diagnostic tests\nCHAPTER 4\nMAC-ELISA. The use of E/M-specific capture IgG ELISA (GAC) allows detection of IgG \nantibodies over a period of 10 months after the infection. IgG antibodies are lifelong as \nmeasured by E/M antigen-coated indirect IgG ELISA, but a fourfold or greater increase \nin IgG antibodies in acute and convalescent paired sera can be used to document \nrecent infections. Test results correlate well with the haemagglutination-inhibition test.", "page": 113, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "e well with the haemagglutination-inhibition test. \nAn ELISA inhibition method (EIM) to detect IgG dengue antibodies (20) is also used \nfor the serological diagnosis and surveillance of dengue cases. This system is based in \nthe competition for the antigen sites by IgG dengue antibodies in the sample and the \nconjugated human IgG anti-dengue. \nThis method can be used to detect IgG antibodies in serum or plasma and filter-paper \nstored blood samples and permits identification of a case as a prima", "page": 113, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "es and permits identification of a case as a primary or secondary \ndengue infection (20,21,22). In general, IgG ELISA lacks specificity within the flavivirus \nserocomplex groups. Following viral infections, newly produced antibodies are less \navid than antibodies produced months or years after infection. \nAntibody avidity is used in a few laboratories to discriminate primary and secondary \ndengue infections. Such tests are not in wide use and are not available commercially. \n4.3.4.3 IgM/IgG rati", "page": 113, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "not available commercially. \n4.3.4.3 IgM/IgG ratio\nA dengue virus E/M protein-specific IgM/IgG ratio can be used to distinguish primary \nfrom secondary dengue virus infections. IgM capture and IgG capture ELISAs are the \nmost common assays for this purpose. In some laboratories, dengue infection is defined \nas primary if the IgM/IgG OD ratio is greater than 1.2 (using patient\u2019s sera at 1/100 \ndilution) or 1.4 (using patient\u2019s sera at 1/20 dilutions). The infection is secondary if the \nratio is", "page": 113, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ons). The infection is secondary if the \nratio is less than 1.2 or 1.4. This algorithm has also been adopted by some commercial \nvendors. However, ratios may vary between laboratories, thus indicating the need for \nbetter standardization of test performance (8).\n4.3.4.4 IgA\nPositive detection for serum anti-dengue IgA as measured by anti-dengue virus IgA \ncapture ELISA (AAC-ELISA) often occurs one day after that for IgM. The IgA titre peaks \naround day 8 after onset of fever and decreases rapidl", "page": 113, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "nd day 8 after onset of fever and decreases rapidly until it is undetectable by day \n40. No differences in IgA titres were found by authors between patients with primary \nor secondary infections. Even though IgA values are generally lower than IgM, both in \nserum and saliva, the two methods could be performed together to help in interpreting \ndengue serology (22,23). This approach is not used very often and requires additional \nevaluation. \n4.3.4.5 Haemagglutination-inhibition test \nThe haemaggl", "page": 113, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": ".5 Haemagglutination-inhibition test \nThe haemagglutination-inhibition (HI) test (see Figure 4.4) is based on the ability of \ndengue antigens to agglutinate red blood cells (RBC) of ganders or trypsinized human \nO RBC. Anti-dengue antibodies in sera can inhibit this agglutination and the potency \nof this inhibition is measured in an HI test. Serum samples are treated with acetone or \nkaolin to remove non-specific inhibitors of haemagglutination, and then adsorbed with \ngander or trypsinized type", "page": 113, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "and then adsorbed with \ngander or trypsinized type O human RBC to remove non-specific agglutinins. Each batch", "page": 113, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "102\nDengue: Guidelines for diagnosis, treatment, prevention and control\nof antigens and RBC is optimized. PH optima of each dengue haemagglutinin requires \nthe use of multiple different pH buffers for each serotype. Optimally the HI test requires \npaired sera obtained upon hospital admission (acute) and discharge (convalescent) or \npaired sera with an interval of more than seven days. The assay does not discriminate \nbetween infections by closely related fl\n aviviruses (e.g. between dengue virus", "page": 114, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "related fl\n aviviruses (e.g. between dengue virus and \nJapanese encephalitis virus or West Nile virus) nor between immunoglobulin isotypes. \nThe response to a primary infection is characterized by the low level of antibodies in \nthe acute-phase serum drawn before day 5 and a slow elevation of HI antibody titres \nthereafter. During secondary dengue infections HI antibody titres rise rapidly, usually \nexceeding 1:1280. Values below this are generally observed in convalescent sera from \npatients w", "page": 114, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "lly observed in convalescent sera from \npatients with primary responses.\n4.3.5 Haematological tests\nPlatelets and haematocrit values are commonly measured during the acute stages of \ndengue infection. These should be performed carefully using standardized protocols, \nreagents and equipment.\nA drop of the platelet count below 100 000 per \u00b5L may be observed in dengue fever \nbut it is a constant feature of dengue haemorrhagic fever. Thrombocytopaenia is usually \nobserved in the period between day 3", "page": 114, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "a is usually \nobserved in the period between day 3 and day 8 following the onset of illness.\nHaemoconcentration, as estimated by an increase in haematocrit of 20% or more \ncompared with convalescent values, is suggestive of hypovolaemia due to vascular \npermeability and plasma leakage.\nFigure 4.4 Haemagglutination-inhibition assay\nHaemagglutination\n= negative result \nHaemagglutination\n= negative result\nnegative result\nInhibition of\nHaemagglutination\n= positive result \nDengue virus\n        antige", "page": 114, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ion\n= positive result \nDengue virus\n        antigens \nRed blood\n           cells \nAnti-dengue virus\n        antibody", "page": 114, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "103\nChapter 4: Laboratory diagnosis and diagnostic tests\nCHAPTER 4\n4.4  Future test developments\nMicrosphere-based immunoassays (MIAs) are becoming increasingly popular as a \nserological option for the laboratory diagnosis of many diseases. This technology is based \non the covalent bonding of antigen or antibody to microspheres or beads. Detection \nmethods include lasers to elicit fluorescence of varying wavelengths. This technology is \nattractive as it is faster than the MAC-ELISA and has poten", "page": 115, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "e as it is faster than the MAC-ELISA and has potential for multiplexing serological \ntests designed to identify antibody responses to several viruses. MIAs can also be used \nto detect viruses.\nRapid advances in biosensor technology using mass spectrometry have led to the \ndevelopment of powerful systems that can provide rapid discrimination of biological \ncomponents in complex mixtures. The mass spectra that are produced can be considered \na specific fingerprint or molecular profile of the bacte", "page": 115, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ific fingerprint or molecular profile of the bacteria or virus analysed. The software \nsystem built into the instrument identifies and quantifies the pathogen in a given sample \nby comparing the resulting mass spectra with those in a database of infectious agents, \nand thus allows the rapid identification of many thousands of types of bacteria and \nviruses. Additionally, these tools can recognize a previously unidentified organism in the \nsample and describe how it is related to those encountere", "page": 115, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "and describe how it is related to those encountered previously. This could be \nuseful in determining not only dengue serotypes but also dengue genotypes during an \noutbreak. Identification kits for infectious agents are available in 96-well format and can \nbe designed to meet specific requirements. Samples are processed for DNA extraction, \nPCR amplification, mass spectrometry and computer analysis. \nMicroarray technology makes it possible to screen a sample for many different nucleic \nacid frag", "page": 115, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "een a sample for many different nucleic \nacid fragments corresponding to different viruses in parallel. The genetic material must \nbe amplified before hybridization to the microarray, and amplification strategy can \ntarget conserved sequences as well as random-based ones. Short oligonucleotides \nattached on the microarray slide give a relatively exact sequence identification, while \nlonger DNA fragments give a higher tolerance for mismatches and thus an improved \nability to detect diverged strai", "page": 115, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "thus an improved \nability to detect diverged strains. A laser-based scanner is commonly used as a reader to \ndetect amplified fragments labelled with fluorescent dyes. Microarray could be a useful \ntechnology to test, at the same time, dengue virus and other arboviruses circulating in \nthe region and all the pathogens responsible for dengue-like symptoms.\nOther approaches have been tested but are still in the early stages of development and \nevaluation. For instance, the luminescence-based techn", "page": 115, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "uation. For instance, the luminescence-based techniques are becoming increasingly \npopular owing to their high sensitivity, low background, wide dynamic range and \nrelatively inexpensive instrumentation.", "page": 115, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "104\nDengue: Guidelines for diagnosis, treatment, prevention and control\n4.5 QUALITY ASSURANCE\nMany laboratories use in-house assays. The main weakness of these assays is the lack of \nstandardization of protocols, so results cannot be compared or analysed in aggregate. It \nis important for national or reference centres to organize quality assurance programmes \nto ensure the profi\n ciency of laboratory staff in performing the assays and to produce \nreference materials for quality control of test k", "page": 116, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "reference materials for quality control of test kits and assays. \nFor nucleic acid amplifi\n cation assays, precautions need to be established to prevent \ncontamination of patient materials. Controls and profi\n ciency-testing are necessary to \nensure a high degree of confi\n dence (24).\n4.6 BIOSAFETY ISSUES\nThe collection and processing of blood and other specimens place health care workers \nat risk of exposure to potentially infectious material. To minimize the risk of infection, safe \nlaborator", "page": 116, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "To minimize the risk of infection, safe \nlaboratory techniques (i.e. use of personal protective equipment, appropriate containers \nfor collecting and transporting samples, etc.) must be practised as described in WHO\u2019s \nLaboratory biosafety manual (25).\n4.7 ORGANIZATION OF LABORATORY SERVICES\nIn a disease-endemic country, it is important to organize laboratory services in the \ncontext of patients\u2019 needs and disease control strategies. Appropriate resources should \nbe allocated and training provid", "page": 116, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "resources should \nbe allocated and training provided. A model is proposed in Table 4.4. Examples of \ngood and bad practice can be found in Table 4.5. \nTable 4.4 Proposed model for organization of laboratory services\n Dengue diagnostic tests \nPrimary health centres \nDistrict centres \nReference centre\n - Virus culture \n \n \n+\n - Nucleic acid detection \n \n \n+\n - Antigen detection \n \n+ \n+\n   \n\u2022 ELISA \n \n+ \n+\n   \n\u2022 Rapid tests \n+ \n+ \n+\n - Serology\n   \n\u2022 ELISA \n \n+ \n+\n   \n\u2022 Rapid tests  \n+ \n+ \n+ \n Func", "page": 116, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "\u2022 ELISA \n \n+ \n+\n   \n\u2022 Rapid tests  \n+ \n+ \n+ \n Functions\n - Training and supervision \n \n+ \n+\n - Quality assurance \n+ \n+ \n+\n - Surveillance activities \n \n+ \n+\n - Outbreak investigations \n \n \n+\n - Referral of problem specimens \n+ \n+ \n+\n - Investigation of problem specimens \n \n \n+", "page": 116, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "105\nChapter 4: Laboratory diagnosis and diagnostic tests\nCHAPTER 4\nTable 4.5 Dengue laboratory diagnosis: examples of good and bad practice \n\t \t\nGood practice\t\nBad practice\n\t 1. When to use a test\t\nConsider the purpose of the testing\t\nUse of inappropriate test leading to \n\t \t\nbefore making a selection (e.g. for\t\nmisinterpretation of results \n\t \t\noutbreak investigations versus  \n\t \t\nclinical diagnosis)\n\t 2. How to use a test\t\nStrictly follow manufacturer\u2019s \t\nNot following the manufacturer\u2019s", "page": 117, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "acturer\u2019s \t\nNot following the manufacturer\u2019s \n\t \t\nrecommendations or updated Standard\t\nrecommendations  \n\t \t\nOperational Procedures with Good \t\nNot following the written laboratory \n\t \t\nLaboratory Practices\t\nprocedures for each test, or modifying \n\t \t\n\t\nthe procedures without prior validation\n\t 3. Laboratory issues\t\nSystem of quality management instituted \t\nResults not reliable or accurate because \n\t \t\nin the laboratory\t\nno quality control was used in the assay, \n\t \t\n\t\nor personnel are not profi", "page": 117, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ed in the assay, \n\t \t\n\t\nor personnel are not proficient, or  \n\t \t\n\t\nequipment not calibrated\n\t \t\n\t\nRecords not properly kept\n\t \t\n\t\nUse of unvalidated test kits\n\t \t\n\t\nMixing reagents from different test kits or  \n\t \t\n\t\ntest lots\n\t \t\n\t\nFalse positive results due to contamination\n\t \t\nPaired serum samples should be tested\t\nOver-interpretation and misinterpretation  \n\t \t\nin the same assay to determine if\t\nof test results \n\t \t\nthere is a four-fold rise in titre\t\nAcute samples not re-tested together wi", "page": 117, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "in titre\t\nAcute samples not re-tested together with \t\n\t \t\n\t\nconvalescent samples", "page": 117, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "106\nDengue: Guidelines for diagnosis, treatment, prevention and control\n4.8 REFERENCES\n1. Vorndam V, Kuno G. Laboratory diagnosis of dengue virus infections. In: Gubler DJ, \nKuno G, eds. Dengue and dengue hemorrhagic fever. New York, CAB International, \n1997:313\u2013333.\n2. Innis B et al. An enzyme-linked immunosorbent assay to characterize dengue infections \nwhere dengue and Japanese encephalitis co-circulate. American Journal of Tropical \nMedicine and Hygiene, 1989, 40:418\u2013427.\n3. PAHO. Dengue and", "page": 118, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "and Hygiene, 1989, 40:418\u2013427.\n3. PAHO. Dengue and dengue hemorrhagic fever in the Americas: guidelines for \nprevention and control. Washington, DC, Pan American Health Organization, 1994 \n(Scientific Publication No. 548).\n4. WHO. Dengue haemorrhagic fever: diagnosis, treatment, prevention and control, \n2nd ed. Geneva, World Health Organization, 1997.\n5. Chanama S et al. Analysis of specific IgM responses in secondary dengue virus \ninfections: levels and positive rates in comparison with primary", "page": 118, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "vels and positive rates in comparison with primary infections. Journal of \nClinical Virology, 2004, 31:185\u2013189.\n6. Kuno G, Gomez I, Gubler DJ. An ELISA procedure for the diagnosis of dengue \ninfections. Journal of Virological Methods, 1991, 33:101\u2013113.\n7. Shu PY et al. Comparison of a capture immunoglobulin M (IgM) and IgG ELISA and \nnon-structural protein NS1 serotype-specific IgG ELISA for differentiation of primary and \nsecondary dengue virus infections. Clinical and Diagnostic Laboratory Imm", "page": 118, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "infections. Clinical and Diagnostic Laboratory Immunology, \n2003, 10:622\u2013630.\n8. Falconar AK, de Plata E, Romero-Vivas CM. Altered enzyme-linked immunosorbent \nassay immunoglobulin M (IgM)/IgG optical density ratios can correctly classify all \nprimary or secondary dengue virus infections 1 day after the onset of symptoms, when \nall of the viruses can be isolated. Clinical and Vaccine Immunology, 2006, 13:1044\u2013\n1051.\n9. Pelegrino JL.  Summary of dengue diagnostic methods. World Health Organizatio", "page": 118, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "engue diagnostic methods. World Health Organization, \nSpecial Programme for Research and Training in Tropical Diseases, 2006 (unpublished \nreport). \n10. Hunsperger EA et al. Evaluation of commercially available anti\u2013dengue virus \nimmunoglobulin M tests. Emerging Infectious Diseases (serial online), 2009, March \n(date cited). Accessible at http://www.cdc.gov/EID/content/15/3/436.htm\n11. Morens DM et al. Simplified plaque reduction neutralization assay for dengue \nviruses by semimicro methods in B", "page": 118, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ssay for dengue \nviruses by semimicro methods in BHK-21 cells: comparison of the BHK suspension test \nwith standard plaque reduction neutralization. Journal of Clinical Microbiology, 1985, \n22(2):250\u2013254.", "page": 118, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "107\nChapter 4: Laboratory diagnosis and diagnostic tests\nCHAPTER 4\n12. Alvarez M et al. Improved dengue virus plaque formation on BHK21 and LLCMK2 \ncells: evaluation of some factors. Dengue Bulletin, 2005, 29:1\u20139.\n13. Halstead SB, Rojanasuphot S, Sangkawibha N. Original antigenic sin in dengue. \nAmerican Journal of Tropical Medicine and Hygiene, 1983, 32:154\u2013156.\n14. Lanciotti RS et al. Rapid detection and typing of dengue viruses from clinical \nsamples by using reverse transcriptase-polymerase", "page": 119, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "samples by using reverse transcriptase-polymerase chain reaction. Journal of Clinical \nMicrobiology, 1992, 30:545\u2013551.\n15. Harris E et al. Typing of dengue viruses in clinical specimens and mosquitoes by \nsingle tube multiplex reverse transcriptase PCR. Journal of Clinical Microbiology, 1998, \n36:2634\u20132639.\n16. Vaughn DW et al. Dengue viremia titer, antibody response pattern and virus serotype \ncorrelate with disease severity. Journal of Infectious Diseases, 2000, 181:2\u20139.\n17. Shu PY, Huang JH.", "page": 119, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "us Diseases, 2000, 181:2\u20139.\n17. Shu PY, Huang JH. Current advances in dengue diagnosis. Clinical and Diagnostic \nLaboratory Immunology, 2004, 11(4):642\u2013650.\n18. Parida MM et al. Rapid detection and differentiation of dengue virus serotypes by \na real-time reverse transcription-loop-mediated isothermal amplification assay. Journal \nof Clinical Microbiology, 2005, 43:2895\u20132903 (doi: 10.1128/JCM.43.6.2895-\n2903.2005).\n19. Vazquez S et al. Serological markers during dengue 3 primary and secondary \ni", "page": 119, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "l markers during dengue 3 primary and secondary \ninfections. Journal of Clinical Virology, 2005, 33(2):132\u2013137.\n20. Fernandez RJ, Vazquez S. Serological diagnosis of dengue by an ELISA inhibition \nmethod (EIM). Mem\u00f3rias do Instituto Oswaldo Cruz, 1990, 85(3):347\u2013351.\n21. Vazquez S, Fernandez R, Llorente C. Usefulness of blood specimens on paper strips \nfor serologic studies with inhibition ELISA. Revista do Instituto de Medicina Tropical de \nS\u00e3o Paulo, 1991, 33(4):309\u2013311.\n22. Vazquez S et al. K", "page": 119, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "Paulo, 1991, 33(4):309\u2013311.\n22. Vazquez S et al. Kinetics of antibodies in sera, saliva, and urine samples from adult \npatients with primary or secondary dengue 3 virus infections. International Journal of \nInfectious Diseases, 2007, 11:256\u2013262.\n23. Nawa M. Immunoglobulin A antibody responses in dengue patients: a useful \nmarker for serodiagnosis of dengue virus infection. Clinical and Vaccine Immunology, \n2005, 12:1235\u20131237.\n24. Lemmer K et al. External quality control assessments in PCR diagno", "page": 119, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "External quality control assessments in PCR diagnostics of dengue \nvirus infections. Journal of Clinical Virology, 2004, 30:291\u2013296.\n25. WHO. Laboratory biosafety manual, 3rd ed. Geneva, World Health Organization, \n2004 (ISBN 92 4 154650 6, WHO/CDS/CSR/LYO/2004.11,\nhttp://www.who.int/csr/resources/publications/biosafety/Biosafety7.pdf).", "page": 119, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "108\nDengue: Guidelines for diagnosis, treatment, prevention and control", "page": 120, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "109\nChapter 5. Surveillance, emergency preparedness and response\nCHAPTER 5\nChapter 5\n \nSurveillance, emergency  \npreparedness and response", "page": 121, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "110\nDengue: Guidelines for diagnosis, treatment, prevention and control", "page": 122, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "111\nChapter 5. Surveillance, emergency preparedness and response\nCHAPTER 5\nChapter 5. Surveillance, emergency preparedness and \nresponse\n5. 1 Overview\nThe prevention of and response to dengue and other arboviruses involve developing \nand implementing preparedness plans. These should include early warning systems, \nepidemiological, entomological and environmental surveillance, laboratory support, \nclinical case management, vector control, environmental controls, risk communication \nand social mob", "page": 123, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ental controls, risk communication \nand social mobilization. Sustainable solutions to dengue control require political will \nand leadership in order to respond effectively to the needs of preparedness planning \nand epidemic response (including insight into community responses to dengue, and \napplied research to devise, test and evaluate new approaches and technologies). \nNational partnerships involving government bodies, research institutions and the private \nsector, as well as international col", "page": 123, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "the private \nsector, as well as international collaborations, are needed for comprehensive plans and \nprogrammes for dengue epidemic preparedness and response. \nThis chapter provides an overview of the key areas of preparedness planning, epidemic \ndetection and emergency response for dengue containment and control in endemic \ncountries. It gives guidance to countries at risk of dengue introduction through the \nmovement of infected persons or vectors. Strategies are suggested for preparedness,", "page": 123, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "tors. Strategies are suggested for preparedness, \nalert and response at local, national and international levels. Table 5.2 provides \nexamples of good and bad practice for dengue surveillance.\n5.2  Dengue surveillance\nThe three major components of dengue surveillance \u2013 disease surveillance, vector \nsurveillance and monitoring of environmental and social risks \u2013 are presented below. \n5.2.1 Disease (epidemiological) surveillance \nEpidemiological surveillance is the ongoing systematic collection, r", "page": 123, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "rveillance is the ongoing systematic collection, recording, analysis, \ninterpretation and dissemination of data reflecting the current health status of a community \nor population so that action may be taken to prevent or control a disease. Surveillance \nis a critical component of any dengue prevention and control programme as it provides \nthe information necessary for risk assessment, epidemic response and programme \nevaluation. Surveillance can utilize both passive and active data collection pr", "page": 123, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "utilize both passive and active data collection processes. \nDepending on the circumstances under investigation, surveillance uses a wide variety of \ndata sources to enhance and expand the epidemiological picture of transmission risk. \n5.2.1.1 Purpose and objectives of the dengue surveillance system\nThe purpose(s) of the surveillance system should be explicitly and clearly described and \nshould include the intended uses of the system. Specific objectives and performance \nindicators (expected resu", "page": 123, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ectives and performance \nindicators (expected results) should be set for each administrative level of the health \nsystem and for other agencies involved in dengue response within countries, as well \nas for international and global surveillance. The objectives of the surveillance system \nwill guide the type of surveillance conducted, the timing of surveillance activities, the", "page": 123, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "112\nDengue: Guidelines for diagnosis, treatment, prevention and control\nsignal(s) and thresholds for investigation and response, the specific surveillance methods \nused and the balance between the desired attributes of the surveillance system. \nThe overall objectives of public health surveillance (1) which are most applicable to \ndengue are as follows:\n \n\u2022 detect epidemics quickly for early intervention;\n \n\u2022 measure the burden of disease and provide data for the assessment of the social \n\t\n\t\nand", "page": 124, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ide data for the assessment of the social \n\t\n\t\nand economic impact of dengue on the affected community;\n \n\u2022 monitor trends in the distribution and spread of dengue over time and  \n \n\t\n\t\ngeographically;\n \n\u2022 evaluate the effectiveness of dengue prevention and control programmes;\n \n\u2022 facilitate planning and resource allocation on the basis of lessons learned from  \n\t\n\t\nprogramme evaluation.\nIn setting up a surveillance system, consideration should be given to balancing the risk of \nan epidemic occu", "page": 124, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "e given to balancing the risk of \nan epidemic occurring, the value of early intervention in reducing the medical, social and \neconomic impact of the disease, and the finite resources available for investigation and \ncontrol. The usefulness of the surveillance system depends on its attributes \u2013 the relative \nimportance given to the timeliness of signal detection, and the system\u2019s sensitivity, positive \npredictive value (PPV) and negative predictive value (NPV) for detecting epidemics. \nMost impor", "page": 124, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "e value (NPV) for detecting epidemics. \nMost importantly, the system must ensure that surveillance is linked to response and to \nthe ability to control or limit an epidemic by:\n \n\u2022 Timeliness is the speed with which cases or alerts are detected and reported.\n \n\u2022 Sensitivity is the proportion of cases or alerts occurring in the geographical area \n\t\n\t\nor population detected by the system. Sensitivity is measured against a \u201cgold \t\n\t\n\t\nstandard\u201d, often laboratory confirmation, to determine the propo", "page": 124, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "en laboratory confirmation, to determine the proportion of dengue \n\t\n\t\nsignals detected by the surveillance system against all real or confirmed cases or \n\t\n\t\nalerts.\n \n\u2022 The PPV is the probability of a dengue signal being a confirmed case or epidemic \n\t\n\t\nand is dependent on the background prevalence of the disease in the \t\n\t\n\t\n\t\npopulation.\n \n\u2022 The NPV is the probability that the surveillance system does not yield a dengue  \n\t\n\t\nsignal when no epidemic is occurring.\nThe quality of data is meas", "page": 124, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "epidemic is occurring.\nThe quality of data is measured by its completeness (accuracy of information, missing \ndata, etc) and representativeness. Representativeness reflects whether the surveillance \nsystem accurately describes the distribution of cases in time (seasonality), place \n(geographical distribution), and the population at risk of dengue. Data may not be \nrepresentative when case ascertainment is incomplete (e.g. in a sentinel surveillance \nsystem or a statistically-based sample). \nThe", "page": 124, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ce \nsystem or a statistically-based sample). \nThe main objective of dengue disease surveillance is usually to detect and forecast \nepidemic activity. Surveillance activities should ideally include the surveillance of \nhuman cases of the disease, laboratory-based surveillance, vector surveillance, and the \nmonitoring of environmental risk factors for dengue epidemics. Effective surveillance of \ndengue also requires the appropriate level of investment of financial and human resources,", "page": 124, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ent of financial and human resources,", "page": 124, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "113\nChapter 5. Surveillance, emergency preparedness and response\nCHAPTER 5\nand training and tools to ensure that increased dengue transmission is detected early \nand that the response is appropriate. Dengue activity may require consultation with, or \nnotification to, WHO under the International Health Regulations (2005) (2), depending \non the risk assessment. For instance, dengue activity may warrant communication with \nWHO in cases such as the first confirmation of locally-acquired dengue in a", "page": 125, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "irst confirmation of locally-acquired dengue in a previously \nunaffected area, a new serotype, the importation of dengue vectors, atypical clinical \npresentations, and excessively high case-fatality rates.\nDepending on whether epidemic detection or trend monitoring, or both, are the main \npurposes of the surveillance system, different system attributes should be emphasized. \nWhere the risk of a dengue epidemic or the introduction of dengue is high, the \nsurveillance system should aim for timelin", "page": 125, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "h, the \nsurveillance system should aim for timeliness, high sensitivity and a low threshold for \ninvestigation, bearing in mind that a higher proportion of signals detected will prove to \nbe false positives and that follow-up investigations are likely to be resource-intensive.\nMonitoring dengue incidence and prevalence over time establishes a baseline \nmeasurement of the background rate of disease so that an unexpected rise in the number \nof cases or the proportion of severe cases will trigger a", "page": 125, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "s or the proportion of severe cases will trigger an alert and further investigation, \nintervention and prevention measures. Early warning of an epidemic enables health \nservices to allocate human and material resources more effectively, to alert clinicians \nto the need to diagnose and properly treat dengue cases, and to better engage the \ncommunity in prevention and control activities, thereby reducing transmission and \nimproving clinical outcomes.\n5.2.1.2 Early warning systems\nEarly warning sys", "page": 125, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "s.\n5.2.1.2 Early warning systems\nEarly warning systems for dengue can include event-based surveillance, case-based \nreporting of human disease or aggregated data reporting, and/or the surveillance of \nrisk factors for human disease. \nEvent-based surveillance\nEvent-based surveillance is designed to rapidly detect unusual or unexpected disease \nevents (signals) such as disease clusters (e.g. of unexplained fever or acute haemorrhagic \nfever syndrome) and unexplained deaths, and may include events", "page": 125, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "e) and unexplained deaths, and may include events related to potential \nexposure for humans (e.g. climatic conditions favourable to oviposition and subsequent \nmaturation of mosquitoes) (3,4). Event-based surveillance uses reports generated by \nthe media and other open sources of information, or via key informants in the affected \ncommunity, as well as reports provided through established surveillance systems. Unlike \nclassical surveillance systems, event-based surveillance uses unstructured and", "page": 125, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ms, event-based surveillance uses unstructured and ad hoc \nreporting of events rather than the routine collection of data and automated thresholds \nfor action (5). To be effective, event-based surveillance requires that a public health unit \nor team is designated to sort incoming information, confirm each reported event, and \ntrigger an immediate response, as appropriate.\nCase-based surveillance and the surveillance of dengue risk factors\nThe utility of traditional dengue surveillance in trigger", "page": 125, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "lity of traditional dengue surveillance in triggering rapid response is strengthened \nby the availability and real-time collection, analysis and interpretation of linked clinical, \nlaboratory and epidemiological data using established case definitions of infection and \ndisease. The surveillance case definitions for dengue and severe dengue are currently \nunder review.", "page": 125, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "114\nDengue: Guidelines for diagnosis, treatment, prevention and control\nThe threshold for alert and response will vary according to the operational level affected \n(local, national, international) and whether the affected area is endemic for dengue or at \nrisk of its introduction. For example, at the local level a single dengue case may trigger \naction. At state or provincial level, the increase in reported cases above an established \nbaseline for the same week or month in preceding years, or in", "page": 126, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "r the same week or month in preceding years, or increasing vector density, \nmay indicate impending epidemic activity. At national level, the detection of changes in \nvirus serotype, subtype or genotype distribution, clinical severity or seropositivity rate, or \nthe introduction of a dengue vector into a new ecological niche, are signals that should \nbe investigated without delay. \nWell-defined triggers (indicators) should be identified and established before the \nemergency occurs in order to int", "page": 126, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ished before the \nemergency occurs in order to intensify surveillance and follow-up, and to initiate the \nemergency response. The following indicators for epidemic detection \u2013 which use the \ndeviation of reported dengue cases or laboratory results from the \u201caverage\u201d \u2013 have \nbeen documented, although these indicators have been tested mostly in one specific \nsetting only (6):\n \n\u2022 \u201cExcess of dengue cases\u201d has been used successfully in Puerto Rico to predict \n\t\n\t\nevery epidemic since 1982, including", "page": 126, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "predict \n\t\n\t\nevery epidemic since 1982, including those involving DEN-4 in 1982, DEN-4 \t\n\t\n\t\nin 1986-87, DEN-2 in 1994, DEN-4 in 1998 and DEN-3 in 2001.\n \n\u2022 \u201cVirus isolation rate in excess of routine virological testing rate\u201d measured as the \n\t\n\t\nincreased proportion of blood samples positive for dengue viruses in the low \t\n\t\n\t\nseason for dengue has proved useful in Puerto Rico (7,8,9).\n \n\u2022 The appearance of a new dengue serotype can be used as an early warning  \n\t\n\t\nsignal but does not predict", "page": 126, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "an early warning  \n\t\n\t\nsignal but does not predict the occurrence of an immediate epidemic (10).\n \n\u2022 \u201cFever alert\u201d \u2013 i.e. an unexpected and unusual increase in the number of fever  \n\t\n\t\ncases \u2013 may be a useful signal of increased dengue activity in locations where the \n \n\t\n\t\nfrequency and differential diagnosis of acute febrile illness is limited. A fever \t\n\t\n\t\nalert is thus useful when used to monitor febrile syndromes such as dengue, \t\n\t\n\t\nmalaria, leptospirosis and West Nile fever (11,12).", "page": 126, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ria, leptospirosis and West Nile fever (11,12).\n \n\u2022 In specific sites, additional indicators such as the \u201cexcess of non-malaria fever  \n\t\n\t\ncases\u201d in malaria-endemic areas may provide complementary information and \t\n\t\n\t\nshould be further evaluated. It has already been tested in French Guiana (13).\nThe routine reporting of dengue cases or dengue-like syndromes can use passive, active \nor enhanced surveillance. \u201cPassive surveillance\u201d is the routine reporting of diseases, by \nwhich notification is", "page": 126, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "reporting of diseases, by \nwhich notification is usually initiated by health care providers (14). A particular challenge \nof passive surveillance systems is continuously to motivate health care providers to report \ncases in accordance with standardized case definitions. Unfortunately, in many dengue-\nendemic countries, surveillance is only passive and relies on reports by local physicians \nwho may not consider dengue in their differential diagnosis and/or fail to report cases \nquickly and routi", "page": 126, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "sis and/or fail to report cases \nquickly and routinely. As a result, an epidemic has often reached or passed its peak \nbefore it is recognized, and opportunities for control are missed. Designating dengue as \na notifiable disease that is covered by public health legislation is one way to increase \ncompliance with reporting. \nIn \u201cactive surveillance\u201d, the disease report is initiated by the health authority which \nsystematically asks health care providers about the disease of interest. This involv", "page": 126, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "oviders about the disease of interest. This involves \noutreach by public health authorities to stimulate reporting; examples include regular \ntelephone calls or visits to laboratories and hospitals to collect data in a timely fashion.", "page": 126, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "115\nChapter 5. Surveillance, emergency preparedness and response\nCHAPTER 5\n\u201cSentinel surveillance\u201d, or the study of disease rates in a specific cohort, geographic \narea or population subgroup, is a form of active surveillance that is useful for answering \nspecific epidemiological questions. Sentinel surveillance may be very effective at \ndetermining disease trends locally, but because sentinel sites may not represent the \ngeneral population or the general incidence of dengue, they may have limit", "page": 127, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "e general incidence of dengue, they may have limited value \nin determining national disease patterns and trends. Sentinel surveillance may also be \nused to detect a \u201cfirst case\u201d (as the word \u201csentinel\u201d suggests), such as testing for dengue \nin a neurology ward to detect cases of dengue-related neurological disease, or post-\nmortem testing for dengue-related deaths. A system to monitor the severe end of the \ndisease spectrum is, therefore, an important component of an early warning system to \ndet", "page": 127, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "rtant component of an early warning system to \ndetect epidemic activity. Detailed clinical protocols should be developed to ensure that \nadequate clinical, haematological and pathological data and samples are obtained. \nDepending on laboratory capacity, the type of samples collected and the circumstances \nof specimen collection, storage and transport, samples may also be processed for virus \nisolation and/or viral RNA by PCR. \n\u201cEnhanced surveillance\u201d is a form of active surveillance usually in r", "page": 127, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "nce\u201d is a form of active surveillance usually in response to an epidemic \nalert. The passive surveillance system is \u201cenhanced\u201d so that it becomes active during \nthe alert period and/or it is extended to municipalities or jurisdictions that are beyond \nthe affected area and that would not normally be included in routine surveillance. Table \n5.1 presents examples of dengue surveillance systems and the types of specimens and \nlaboratory tests required.\n5.2.1.3 Laboratory support for surveillance\nTh", "page": 127, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ed.\n5.2.1.3 Laboratory support for surveillance\nThe effective prevention and control of epidemic dengue requires an active laboratory-\nbased disease surveillance programme that can provide early warning of impending \nepidemic transmission. Laboratory methods should include both serological and \nvirological diagnosis. Quality control for laboratory diagnostics should be provided by a \nnational dengue reference laboratory and/or an international reference laboratory. At a \nminimum, diagnostic labo", "page": 127, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ference laboratory. At a \nminimum, diagnostic laboratories should be capable of performing IgM antibody-capture \nELISA (MAC-ELISA) as a front-line screening test for current or recent dengue infection. \nConfirmatory tests are needed to exclude cross-reactivity with other flaviviruses, and \nbecause IgM will not be detectable in the first few days after onset of illness (especially in \nprimary dengue infections) and may persist for several weeks after infection (Chapter 4)\nSentinel laboratory surv", "page": 127, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ter infection (Chapter 4)\nSentinel laboratory surveillance systems provide high-quality virological and serological \ndata and are useful for detecting rare diseases (e.g. introduced dengue), but data \nthat are not linked to clinical and epidemiological information must be interpreted with \ncaution. Data that may be provided include: participating laboratory identifier, onset \nof illness, specimen collection date, patient identifier, organism, patient\u2019s sex, date of \nbirth or age, place of reside", "page": 127, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ient\u2019s sex, date of \nbirth or age, place of residence, specimen source, clinical diagnosis and the method \nof diagnosis. There are certain biases inherent in de-linked laboratory surveillance data \n(e.g. the number of participating laboratories may vary over time and some jurisdictions \nmay have a larger number of participating laboratories than others). Also, changes in \ndiagnostic practices \u2013 particularly the introduction of new testing methodologies \u2013 may \naffect laboratory reports. The abili", "page": 127, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "logies \u2013 may \naffect laboratory reports. The ability of laboratory tests to distinguish acute infection from \npast infection without a clinical history must also be taken into account when interpreting \nthe data. Although changes in incidence cannot be determined with precision from such \ndata, general trends can be observed (e.g. with respect to seasonality and the age-sex \ndistribution of dengue cases).", "page": 127, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "116\nDengue: Guidelines for diagnosis, treatment, prevention and control\nTable 5.1 Components of dengue surveillancea,b \n\t Type of surveillance\t\nSamplesb\t\nApproach\n\t Event-based surveillance\t Blood from all or representative cases of \t\nOnce the details of the reported event are \n\t \t\ndengue-like illness, taken 3\u201315 days \t\nvalidated, a rapid response team  \n\t \t\nafter onset of illness\t\ninvestigates the event as an outbreak\n\t \t\n\t\nCases detected through active case-finding \t\n\t \t\n\t\nfor acute febrile il", "page": 128, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "h active case-finding \t\n\t \t\n\t\nfor acute febrile illness and/or laboratory \t\n\t \t\n\t\nconfirmation during outbreak investigations \t\n\t \t\n\t\ncan also constitute an event.\n\t Fever alert system\t\nBlood samples from representative cases\t\nIncreased febrile illness in the community is   \n\t \t\nof acute febrile illness\t\ninvestigated immediately; samples are \t\t\n\t \t\n\t\ntested as above.\n\t Routine reporting \t\nBlood from clinical cases of dengue-like\t\nHighly dependent on clinicians considering \n\t (passive surveillanc", "page": 128, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "on clinicians considering \n\t (passive surveillance)\t\nillness \t\ndengue in the differential diagnosis and on \n\t \t\n\t\nthe availability of diagnostic support \n\t \t\n\t\nIdeally, clinical, laboratory and \t\n\t\n\t \t\n\t\nepidemiological data are linked. Reporting \t\n\t \t\n\t\nis based on case definitions and case \t\t\n\t \t\n\t\nclassification (e.g. laboratory-confirmed, \t\n\t \t\n\t\nprobable, or suspected cases).\n\t Sentinel clinic and \t\nBlood from all or representative cases of \t\nRepresentative samples or purposeful \n\t physici", "page": 128, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "Representative samples or purposeful \n\t physician network\t\ndengue-like illness, taken 3\u201315 days after \t sampling taken year-round or at specific \n\t \t\nonset of illness\t\ntimes of the year are processed weekly for \n\t \t\n\t\nIgM antibodies, and for virus isolation \t\t\n\t \t\n\t\nand/or PCR if available.\n\t Sentinel hospital \t\nBlood and tissue samples taken during\t\nAccording to the outcome of interest, all \n\t surveillance system\t\nhospitalization and/or at death\t\nsevere disease and all viral syndromes with", "page": 128, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ath\t\nsevere disease and all viral syndromes with \t\n\t \t\n\t\nfatal outcome are investigated immediately \t\n\t \t\n\t\nand tested as above.\n\t Sentinel laboratory-\t\nBlood and other clinical samples\t\nUsually there are no denominator data. \n\t based surveillance \t\n\t\nHence changes in incidence cannot be \t\n\t \t\n\t\ndetermined. General trends can be \t\n\t\n\t \t\n\t\nobserved if the same laboratories report \t\n\t \t\n\t\nregularly (e.g. with respect to seasonality \t\n\t \t\n\t\nand the age and sex distribution of patients).\n\t National", "page": 128, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "age and sex distribution of patients).\n\t National notifiable \t\nBlood from cases of dengue-like illness\t\nMandatory reporting of, for instance, \n\t disease surveillance\t\nand/or clinical samples from cases \t\nlaboratory-confirmed cases by time, place, \n\t system\t\nthat test positive for dengue \t\nperson \u00b1 risk factor data. May also include \t\n\t \t\n\t\nprobable and suspected dengue cases, \n\t \t\n\t\ndepending on the sensitivity of the \t\n\t\n\t \t\n\t\nsurveillance system.\na \tSource: adapted from Gubler (15)\nb \tEmphasis", "page": 128, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "m.\na \tSource: adapted from Gubler (15)\nb \tEmphasis should be placed on the inter-epidemic period using a simplified case definition. After an epidemic begins and after the \t\n\t virus serotype(s) is known, the case definition should be made more specific and surveillance should be focused on severe disease.", "page": 128, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "117\nChapter 5. Surveillance, emergency preparedness and response\nCHAPTER 5\n5.2.2 Entomological surveillance\n5.2.2.1 Overview \nEntomological surveillance is used for operational (and research) purposes to determine \nchanges in geographical distribution of vectors, for monitoring and evaluating control \nprogrammes, for obtaining relative measurements of the vector population over time, \nand for facilitating appropriate and timely decisions regarding interventions. There are \na number of methods fo", "page": 129, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "g interventions. There are \na number of methods for monitoring dengue vectors (mostly for Ae. aegypti). However, \nthe selection and use of method requires a clear understanding of the surveillance \nobjectives, the availability of skills and resources, and in some instances the level of \ninfestation. \nSurveillance may serve to identify areas of high-density infestation or periods of mosquito \npopulation increase. In areas where the vector is no longer present, entomological \nsurveillance is criti", "page": 129, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "nger present, entomological \nsurveillance is critical in order to detect new introductions rapidly before they become \nwidespread and difficult to eliminate. Monitoring of the vector population\u2019s susceptibility \nto insecticide should also be an integral part of any programme that uses insecticides. \n\t\nThis section describes a variety of sampling methods but by no means provides an \nexhaustive list of all available methods. \n5.2.2.2 Sampling larvae and pupae \nFor reasons of practicality and repro", "page": 129, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "e and pupae \nFor reasons of practicality and reproducibility, the most common survey methodologies \nemploy larval (active immatures, including pupae) sampling procedures rather than \negg or adult collections. The basic sampling unit is the house or premise, which is \nsystematically searched for water-holding containers. \nContainers are examined for the presence of mosquito larvae, pupae, and larval and \npupal skins. Depending on the objectives of the survey, the search may be terminated \nas soon", "page": 129, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "the survey, the search may be terminated \nas soon as aedine larvae are found, or it may be continued until all containers have \nbeen examined. Laboratory examination is usually necessary to confirm the species. The \nfollowing three indices are commonly used to record Ae. aegypti infestation levels:\n \n\u2022 House (premise) index (HI) \u2013 i.e. percentage of houses infested with larvae \n\t\n\t\nand/or pupae.\n\t\n\t\n\t\nHI =  Infested houses X 100 \n\t\n\t\n\t\n     houses inspected \n \n\u2022 Container index (CI) \u2013 i.e. perc", "page": 129, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "es inspected \n \n\u2022 Container index (CI) \u2013 i.e. percentage of water-holding containers infested with \t\n\t\n\t\nlarvae or pupae.\n \n\t\n\t\n\t\nCI =  Containers positive X 100\n\t\n\t\n\t\n      containers inspected \n \n\u2022 Breteau index (BI) \u2013 i.e. number of positive containers per 100 houses inspected.\n \n\t\n\t\n\t\nBI =  Number of positive containers X 100\n\t\n\t\n\t\nhouses inspected", "page": 129, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "118\nDengue: Guidelines for diagnosis, treatment, prevention and control\nThe house index has been used most widely for measuring population levels, but it \ndoes not take into account the number of positive containers or the productivity of those \ncontainers. Similarly, the container index provides information only on the proportion of \nwater-holding containers that are positive. The Breteau index establishes a relationship \nbetween positive containers and houses, and is considered to be the most", "page": 130, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ners and houses, and is considered to be the most informative, but \nagain there is no accommodation of container productivity. Nevertheless, in the course \nof gathering the basic information for calculating the Breteau index, it is possible (and \nhighly desirable) to obtain a profile of the larval habitat characteristics by simultaneously \nrecording the relative abundance of the various container types either as potential or \nactual sites of mosquito production (e.g. the number of positive drums", "page": 130, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "uito production (e.g. the number of positive drums per 100 houses, \nthe number of positive tyres per 100 houses). These data are particularly relevant for \nfocusing larval control efforts on the management or elimination of the most common \nhabitats and for the orientation of educational messages for community-based initiatives \n(see also the section below on pupal/demographic surveys). A problem here is that the \nmost common container (e.g. the drinks bottle) is often not the most productive (1", "page": 130, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "drinks bottle) is often not the most productive (16).\nIt should be noted that larval indices are a poor indication of adult production. For \ninstance, the rate of emergence of adult mosquitoes from rainwater drums is likely to \ndiffer markedly from the rate from discarded cans or house plants, yet the larval survey \nregisters them only as positive or negative. The implication is that for localities with similar \nlarval indices but different container profiles, adult abundance and hence transmiss", "page": 130, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "iner profiles, adult abundance and hence transmission \npotentials may be quite different. \n5.2.2.3 Pupal/demographic surveys \nIf the classes of containers with the highest rates of adult mosquito emergence are \nknown in a community, their selective targeting for source reduction (e.g. elimination) \nor other vector control interventions can be the basis for the optimized use of limited \nresources (17). The pupal/demographic survey is a method of identifying these most \nepidemiologically important", "page": 130, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "dentifying these most \nepidemiologically important types of containers and may therefore be considered an \noperational research tool (Chapter 3). Unlike the traditional Stegomyia (Aedes) indices \ndescribed above, pupal/demographic surveys measure the total number of pupae in \ndifferent classes of containers in a given community. Such surveys are far more labour-\nintensive than the above-mentioned larval surveys and are not envisaged for the routine \nmonitoring of Ae. aegypti populations. \nThe co", "page": 130, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ne \nmonitoring of Ae. aegypti populations. \nThe collection of demographic data enables the calculation of the ratio between the \nnumbers of pupae (a proxy for adult mosquitoes) and persons in the community. There is \ngrowing evidence that, together with other epidemiological parameters such as dengue \nserotype-specific seroconversion rates and temperature, it is possible to determine how \nmuch vector control is needed in a specific location to inhibit virus transmission. This \nremains an importa", "page": 130, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "hibit virus transmission. This \nremains an important area for research with potential for public health application.\nSimilar methods have been used to measure total populations of larvae.\n5.2.2.4 Passive collection of larvae and pupae\nFunnel traps have been used for sampling Aedes species and other container-breeding \norganisms in sites with poor or difficult access, such as wells (18). The funnel trap \ncomprises a weighted funnel attached to a bottle that inverts on entry to and exit from \nthe", "page": 130, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ottle that inverts on entry to and exit from \nthe water surface where it floats. The device collects organisms such as fish, copepods,", "page": 130, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "119\nChapter 5. Surveillance, emergency preparedness and response\nCHAPTER 5\nmosquitoes, ostracods and tadpoles as they return to the surface. Calibration of the \ndevice, using known numbers of Ae. aegypti larvae, enables the size of the larval \npopulation to be estimated (19). In some locations the device has focused attention \non the importance of subterranean habitats and harbourages during winter or in dry \nconditions (20). The funnel trap captures a lower proportion of pupae because they are", "page": 131, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ures a lower proportion of pupae because they are \nless active than larvae.\n \nQuantification of the funnel trap allows results to be compared with larval counts in other \ncontainers and allows estimates to be made of the relative importance of the various \ntypes of containers. However, there is no way to relate funnel trap captures to the risk of \ntransmission because there is no direct relationship between larval densities and density-\ndependent larval survival. \n5.2.2.5 Sampling the adult mosq", "page": 131, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "larval survival. \n5.2.2.5 Sampling the adult mosquito population \nAdult vector sampling can provide valuable data for studies of seasonal population \ntrends or evaluation of adulticiding measures. However, results are less reproducible \nthan those obtained from sampling of immature stages. The methods for collection of \nadult mosquitoes also tend to be labour-intensive and depend heavily on the collector\u2019s \nproficiency and skill. \n5.2.2.6 Landing collections \nAlthough landing collections on hum", "page": 131, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "g collections \nAlthough landing collections on humans are a sensitive means of detecting low-level \ninfestations and for studying the biting times and places of host attraction, the method \nis both labour-intensive and expensive. Moreover, the method poses safety and ethical \nissues in areas endemic for disease. Both male and female Ae. aegypti are attracted \nto humans. Because adult mosquitoes, especially males, have low dispersal rates, their \npresence can be a reliable indicator of proximity", "page": 131, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "presence can be a reliable indicator of proximity to hidden larval habitats. Rates of \ncapture, typically using hand nets or aspirators as mosquitoes approach or land on the \ncollector, are usually expressed in terms of landing rates per man-hour. \n5.2.2.7 Resting collections \nDuring periods of inactivity, adult Ae. aegypti typically rests indoors, especially in \nbedrooms, and mostly in dark places such as clothes closets and other hidden sites. \nResting collections involve the systematic search", "page": 131, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "Resting collections involve the systematic searching of these sites with the aid of a \nflashlight and the capture of adults using mouth- or battery-powered aspirators and \nhand-held nets. Backpack aspirators powered by rechargeable 12-volt batteries have \nproven to be an efficient and effective alternative means of collecting resting adult \nmosquitoes in and around human habitation. Following a standard collection routine, \ndensities are recorded as the number of adult mosquitoes per house (fem", "page": 131, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "d as the number of adult mosquitoes per house (females, males, or \nboth) or the number of adults per man-hour of effort. Where infestation levels are low, \nthe percentage of houses positive for adults is sometimes used. \n5.2.2.8 Sticky trap collections \nVarious sticky trap devices have been used for sampling adult Ae. aegypti. They may \nbe designed to be visually attractive, odour-baited, or both, or are simply located at \nconstricted access points through which adult mosquitoes pass (e.g. at po", "page": 131, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ts through which adult mosquitoes pass (e.g. at points of exit and \nentry from subterranean habitats such as keyholes in service manhole covers in roads).", "page": 131, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "120\nDengue: Guidelines for diagnosis, treatment, prevention and control\nAge and viral infection have been determined in adult mosquitoes collected with \nsticky traps though mainly in a research context. \n5.2.2.9 Sampling the ovipositing population \nOviposition traps\nThese devices, also known as \u201covitraps\u201d, constitute a sensitive and economical \nmethod for detecting the presence of Ae. aegypti and Ae. albopictus in situations \nwhere infestations are low and larval surveys are generally unproducti", "page": 132, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "re low and larval surveys are generally unproductive (e.g. when \nthe Breteau index is <5). They have proved especially useful for the early detection \nof new infestations in areas from which the mosquito has been eliminated. For this \nreason, oviposition traps are useful for surveillance at international ports of entry \nwhich, in accordance with international sanitary codes, should be kept free of vector \nfoci. \nThe standard ovitrap is a wide-mouth 0.5 litre glass jar painted black on the outsid", "page": 132, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "th 0.5 litre glass jar painted black on the outside \nand equipped with a hardboard or wooden paddle that is clipped vertically to the \ninside with its rough side facing inwards. The jar is partially filled with clean water \nand is appropriately placed in a rain-sheltered site \u2013 usually outdoors and close to \nhabitation. \n\t\nOvitraps are usually serviced weekly and the paddles are examined for the presence \nof Ae. aegypti eggs. The percentage of positive ovitraps provides the simplest index \nof in", "page": 132, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "sitive ovitraps provides the simplest index \nof infestation levels. In more detailed studies, all the eggs on each paddle are \ncounted and the mean number of eggs per ovitrap is calculated. Ovitraps with plant \ngermination paper as a substrate for egg deposition can also be used. For accurate \ninterpretation, field records must indicate the location of each ovitrap and its condition \nat the time of servicing. If a trap is flooded, dry, missing, or overturned, the data \nshould be discarded. Ovitr", "page": 132, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "r overturned, the data \nshould be discarded. Ovitraps are inexpensive and it is possible to install and service \nthem over large areas relatively quickly. They can also be used by people without \nspecialized training.\nAn \u201cenhanced CDC ovitrap\u201d is considerably more attractive to ovipositing females \nand yields many more Ae. aegypti eggs than the standard version. In this double \novitrap method, one jar contains an olfactory attractant made from a \u201cstandardized\u201d \n7-day-old hay infusion, while the", "page": 132, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "\u201cstandardized\u201d \n7-day-old hay infusion, while the other contains a 10% dilution of the same infusion. \nUnlike the original version, with which positivity rates and egg counts are seldom \nsufficiently high, the enhanced ovitrap has proved suitable for monitoring changes in \nthe adult female populations daily rather than weekly and has been successfully used \nto assess the impact of adulticidal space spraying on adult females. Alternatives to \nhay infusions have also been used to improve the attra", "page": 132, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "infusions have also been used to improve the attraction of standard ovitraps.\nWhile ovitraps can be used to monitor changes in oviposition activity over time, \ncomparisons between areas are not reliable because the availability of larval habitats \nin which females can choose to lay eggs will differ. Similarly, it can be misleading \nto monitor and interpret ovitrap data over time in a given area where vector control \ninterventions include source reduction measures.", "page": 132, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "eduction measures.", "page": 132, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "121\nChapter 5. Surveillance, emergency preparedness and response\nCHAPTER 5\nTyre section larvitraps\nTyre section larvitraps of various designs have also been used for monitoring oviposition \nactivity. The simplest of these is a water-filled radial section of a tyre. A prerequisite for \nany tyre section larvitrap is that it facilitates either visual inspection of the water in situ \nor the ready transfer of the contents to another container for examination. Tyre larvitraps \ndiffer functionally from", "page": 133, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ination. Tyre larvitraps \ndiffer functionally from ovitraps in that water level fluctuations caused by rainfall induce the \nhatching of eggs, and it is the larvae that are counted rather than the eggs deposited on \nthe inner surfaces of the trap. The usefulness of tyre section larvitraps as an alternative to \nthe ovitrap for early detection of new infestations and for surveillance of low-density vector \npopulations has been well demonstrated. \nInsecticide susceptibility testing\nThe initial and c", "page": 133, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "secticide susceptibility testing\nThe initial and continued susceptibility of the vector to specific insecticides is of fundamental \nimportance for the success of larviciding or adulticiding operations. The development of \nresistance may lead to failure of the control programme unless it is carefully monitored and \na timely decision is made to use alternative insecticides or control strategies.\nStandard WHO bioassay procedures and kits are available for determining the \nsusceptibility or resistan", "page": 133, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "le for determining the \nsusceptibility or resistance of mosquito larvae and adults to insecticides. Biochemical and \nimmunological techniques are also available for testing individual mosquitoes but are not \nwidely used by programmes. \nSampling strategies\nOnly in exceptional conditions are larval surveys of every house (i.e. census) warranted. \nSuch situations arise when the objective is one of vector eradication and larval infestation \nlevels have been reduced to very low levels (HI = <1.0%). A", "page": 133, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ve been reduced to very low levels (HI = <1.0%). At this point it is necessary \nto locate and control every infested and potentially infested container, or to verify that \neradication has indeed been achieved, or to ensure that re-infestation has not occurred. In \nother situations, the number of houses to be inspected should be based on considerations \nof available resources, the desired level of precision of the results, and the total number \nof houses in the locality. This is contrary to the r", "page": 133, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "houses in the locality. This is contrary to the routine procedures employed in many \nvector control programmes in which eradication campaign methodologies have persisted \nand entomological data are collected from every house immediately prior to insecticide \ntreatment \u2013 usually by the person who administered the treatment. Such practices, if \nused solely for measuring infestation levels, are wasteful and are likely to result in poor-\nquality reporting due to conflicts of worker interest and the", "page": 133, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "orting due to conflicts of worker interest and the tedious nature of the work. \nWhenever possible, it is recommended that a different team or individual should conduct \nthe entomological evaluation, or that the two tasks should be performed separately. The \nsample size for routine surveys can be calculated by statistical methods based on the \nexpected level of infestation and the desired level of confidence in the results.\n \nSeveral sampling procedures that eliminate or minimize bias can be appl", "page": 133, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "edures that eliminate or minimize bias can be applied equally well \nto the selection of houses for larval, adult, ovitrap, or knowledge-attitude-practice (KAP) \nsurveys. These are as follows: \n \n\u2022 Systematic sampling applies to every \u201cn\u201dth house (where \u201cn\u201d equals an agreed  \n\t\n\t\nnumber) throughout a community or along linear transects through the community. \n \n\t\n\t\nFor example, if a sample of 5% of the houses is to be inspected, every 20th \t\n\t\n\t\nhouse (= 100/5) would be inspected. This is a pract", "page": 133, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ouse (= 100/5) would be inspected. This is a practical option for rapid assessment \n \n\t\n\t\nof infestation levels, especially in areas where there is no house-numbering system. \n \n\t\n\t\nAll areas of the locality are well represented.", "page": 133, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "122\nDengue: Guidelines for diagnosis, treatment, prevention and control\n \n\u2022 Simple random sampling means that houses to be selected are obtained from a  \n\t\n\t\nlist of random numbers (either from tables of random numbers in a statistical text \n\t\n\t\nbook or from a calculator or a computer-generated list). This is a more laborious \n \n\t\n\t\nprocess since detailed house maps or lists of street addresses are a prerequisite \n \n\t\n\t\nfor selecting the houses. Many statistical tests require random sampling.", "page": 134, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "Many statistical tests require random sampling. \t\n\t\n\t\n\t\nUnfortunately, although every house has an equal chance of being selected, \t\n\t\n\t\nsome areas of the locality are usually under-represented and others are over-\t\n\t\n\t\nrepresented. \n \n\u2022 Stratified random sampling minimizes the problem of under-representation and  \n\t\n\t\nover-representation by subdividing the localities into sectors or \u201cstrata\u201d. These \t\n\t\n\t\nare usually based on identified risk factors \u2013 such as areas with houses without \t\n\t\n\t\na pi", "page": 134, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ors \u2013 such as areas with houses without \t\n\t\n\t\na piped water supply, areas not served by sanitation services, and densely-\t\n\t\n\t\npopulated areas. A simple random sample is taken from each stratum, with \t\n\t\n\t\nthe number of houses inspected being in proportion to the number of houses in \t\n\t\n\t\neach stratum. \n \n\u2022 Cluster sampling may be conducted in large cities or geographical areas where \n\t\n\t\nit may be difficult or impossible to use random or systematic sampling because \t\n\t\n\t\nof limitations of time,", "page": 134, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "tic sampling because \t\n\t\n\t\nof limitations of time, money and personnel, or because of other logistical \t \t\n\t\n\t\nconstraints. In these circumstances, the sample may be selected in two stages \t\n\t\n\t\nin order to minimize the resources needed for the survey. The first stage is \t  \n\t\n\t\nobtained by simple or stratified random sampling of population groups or clusters \n\t\n\t\n(e.g. city blocks, villages, or administrative districts). Having identified these \t\n\t\n\t\nclusters, simple or stratified random sampli", "page": 134, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "clusters, simple or stratified random sampling procedures are again applied to \t\n\t\n\t\nidentify the specific houses within each cluster for inclusion in the survey. \n5.2.2.10 Frequency of sampling\n \nThe frequency of sampling depends on the frequency and expected duration of the \ncontrol measures. For programmes that use larvicides, it is important to monitor the \nduration of efficacy to ensure that intervals between cycles of treatment are optimal. \nThis may vary from weeks to months. For pr", "page": 134, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "timal. \nThis may vary from weeks to months. For programmes using integrated strategies, such \nfrequent intervals for routine assessment of the impact of the measures applied may \nbe unnecessary. This is especially true when the effect of some of the nonchemical \nintervention strategies exceed the impact of residual insecticides (e.g. larvivorous fish \nin large storage containers of potable water, source reduction, or mosquito-proofing \nof containers). On the other hand, rapid feedback at monthly", "page": 134, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ers). On the other hand, rapid feedback at monthly intervals is desirable \nto evaluate and guide community action activities, indicating sectors that need more \nattention and activities that need to be reinforced. For specific research studies, it may \nbe necessary to sample on a weekly, daily or even on an hourly basis (e.g. to determine \nthe diel pattern of host-seeking activity). \n5.2.3 Monitoring environmental and social risks\nIn addition to the evaluation of aspects directly pertaining to v", "page": 134, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "the evaluation of aspects directly pertaining to vector densities and \ndistribution, community-oriented, integrated vector management strategies require that \nother parameters be measured or periodically monitored.\nVarious factors have been determined to influence a community\u2019s vulnerability to \ndengue epidemics. The distribution and density of the human population, settlement \ncharacteristics, conditions of land tenure, housing styles, education, and socio-economic", "page": 134, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": ", and socio-economic", "page": 134, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "123\nChapter 5. Surveillance, emergency preparedness and response\nCHAPTER 5\nstatus are all interrelated and fundamentally important for planning and for assessing \ndengue risk. Knowledge of changes in the distribution of water supply services and \ntheir quality and reliability over time, as well as knowledge of domestic water storage \npractices and solid waste disposal services, are of particular relevance. This type of \ninformation helps in establishing ecological profiles that can be of value f", "page": 135, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "lishing ecological profiles that can be of value for planning \ntargeted source reduction or management activities and for organizing epidemic \nintervention measures. \nSome of these data sets are generated by the health sector, while others are derived \nfrom external sources. In most cases, annual or even less frequent updates will suffice \nfor programme management purposes. However, in the case of meteorological data, \nespecially rainfall patterns, a more frequent analysis (such as weekly or mon", "page": 135, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "s, a more frequent analysis (such as weekly or monthly) is \nwarranted if the data are to be of predictive value in determining seasonal trends and \nshort-term fluctuations of the vector population.\n5.3 Dengue preparedness planning and response\n5.3.1 \tOverview\nThis section provides an overview of the elements of a comprehensive dengue \nprevention and control programme. Emergency preparedness and anticipated response \n(contingency) planning must be explicitly included in dengue surveillance and co", "page": 135, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "explicitly included in dengue surveillance and control \npolicies and should be reviewed regularly. Emergency preparedness and response are \noften overlooked by programme managers and policy-makers.\nWhen the dynamics of dengue activity are known, the timing of response activities can \nbe adjusted to maximize their effectiveness. In dengue-endemic areas, activities can be \ngrouped into those that should occur continuously, those that should occur during an \nepidemic, and those that should be carr", "page": 135, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "during an \nepidemic, and those that should be carried out in the post-epidemic period. Different \nactivities and approaches may be required in areas where dengue occurs sporadically \nand in dengue-free areas at risk of transmission. In epidemic-prone areas, a multisectoral \ndengue action committee should be convened with the responsibility of coordinating the \nresponse.\nThe two major components of the emergency response to a dengue outbreak are: \n(i) emergency vector control to curtail transmiss", "page": 135, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "(i) emergency vector control to curtail transmission of the dengue virus as rapidly as \npossible and (ii) early diagnosis and the appropriate clinical case management of \nsevere dengue to minimize the number of dengue-associated deaths. These responses \nshould occur concurrently.\n5.3.2 \tDengue emergency response planning\nThere are three levels of dengue emergency response planning (21), namely:\n \n\u2022 Ongoing prevention \u2013 where there is no current dengue activity in the area;\n \n\u2022 Response to spora", "page": 135, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "dengue activity in the area;\n \n\u2022 Response to sporadic cases or other risk indicators \u2013 where there is no epidemic \n\t\n\t\ndengue activity in the area but either (i) sporadic cases are being reported \t\n \n\t\n\t\nthrough the surveillance system or (ii) there is increased virus activity or the \t\t\n\t\n\t\nintroduction of serotypes that have not previously or recently been recorded in \t\n\t\n\t\nthe area;", "page": 135, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "124\nDengue: Guidelines for diagnosis, treatment, prevention and control\n \n\u2022 Outbreak response \u2013 where there is epidemiological evidence of epidemic  \n\t\n\t\nactivity. The best response to a dengue epidemic is preparedness to prevent \t\n\t\n\t\ninfections, thereby reducing ongoing transmission, and to minimize its effects on \n \n\t\n\t\nthose who become ill.\nThe dengue emergency response plan should clearly articulate its aims, objectives and \nscope, the lead (coordinating) agency, the organizational links wi", "page": 136, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "(coordinating) agency, the organizational links with other agencies \nthat have direct responsibility for implementing aspects of the plan, and the \u201csupport\u201d \nagencies (e.g. social welfare) that may be more involved in the recovery phase after \nan epidemic. Each agency should be assigned specific roles and responsibilities \nunder the plan, and costs and resources should be identified. Hard copies of the plan \nshould be distributed to all response and supporting agencies and should be available \ne", "page": 136, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "and supporting agencies and should be available \nelectronically if possible. The plan should ideally include a monitoring and evaluation \nframework with performance indicators for each of the response and support agencies \nas well as overall indicators of the plan\u2019s effectiveness.\nClear triggers for the activation, escalation and deactivation should be written into the \nplan and reviewed as required. Wherever possible, the plan should be tested through \nexercises.\nSome emergency response plans e", "page": 136, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "hrough \nexercises.\nSome emergency response plans emphasize the temporal aspects of the response (i.e. \nthe alert phase, declaration of an emergency, and the emergency phase). As mentioned \nearlier in this chapter, there may be reluctance on the part of public health officials to \nimplement a dengue emergency response plan until the case count and fatality numbers \nare elevated. It is recommended that the plan should include objective criteria for \ndefining an epidemic on the basis of specific lo", "page": 136, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "defining an epidemic on the basis of specific local data and not general concepts.\n \nWhile plans have frequently been prepared in dengue-endemic countries, they are seldom \nvalidated. Once the dengue emergency response plan has been drafted and approved \nby participating groups, it is important to conduct simulations or \u201ctable top\u201d exercises. \nSince the emergency response is usually multisectoral, exercises provide opportunities \nfor all partners to participate and better understand their role", "page": 136, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "rs to participate and better understand their roles, responsibilities, channels \nof command and communication, and to ensure the availability of the human resources, \nequipment and supplies needed for a rapid emergency response. Formal debriefing \nsessions should take place with the partners after exercises and after epidemics. Lessons \nlearned should be incorporated into a revised emergency response plan. \n5.3.2.1 Priority areas for emergency response plans\nRigau-P\u00e9rez and Clark (7) have identi", "page": 136, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "sponse plans\nRigau-P\u00e9rez and Clark (7) have identified 10 priority areas for dengue emergency \nresponse planning, namely:\n\t\n1.\t Establishing a multisectoral dengue action committee.\n\t\n2.\t Formalizing an emergency action plan.\n\t\n3.\t Enhancing disease surveillance.\n\t\n4.\t Diagnostic laboratory testing.\n\t\n5.\t Enhancing vector surveillance and control.\n\t\n6.\t Protecting special populations.\n\t\n7.\t Ensuring appropriate patient care.", "page": 136, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "125\nChapter 5. Surveillance, emergency preparedness and response\nCHAPTER 5\n\t\n8.\t Educating the community and relevant professional groups about the current \t\n\t\n\t\nprocedures \nused \nfor \ndengue \ncontrol \nby \nthe \nresponsible \nauthorities \nin \ntheir \njurisdiction \n\t\n\t\n(local, provincial and national governments, as appropriate) as well as their roles \n \n\t\n\t\nand responsibilities in dengue prevention and control.\n\t\n9.\t Investigating the epidemic.\n\t 10.  Managing the mass media.\nFor endemic countries,", "page": 137, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": ".  Managing the mass media.\nFor endemic countries, the overall aim of a dengue emergency response plan is to reduce \nthe risk of dengue epidemics and to strengthen control measures for any future epidemics \n\u2013 thereby minimizing the clinical, social and economic impact of the disease. \nFor receptive countries (i.e. dengue vectors present without circulating virus), risk \nmanagement plans should focus on strategies for risk reduction. These should include \nrapid investigation of sporadic cases (cl", "page": 137, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "include \nrapid investigation of sporadic cases (clinically suspected or laboratory confirmed) to \ndetermine whether they are imported or locally-acquired, monitoring of vectors and \ntheir abundance (particularly in regions with recorded or suspected cases), social \nmobilization, and environmental management efforts. Once a locally acquired case \nis confirmed, the response may be escalated to epidemic response to prevent further \nspread and/or interruption of transmission.\n \nIn countries at risk", "page": 137, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "erruption of transmission.\n \nIn countries at risk of the introduction of dengue vectors, the focus of activities may be on \nentomological surveillance at ports of entry and education of the health care community \nabout the risk of dengue in travellers, and its diagnosis and reporting requirements.\n5.3.2.2 Establishment of a multisectoral dengue action committee\nIf the prevention and control of dengue are to be effective and sustainable, a multisectoral, \nmultidisciplinary and multilevel approach", "page": 137, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ctoral, \nmultidisciplinary and multilevel approach is required. It is not possible for a single \ngovernment agency to control the causes and consequences of dengue epidemics and \nto protect population health. For this reason it is recommended that countries establish \na multisectoral dengue action committee. The committee must have solid funding and a \ndesignated national coordinator with the political mandate to make policy and financial \ndecisions and to coordinate the multisectoral preparedne", "page": 137, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ons and to coordinate the multisectoral preparedness and response strategy at \nlocal, state and national levels. \nDepending on the epidemiological situation in each country, membership of the \ndengue action committee may include, but need not be limited to, heads of government \nagencies (e.g. health, ambulance services, agriculture, emergency services, customs \nand immigration, port health authorities, telecommunications, media, education, \nenvironment, water, solid waste disposal) and NGOs, and", "page": 137, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "onment, water, solid waste disposal) and NGOs, and must also include relevant \nprivate-sector groups (e.g. industrial, commercial, private education, labour unions). For \ncountries at lower risk of dengue transmission, the dengue action committee may be \nconstituted within the affected jurisdiction (e.g. local government area, state, province).\nA major responsibility of the dengue action committee is to develop the dengue \nemergency response plan, review it regularly, and update it as necessary", "page": 137, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": ", review it regularly, and update it as necessary on the basis \nof the lessons learned from its implementation or simulation. Members of the committee \nshould communicate regularly with their stakeholders \u2013 including local government, health \ncare providers in the public and private sectors, vector control personnel, laboratory \nscientists, industry groups and community representatives.", "page": 137, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "126\nDengue: Guidelines for diagnosis, treatment, prevention and control\n5.3.3 Risk assessment\n5.3.3.1 Populations at risk\nBecause of their rapid expansion and long duration, dengue epidemics reduce the \nproductive capacity and economic development of many sections of society. Some \ngroups need special attention because of their dependence on others who take care \nof them and their immediate surroundings (e.g. older or incapacitated persons who live \nalone or in institutions, travellers, pre-scho", "page": 138, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ve \nalone or in institutions, travellers, pre-school children in day care programmes, students, \nmigrant workers and soldiers). If not properly screened or air-conditioned, health care \nsettings may also be at high risk for dengue transmission.\nMigrant workers living in poorly constructed and maintained facilities can be particularly \nat risk of the transmission or introduction of dengue. \nA study on knowledge of and attitudes towards dengue, conducted in the Caribbean \nby the Assessments of Imp", "page": 138, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ducted in the Caribbean \nby the Assessments of Impacts and Adaptations to Climate Change (AIACC) project, \nindicated that the most vulnerable to the disease were the poor who lived in informal \nor squatter settlements. These typically lacked basic community infrastructure, including \naccess to piped water and adequate garbage disposal, and lacked both the \norganization needed for collective action against the threat of a dengue fever epidemic \nand the understanding about how they could contribut", "page": 138, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "d the understanding about how they could contribute to preventive actions to mitigate \nthe risk (22). Communication for Behavioural Impact (COMBI) for dengue prevention \nand control needs to be tailored to the various populations at risk and delivered in a \nculturally appropriate way to ensure sustainability (23). \n5.3.3.2 Cross-border spread and ports of entry\nThe rapid spread of dengue since the 1970s has been attributed to increasing \nurbanization and the increasing use of (often disposable)", "page": 138, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "tion and the increasing use of (often disposable) man-made containers (24) \nthat are ideal larval habitats for dengue mosquitoes. In addition, international trade \nin, and inadequate disposal of, vehicle tyres similarly provide larval habitats, and \ninternational air travel results in the movement of viraemic individuals and vectors over \nlong distances. Increased international travel and trade provide ideal means for infected \nhuman transport of dengue viruses and/or vectors, resulting in a fre", "page": 138, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "dengue viruses and/or vectors, resulting in a frequent exchange of \ndengue viruses among endemic countries, the risk of dengue introduction to receptive \nareas, and the spread of vectors into new ecological niches. The international movement \nof human cases, vectors which carry infection, or goods that are contaminated, may \ncause international disease spread and require notification to WHO under Article 9 of \nthe 2005 International Health Regulations (2).\nIn areas that are highly receptive to", "page": 138, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ations (2).\nIn areas that are highly receptive to dengue, a single imported case can start an \nepidemic. Because of the risk of a viraemic traveller initiating an outbreak, surveillance \nfor clinical cases of dengue is very important since it enables action to be taken promptly \nto reduce the risk of local transmission.\nCountries should undertake a dengue risk assessment as the basis for preparedness \nplans. Dengue-related risks will vary considerably both within and between countries. \nRisk ass", "page": 138, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "rably both within and between countries. \nRisk assessment is conducted so that each country can match the level of risk (e.g. risk \nof epidemics or risk of virus introduction) with appropriate activities and investment and", "page": 138, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "127\nChapter 5. Surveillance, emergency preparedness and response\nCHAPTER 5\nthus avoid introducing costly and demanding measures that are not justified by the \nepidemiological situation. \n5.3.3.3 Vector ecology\nAs part of their risk assessment, countries at risk of dengue should conduct entomological \ninvestigations to identify and map the distribution of potentially competent dengue \nvectors.\n5.3.3.4 Ensuring appropriate patient care\nA case of severe dengue requires careful observation and repea", "page": 139, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "vere dengue requires careful observation and repeated laboratory tests \nthroughout the illness (Chapters 2 and 4). It is imperative that medical and nursing staff \nunderstand the rationale and priorities for patient care under epidemic conditions.\nThe principal burden that dengue epidemics create for affected countries is not the \nnumber of deaths but the enormous number of hospitalizations and days of illness. \nProviding care for an elevated number of dengue cases requires criteria for triage,", "page": 139, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ber of dengue cases requires criteria for triage, \ntrained physicians and nursing personnel, beds, supplies and equipment, and training \nguidelines for treatment and patient isolation. Isolation refers not only to routine precautions \nfor manipulation of blood and other body fluids but also to the use of (insecticide-\ntreated) mosquito nets to prevent mosquitoes from biting viraemic (febrile) patients and \nsubsequently spreading the virus within the community. It is essential to train profession", "page": 139, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "the community. It is essential to train professionals \nin the early detection of cases and to educate the community to seek medical attention \nwhen dengue symptoms appear. Planning for sufficient provisions during a dengue \nepidemic can be guided by hospitalization rates in previous outbreaks. \n\t\n5.3.3.5 Communication for Behavioural Impact and Risk Communication\nPrimary prevention is the most effective measure in dengue prevention and control since \nno vaccine is currently available. An intensi", "page": 139, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "nce \nno vaccine is currently available. An intensive COMBI programme (23) that ensures \naccurate and timely information for the public should be implemented concurrently \nwith vector control activities in order to engage the community in practices that reduce \ndengue transmission.\nA weakness of some current dengue prevention strategies is that they are reactive rather \nthan anticipatory. They may often be implemented late, thus reducing the opportunities \nfor preventing transmission and controll", "page": 139, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "tunities \nfor preventing transmission and controlling the epidemic. In general, such reactive \nstrategies lead only to short-term behavioural change and fail to institutionalize the \nidea of community and personal responsibility for dengue prevention and control in \npartnership with government efforts. \nPublic education must continue to reinforce how important it is for people to seek medical \nattention if they have dengue symptoms, and should stress the need to reduce larval \nhabitats and the o", "page": 139, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ress the need to reduce larval \nhabitats and the options for personal protection.\nEpidemics are frequently marked by uncertainty, confusion and a sense of urgency. \nDuring an epidemic the aim of public risk communication, generally through the media, \nis to build trust. It does this by announcing the epidemic early, providing accurate \ninformation, communicating openly and honestly with the public (transparency), and", "page": 139, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "128\nDengue: Guidelines for diagnosis, treatment, prevention and control\nproviding specific information about what people can do to make themselves and their \ncommunity safer. This gives people a sense of control over their own health and safety, \nwhich in turn allows them to react to the risk with more reasoned responses (25). In \nendemic countries, involving the media before the occurrence of the seasonal increase \nin dengue enhances the opportunity to increase public awareness of the disease a", "page": 140, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "nity to increase public awareness of the disease and of \nthe personal and community actions that can be taken to mitigate the risk.\n5.3.4 Identifying outbreaks and triggers for an epidemic response\nAs indicated in previous sections, the more sensitive, extensive, responsive and functional \nthe dengue surveillance system, the better will be the information that is generated. \nInformation about an impending increase in the incidence of dengue will provide \nvaluable time to make final preparations", "page": 140, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "provide \nvaluable time to make final preparations and implement the contingency plan. The \npublic health community is increasingly observing the implementation of emergency \nresponses to diseases such as avian influenza in preparation for pandemic influenza. \nThese can serve as examples for the preparation of dengue contingency plans.\nIn areas where a comprehensive surveillance system exists, detailed information \nabout when and where dengue outbreaks/epidemics occurred in the past can be a \nuse", "page": 140, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "reaks/epidemics occurred in the past can be a \nuseful guide to the potential magnitude and severity of future epidemics. If there is no \nsurveillance system in place, the \u201cearly warning\u201d element of the programme and the \nvaluable time needed to make preparations for the response are lost. In such a situation, \nthe emergency may rapidly overwhelm the public health and medical care agencies \nwithout warning. \n5.4 Programme assessment\nDengue programme assessment is part of risk assessment. It aims", "page": 140, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "me assessment is part of risk assessment. It aims to identify strengths \nand weaknesses in programmatic and public health infrastructure that can reduce or \nincrease vulnerability to respond to dengue. Programme assessment should review areas \nsuch as the dengue emergency response plan, human resource planning (including \ntraining), the effectiveness of the dengue surveillance system in providing early warning, \nthe effectiveness of the vector control programme, laboratory capacity, stockpiling", "page": 140, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ntrol programme, laboratory capacity, stockpiling and \napplied research needs (26). In order to develop a meaningful preparedness plan during \nthe inter-epidemic period, it is important to estimate the population at risk, expected \nadmission rates, the equipment, supplies and personnel required for vector control and \npatient management, and to document the location of resources. \n5.4.1 Human resource planning\nIn addition to human resource planning for surge situations such as epidemics, the \ned", "page": 140, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ng for surge situations such as epidemics, the \neducation of health care workers should draw attention to the importance of laboratory \ntesting and case notification. Many health care providers fail to report dengue activity \nuntil they receive a positive laboratory diagnosis because they are unaware that prompt \nvector control measures can be initiated as soon as suspected cases are notified. Some \ndoctors may not request tests during an outbreak because they may be confident of their \nability", "page": 140, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "k because they may be confident of their \nability to diagnose dengue clinically. Other doctors may not be aware of the value of \nlaboratory confirmation or may not be familiar with the tests available, the timing of \ninvestigations, and the problems inherent in interpreting laboratory results when more", "page": 140, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "129\nChapter 5. Surveillance, emergency preparedness and response\nCHAPTER 5\nthan one flavivirus is circulating or the patient has been exposed to dengue or other \nflaviviruses in the past. \nPhysicians, nurses and laboratory staff should receive regular clinical training in the \nmanagement of dengue patients. This must include specific training on aspects of \nemergency response.\nClinicians\u2019 education in the emergency response to a dengue epidemic relates principally \nto raising awareness of the sp", "page": 141, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "elates principally \nto raising awareness of the spectrum of disease and the essentials and complexities of \ntreatment. It is important to emphasize that treatment of dengue consists of appropriate \nhydration and the administration of paracetamol/acetaminophen to control pain \nand fever (never acetylsalicylic acid [aspirin]). Physicians must be able to distinguish \nbetween typical and atypical dengue syndromes, and access to laboratory diagnosis \nis useful. Contact should be made with national an", "page": 141, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "is useful. Contact should be made with national and regional reference laboratories for \ndiagnostic support and verification functions prior to the occurrence of an epidemic. \nEpidemics also offer unique opportunities to identify risk factors for the disease through \napplied research.\nClinicians are often the first point of contact for community education and social \nmobilization. From initial contact with medical and public health personnel, the patients \nand their household members should be g", "page": 141, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "patients \nand their household members should be given orientation in eliminating adult mosquitoes \nand water-holding containers in and around their residence to avoid mosquito bites. \n5.4.2 Assessment of the surveillance system\nDengue surveillance systems should be adapted to country needs and resources. Priority \nshould be given to: (i) improving routine reporting using standardized case definitions, \n(ii) improving laboratory support for diagnosis through greater access to laboratory \nservice", "page": 141, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "osis through greater access to laboratory \nservices, standardized test procedures, access to more sophisticated diagnostics for \nvirus tracking and quality assurance, and (iii) introducing active surveillance as a \ncomplementary measure. At all times, appropriate and timely data analysis and response \nat the lowest operational level possible are crucial, as is data sharing in the system. This \nmay mean that core capacities in surveillance and response need to be developed in \naccordance with the", "page": 141, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ponse need to be developed in \naccordance with the International Health Regulations (2005) (2). Reporting of dengue \nshould be consistent both within and between countries, and reported cases should \nhave a defined severity level (Chapter 1). Once a vaccine becomes available, effective \ndisease surveillance will be critical in determining priority areas for vaccine use and \nevaluating vaccine effectiveness in reducing dengue incidence. \n5.4.3 Assessment of diagnostic resources \nA detailed descri", "page": 141, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "essment of diagnostic resources \nA detailed description of the laboratory diagnosis of dengue is provided in Chapter \n4. Resource planning and assessment should include auditing of, for instance: the \navailability of diagnostic laboratories and staff trained in dengue diagnosis, verification \nand reference functions; reagents and laboratory equipment (including stockpiling for \nepidemics); quality assurance; and the continuous application of appropriate levels \nof biosafety. The capacity to perf", "page": 141, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "opriate levels \nof biosafety. The capacity to perform dengue virus genotyping, whether locally or \nat an international dengue reference laboratory, is particularly important for tracking \ngenetically the potential origins of outbreaks and the international spread of the virus.", "page": 141, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "130\nDengue: Guidelines for diagnosis, treatment, prevention and control\n5.4.4 Assessment of resources for clinical care\nChapter 2 summarizes current international best practice for the clinical case management \nof dengue. Hospital emergency response plans for dengue should include a detailed \nresource plan that covers anticipated hospital bed occupancy, including high-dependency \ncare beds, staffing levels and surge capacity needs, and stock management (intravenous \nfluids, drug supplies etc). S", "page": 142, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "gement (intravenous \nfluids, drug supplies etc). Similar assessments should be conducted for outpatient care in \nthe public and private sectors in dengue-endemic areas.\n5.4.5 Assessment of vector control resources\nThe adequacy of equipment for insecticide application and the availability of insecticides \nshould be part of the needs assessment of the vector programme. \n5.4.6 Information products\nSuccessful dengue control programmes have integrated vector control with public health \neducation and", "page": 142, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "vector control with public health \neducation and community involvement in risk reduction activities. Public education on \ndengue is often promoted through posters in a variety of public places, including public \ntransport facilities, advertisements in newspapers, dengue messages on radio and \nother media channels, and through face-to-face communication. Affected communities \nare encouraged to eliminate containers of stagnant water that can potentially provide \nlarval habitats in homes and neigh", "page": 142, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "tially provide \nlarval habitats in homes and neighbourhoods. Grassroots groups, community volunteers, \nschools and the private sector should be updated regularly for active engagement of the \npublic in dengue prevention and control.\nPersonal protective measures include the application of topical repellents for the skin \n(personal insect repellents), use of household aerosol insecticides, or use of insecticide-\ntreated bednets for persons sleeping during the daylight hours. However, personal \npro", "page": 142, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "during the daylight hours. However, personal \nprotective measures come at a cost, thereby limiting their possible use by the poorest, \nwho are the most vulnerable.\nPublic education must also continue to reinforce the importance of people seeking \nmedical attention if they have dengue symptoms.", "page": 142, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "131\nChapter 5. Surveillance, emergency preparedness and response\nCHAPTER 5\nTable 5.2  Dengue surveillance: examples of good and bad practice\n\t\n\t\nGood practice\t\nBad practice\n\t\n1\t\nIntegrating disease surveillance, vector \t\nNo information exchange on data and analysis  \n\t\n\t\nsurveillance and monitoring of environmental \t\nbetween agencies involved in disease  \n\t\n\t\nand social risks\t\nsurveillance, vector surveillance and the monitoring \t\n\t\n\t\n\t\nof environmental and social risks\n\t\n2\t\nConsidering surveill", "page": 143, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "nmental and social risks\n\t\n2\t\nConsidering surveillance always in the context \t\nData collection in surveillance for academic \n\t\n\t\nof monitoring and a planned response\t\npurposes only\n\t\n3\t\nCombining event-based and case-based \t\nRelying on case-based surveillance data only \n\t\n\t\nsurveillance data\t\n\t\n4\t\nDefining and implementing surveillance \t\nNo defined indicators for surveillance \n\t\n\t\nindicators with the aim of an early response  \n\t\n\t\nto dengue cases and outbreaks\t\n\t\n5\t\nDefining, agreeing on and rea", "page": 143, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "and outbreaks\t\n\t\n5\t\nDefining, agreeing on and reacting to triggers \t\nReacting to dengue outbreaks only when  \n\t\n\t\nfor early outbreak response\t\noutbreaks are evident\n\t\n6\t\nUnrestricted and timely information-sharing \t\nNot sharing or suppressing information about  \n\t\n\t\nabout dengue cases and risks nationally and \t\ndengue cases and risks \n\t\n\t\nwith the international community\t\n\t\n7\t\nDevelopment of dengue preparedness plans \t\nRelying on ad hoc planning for dengue prevention \n\t\n\t\nwith components for em", "page": 143, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "for dengue prevention \n\t\n\t\nwith components for emergency situations, \t\nand control \n\t\n\t\nincluding simulation exercises\t\n \n\t\n8\t\nIdentifying the membership of an intersectoral \t\nAwaiting dengue outbreaks to define the dengue \n\t\n\t\ndengue action committee at national \t\naction committee \n\t\n\t\nor district level\t\n \n\t\n9\t\nIntegration of a combination of evidence-based \t\nPlanning for interventions without considering \n\t\n\t\ninterventions for dengue prevention and control \t\nefficacy and community effectivene", "page": 143, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "n and control \t\nefficacy and community effectiveness \n\t\n\t\nin the dengue preparedness plan\t\n \n\t\n10\t\nLinking preparedness planning to surge capacity\t\nNot incorporating health care delivery, including  \n\t\n\t\nin health care, delivering appropriate triage \t\nsurge capacity, in preparedness plans \n\t\n\t\nand treatment of severe cases\t\n \n\t\n11\t\nAssessment of dengue surveillance systems \t\nNot examining and updating dengue surveillance \n\t\n\t\nincluding preparedness plans nationally \t\nsystems and preparedness pla", "page": 143, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ss plans nationally \t\nsystems and preparedness plans \n\t\n\t\nand internationally\t\n\t\n12\t\nIntegrating communities in dengue prevention \t\nExclusively top-down approach to dengue \n\t\n\t\nand control using appropriate methodology \t\noutbreak response \n\t\n\t\n(e.g. COMBI)", "page": 143, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "132\nDengue: Guidelines for diagnosis, treatment, prevention and control\n5.5 REFERENCES\n1. Centers for Disease Control and Prevention. Updated guidelines for evaluating public \nhealth surveillance systems. Morbidity and Mortality Weekly Report, 2001, 50/RR-13.\n2. WHO. Revision of the International Health Regulations. World Health Assembly \nResolution WHA58.3, adopted by the 58th World Health Assembly, 2005 (http://\nwww.who.int/gb/ebwha/pdf_files/WHA58/WHA58_3-en.pdf).\n3. Koopman JS et al. Determi", "page": 144, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "HA58/WHA58_3-en.pdf).\n3. Koopman JS et al. Determinants and predictors of dengue infection in Mexico. \nAmerican Journal of Epidemiology, 1991, 133(11):1168\u20131178.\n4. Jury MR. Climate influence on dengue epidemics in Puerto Rico. International Journal \nof Environmental Health Research, 2008, 18(5):323\u2013334.\n5. WHO/WPRO. A guide to establishing event-based surveillance. Manila, World \nHealth Organization Regional Office for the Western Pacific, 2008 (http://www.\nwpro.who.int/NR/rdonlyres/92E766DB-DF", "page": 144, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "(http://www.\nwpro.who.int/NR/rdonlyres/92E766DB-DF19-4F4F-90FD-C80597C0F34F/0/\neventbasedsurv.pdf, accessed 19 September 2008).\n6. Runge-Ranziger S et al. What does dengue disease surveillance contribute to \npredicting and detecting outbreaks and describing trends. Tropical Medicine and \nInternational Health, 2008, 13:1022\u20131041.\n7. Rigau-P\u00e9rez JG, Clark GG. C\u00f2mo responder a una epidemia de dengue: vision \nglobal y experiencia en Puerto Rico. Pan American Journal of Public Health, 2005, \n17:282\u20132", "page": 144, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "American Journal of Public Health, 2005, \n17:282\u2013293.\n8. Rigau-P\u00e9rez JG, Vorndam AV, Clark GG. The dengue and dengue hemorrhagic \nfever epidemic in Puerto Rico, 1994-1995. American Journal of Tropical Medicine and \nHygiene, 2001, 64:67\u201374.\n9. Tien NTK et al. Predictive indicators for forecasting epidemic of dengue/dengue \nhaemorrhagic fever through epidemiological, virological and entomological surveillance. \nDengue Bulletin, 1999, 23.\n10. De Simone TS et al. Dengue virus surveillance: the co-ci", "page": 144, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "one TS et al. Dengue virus surveillance: the co-circulation of DEN-1, DEN-2 \nand DEN-3 in the State of Rio de Janeiro, Brazil. Royal Society of Tropical Medicine \nand Hygiene, 2004, 98:553\u2013562.\n11. Pirard M et al. Desarrollo de un Sistema de Vigilancia para dengue en Santa Cruz, \nBolivia. Bol. cient. CENETROP, 1997, 16(1):16\u201323 (in Spanish). \n12. Kour\u00ed G et al. Reemergence of dengue in Cuba: a 1997 epidemic in Santiago de \nCuba. Emerging Infectious Diseases, 1998, 4:89\u201392.\n13. Carme B et al. Non", "page": 144, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "us Diseases, 1998, 4:89\u201392.\n13. Carme B et al. Non-specific alert system for dengue epidemic outbreaks in \nareas of endemic malaria. A hospital-based evaluation in Cayenne (French Guiana). \nEpidemiology and Infection, 2003, 130:93\u2013100.", "page": 144, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "133\nChapter 5. Surveillance, emergency preparedness and response\nCHAPTER 5\n14. Brachman PS. Control of communicable diseases manual, 17th ed. Washington, \nDC, American Public Health Association, 2000 (ISBN 0-87553-182-2).\n15. Gubler DJ. Dengue and dengue hemorrhagic fever. Clinical Microbiology Reviews, \n1998, 11(3):480\u2013496.\n16. \nFocks \nDA, \nAlexander \nN. \nMulticountry \nstudy \nof \nAedes \naegypti \npupal \nproductivity \nsurvey \nmethodology: findings and recommendations. Geneva, World Health Organiz", "page": 145, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "and recommendations. Geneva, World Health Organization, \nSpecial Programme for Research and Training in Tropical Diseases, 2006 (Document \nTDR/IRM/Den/06.1).\n17. Nathan MB, Focks DA, Kroeger A. Pupal/demographic surveys to inform dengue-vector \ncontrol. Annals of Tropical Medicine and Parasitology, 2006, 100(Suppl):1S1\u20131S3.\n18. Kay BH et al. Evaluation of a funnel trap for the collection of copepods and \nimmature mosquitoes from wells. Journal of the American Mosquito Control Association, \n1992", "page": 145, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "f the American Mosquito Control Association, \n1992, 8:372\u2013375.\n19. Russell BM, Kay BH. Calibrated funnel trap for quantifying mosquito (Diptera: \nCulicidae) abundance in wells. Journal of Medical Entomology, 1999, 36(6):851\u2013\n855(5).\n20. Gionar YR et al. Use of a funnel trap for collecting immature Aedes aegypti and \ncopepods from deep wells in Yogyakarta, Indonesia. Journal of the American Mosquito \nControl Association, 1999, 15(4):576\u2013580.\n21. Queensland Health. Dengue fever management plan for", "page": 145, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ueensland Health. Dengue fever management plan for North Queensland, \n2005\u20132010. http://www.health.qld.gov.au/dengue/managing_outbreaks/default.\nasp (site last updated 11 January 2007).\n22. Taylor MA et al. Adapting to dengue risk\u2014what to do? Washington, DC, \nAssessments of Impacts and Adaptations to Climate Change, 2006 (AIACC Working \nPaper No. 33) http://www.aiaccproject.org/working_papers/Working%20Papers/\nAIACC_WP33_Taylor.pdf.\n23. Parks W, Lloyd LS. Planning social mobilization and communi", "page": 145, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "Lloyd LS. Planning social mobilization and communication for dengue \nfever prevention and control: a step-by-step guide. Geneva, World Health Organization, \n2004 \n(available \nat: \nhttp://www.who.int/tdr/publications/publications/pdf/\nplanning_dengue.pdf; accessed October 2008).\n24. Barbazan P et al. Assessment of a new strategy, based on Aedes aegypti (L.) pupal \nproductivity, for the surveillance and control of dengue transmission in Thailand. Annals \nof Tropical Medicine and Parasitology, 2008", "page": 145, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "nnals \nof Tropical Medicine and Parasitology, 2008, 102(2):161\u2013171.\n25. WHO. WHO outbreak communication guidelines. Geneva, World Health \nOrganization, \n2005 \n(http://www.who.int/infectious-disease-news/IDdocs/\nwhocds200528/whocds200528en.pdf).\n26. WHO. Guidelines for conducting a review of a national dengue prevention and \ncontrol programme. Geneva, World Health Organization, 2005 (Document WHO/\nCDS/CPE/PVC/2005.13).", "page": 145, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "134\nDengue: Guidelines for diagnosis, treatment, prevention and control", "page": 146, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "135\nChapter 6. New avenues\nCHAPTER 6\nChapter 6\n \nNew avenues", "page": 147, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "136\nDengue: Guidelines for diagnosis, treatment, prevention and control", "page": 148, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "137\nChapter 6. New avenues\nCHAPTER 6\nChapter 6. NEW AVENUES\n6.1 Overview\nPrimary prevention of dengue is currently possible only with vector control and personal \nprotection from the bites of infected mosquitoes. However, the development of vaccines \nand drugs has the potential to change this. This chapter describes the current development \nof vaccines (section 6.2) and drugs (section 6.3). \n6.2 Dengue vaccines\n6.2.1 \tOverview \nDespite formidable challenges to developing tetravalent dengue vacci", "page": 149, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "challenges to developing tetravalent dengue vaccines, significant \nprogress has been made in recent years and the pace towards clinical efficacy trials has \naccelerated substantially (1,2,3,4). Box 6.1 summarizes the complexity of developing a \ndengue vaccine. Triggered by the continued unchecked spread of dengue worldwide, \nthere has been renewed interest in dengue by researchers, funding agencies, policy-\nmakers and vaccine manufacturers alike. The creation of public\u2013private partnerships \nfor", "page": 149, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": ". The creation of public\u2013private partnerships \nfor product development has facilitated the process. Recent studies of the burden of \ndisease have quantified the cost of dengue both to the public sector and to households \nand have demonstrated the potential cost-effectiveness of a dengue vaccine (5,6,7,8). \nThe vaccine pipeline is now sufficiently advanced for it to be possible to have a first-\ngeneration dengue vaccine licensed within the next five to seven years (3). In addition, \na number of d", "page": 149, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ve to seven years (3). In addition, \na number of diverse candidates are at earlier stages of evaluation and could become \nsecond-generation vaccines.\n6.2.2 Product development \nA primary immunological mechanism that confers protection from dengue illness is virus \nneutralization through antibodies, and all current dengue vaccine candidates aim to \nelicit high levels of neutralizing antibody. The increasing co-circulation of the four dengue \nvirus types means that a vaccine is needed that protect", "page": 149, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "types means that a vaccine is needed that protects against all four of them; hence, \nthe vaccine needs to be tetravalent. Moreover, the induction of protective, neutralizing \nantibody responses against all four serotypes of dengue virus simultaneously should \navoid the theoretical concern of vaccine-induced antibody-dependent enhancement in \nvaccine recipients. Dengue vaccines in development are of four types: live attenuated \nviruses, chimeric live attenuated viruses, inactivated or sub-unit v", "page": 149, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "live attenuated viruses, inactivated or sub-unit vaccines, and nucleic \nacid-based vaccines.\nLive attenuated vaccines (LAVs) can induce durable humoral and cellular immune \nresponses since they most closely mimic a natural infection. Several parameters are \ncrucial for LAVs: \n \n\u2022 The viruses must be sufficiently attenuated and viral replication reduced so that  \n\t\n\t\nviraemia is low and symptoms of illness are minimal.\n \n\u2022 Transmission of the viruses by mosquitoes is reduced or eliminated.", "page": 149, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ses by mosquitoes is reduced or eliminated.", "page": 149, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "138\nDengue: Guidelines for diagnosis, treatment, prevention and control\n \n\u2022 The viruses should replicate well in cell culture and be sufficiently immunogenic  \n\t\n\t\nto provide long-lasting immunity in humans, so that low doses can be used.\n \n\u2022 A balanced immune response to all four dengue viruses must be elicited.\n \n\u2022 The genetic basis for attenuation must be known and must be stable (4). \nSeveral live attenuated vaccines are in advanced stages of development. One is a \nchimeric tetravalent vacci", "page": 150, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "development. One is a \nchimeric tetravalent vaccine in which the structural genes (prM and E) of each of the \nfour dengue viruses were inserted individually to replace those of yellow fever virus \nin the backbone of the yellow fever 17D vaccine. Thus, the nonstructural genes of \nyellow fever are provided to allow replication of the chimeric virus, and attenuation is \nimparted by the yellow fever portion of the chimera. Monovalent vaccines, as well as \ntetravalent mixtures of all four viruses, h", "page": 150, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ll as \ntetravalent mixtures of all four viruses, have been given to human volunteers of varying \nages in phase 1 and phase 2 trials in both non-endemic and endemic regions. At least \ntwo doses were required to achieve high rates of tetravalent neutralizing antibodies, \nand somewhat higher seroconversion rates were observed in subjects with pre-existing \nimmunity to yellow fever (2). \nAnother comprises strains of the four serotypes of the dengue virus, each attenuated by \npassage in primary dog k", "page": 150, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "irus, each attenuated by \npassage in primary dog kidney cells and initially prepared as candidate vaccines in \nfetal rhesus monkey lung cells (FRhL). Each attenuated dengue virus was rederived by \ntransfecting cells with purified viral RNA. Original and rederived attenuated viruses have \nbeen extensively tested both individually and in tetravalent formulation in phase 1 and \nphase 2 trials in human volunteers of different ages. Tetravalent anti-DEN neutralizing \nantibodies are raised to high rat", "page": 150, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "EN neutralizing \nantibodies are raised to high rates following the administration of at least two doses \nat an interval of six months, especially if volunteers have previously been exposed to \nflaviviruses.\nOther vaccine candidates in phase 1 testing include live attenuated viruses. Here, \nvaccine development is being approached in two ways: (i) via direct removal of 30 \nnucleotides in the 3\u2019 untranslated region of DEN-1 and DEN-4, and (ii) the construction \nof chimeric viruses consisting of DEN", "page": 150, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "onstruction \nof chimeric viruses consisting of DEN-2 and DEN-3 structural genes in the non-structural \nbackbone of the DEN-4 strain with 30 nucleotides deleted from the 3\u2019 untranslated \nregion. Satisfactory attenuation, immunogenicity and protection have been obtained in \nrhesus monkeys for each of the four dengue viruses in this way (4). Phase 1 testing has \ntaken place with all four monovalent vaccines.\nDengue vaccines in advanced preclinical development include DEN-DEN chimeras. In \nthis vacc", "page": 150, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "evelopment include DEN-DEN chimeras. In \nthis vaccine, the prM and E protein genes of DEN-1, DEN-3 and DEN-4 were each \ninserted into the infectious clone of PDK-passaged, attenuated DEN-2 (PDK53). The \nthree attenuating mutations are located outside the structural protein genes of PDK53 \nand appear to be quite stable. The tetravalent vaccine produced by combining the four \nchimeric dengue viruses is protective when administered to mice. Monkey challenge \nexperiments have been conducted but prep", "page": 150, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "hallenge \nexperiments have been conducted but preparations for clinical trials are underway.\nSeveral DNA vaccines designed to deliver structural dengue viral genes into cells have \nbeen generated, and a monovalent DEN-1 DNA vaccine is currently undergoing phase \n1 testing. In addition, candidate vaccines that have successfully protected monkeys \nfrom viraemic challenge include recombinant 80% envelope protein from the four DEN \nserotypes in conjunction with DEN-2 NS1 administered with several ne", "page": 150, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "nction with DEN-2 NS1 administered with several new-generation \nadjuvants. There is also work in progress on subunit vaccines based on domain III", "page": 150, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "139\nChapter 6. New avenues\nCHAPTER 6\nof the E protein, which is considered to be the principal neutralizing epitope region \nof the virus, employing different strategies to increase immunogenicity. A tetravalent \nreplication-defective-recombinant adenovirus (cAdVaX) has also been prepared, as have \nformalin-inactivated vaccines of the four dengue viruses. Finally, prime-boost strategies \ncombining vaccines of distinct formulations are under investigation.\n6.2.3 Challenges \nSince dengue is caused", "page": 151, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "igation.\n6.2.3 Challenges \nSince dengue is caused by four serologically related viruses, the first major problem \nin developing a dengue vaccine is to develop not just one immunogen but four \nimmunogens that will induce a protective immune response against all four viruses \nsimultaneously. Therefore, the vaccine must be tetravalent. Interference between the \nfour vaccine viruses must be avoided or overcome, and neutralizing titres to all four \nviruses need to be achieved regardless of the previo", "page": 151, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ruses need to be achieved regardless of the previous immune status of the vaccinated \nindividuals. Thus, the tetravalent formulations must balance viral interference with long-\nlasting immunogenicity and reactogenicity.\nThe second issue is the lack of a validated correlate of protection since the mechanism \nof protective immunity against DEN infection is not fully understood. A wealth of data \nsuggests that neutralizing antibodies are the main effector of protection against DEN \nvirus infection.", "page": 151, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "fector of protection against DEN \nvirus infection. However, neither the precise antibody titres nor neutralizing epitopes \nnor the contributions of other immune mechanisms to protection have been defined. \nFurther studies are necessary to elucidate the mechanism of protective immunity so that \ncorrelates of protection can be established to demonstrate that the candidate vaccines \ninduce a protective immune response (9). \nThe dengue viruses are arboviruses whose normal transmission cycle involves", "page": 151, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "boviruses whose normal transmission cycle involves mosquitoes \n(most commonly Ae. aegypti and Ae. albopictus) with humans as the vertebrate host, \nwithout relying on other animal reservoirs. Herein lies the third problem. Two animal \nmodels (mice and non-human primates) are used to evaluate candidate vaccines, \nbut neither of these faithfully recapitulates both the disease outcome and the immune \nresponse in humans. Mice are often used as a small animal model to evaluate initially \nthe ability o", "page": 151, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "animal model to evaluate initially \nthe ability of candidate vaccines to induce a protective immune response, and good \nprogress has been made recently in developing mouse models for DEN virus infection \nand disease. However, the results are not always predictive of what will happen in \nhigher animal species \u2013 i.e. a candidate vaccine that protects mice may not be as \neffective in other animal models. The second animal model is the non-human primate, \nand a variety of species have been used as", "page": 151, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "mate, \nand a variety of species have been used as models to evaluate candidate dengue \nvaccines. Unfortunately, non-human primates do not present clinical disease but do \ndemonstrate viraemia (originally measured as infectivity, now normally measured by \nreal-time RT-PCR and immunological parameters as proxies). Clearly, the mouse and \nnon-human primate models must be used to evaluate candidate dengue vaccines before \nthey are tested in humans. However, unexpected discordance has occasionally be", "page": 151, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "owever, unexpected discordance has occasionally been \nobserved between preclinical and clinical outcomes (10). \nThe fourth challenge for the development of dengue vaccines is the potential for immune \nenhancement, including antibody-dependent enhancement. It is clear that an infection \nby one dengue virus leads to lifelong protective immunity against the infecting virus, i.e. \nhomotypic immunity. However, many studies have shown that some secondary DEN \ninfections (i.e. infection by one dengue v", "page": 151, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ry DEN \ninfections (i.e. infection by one dengue virus followed by infection by a different DEN \nserotype) can lead to severe disease (DHF/DSS) and that anti-DEN antibodies passively", "page": 151, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "140\nDengue: Guidelines for diagnosis, treatment, prevention and control\ntransferred from mothers to infants increase the risk of DHF/DSS in the infants for a \ncertain period of time. Thus, there is theoretically a danger that a dengue vaccine could \npotentially cause severe disease (including DHF or DSS) in vaccine recipients if solid \nimmunity was not established against all four serotypes. It should be emphasized that, \nto date, there is no evidence that a vaccine recipient who has received a", "page": 152, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "dence that a vaccine recipient who has received a candidate \nvaccine has subsequently succumbed to severe disease. Rather, vaccine recipients have \nshown evidence of immunity for varying lengths of time. This may be influenced by the \ncandidate vaccine. Also vaccine recipients may have been exposed to less symptomatic \nDEN infections than control groups, although this is based on small numbers thus far \n(11). Nonetheless, the risk of immune enhancement by a candidate vaccine must be \nevaluated t", "page": 152, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "cement by a candidate vaccine must be \nevaluated through prolonged follow-up of vaccinated cohorts.\nBox 6.1 The complexity of developing a dengue vaccine\n\t Development\t\n\t\n\t\n  \n\u2022 Need for a tetravalent vaccine with not just one but four immunogens that will give a balanced immune \n\t \t\n\t\nresponse whereby a protective long-lasting immunity is induced against all four viruses simultaneously \t\n\t\n\t \t\n\t\n(balancing viral interference, immunogenicity, and reactogenicity).\n  \n\u2022 Lack of immune correlate of", "page": 152, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "reactogenicity).\n  \n\u2022 Lack of immune correlate of protection since the mechanism of protective immunity against DEN infection is  \n\t \t\n\t\nonly partially understood. It is assumed that neutralizing antibodies are the main effector of protection against \t\n\t \t\n\t\nDEN infection.\n  \n\u2022 Lack of a suitable animal model that recapitulates human disease and can be used to evaluate candidate  \n\t \t\n\t\nvaccines.\n  \n\u2022 Potential immunopathogenesis, including antibody-dependent enhancement\n\t Implementation", "page": 152, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "body-dependent enhancement\n\t Implementation\t\n\t\n\t\n  \n\u2022 Need for long-term follow-up.\n  \n\u2022 Need for testing in both Asia and the Americas.\n  \n\u2022 Ideally, can be tested against all four DEN serotypes.\n  \n\u2022 The exact location, timing and serotype/genotype composition of dengue epidemics varies from year to year  \n\t \t\n\t\nand is somewhat unpredictable.\n6.2.4 Implementation\nThe clinical evaluation of candidate vaccines for dengue has several unique aspects, \nsome of which are related to the above-mention", "page": 152, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "s, \nsome of which are related to the above-mentioned challenges. Dengue illness has \nmany clinical manifestations and poses diagnostic challenges. Ideally, a vaccine \nshould be efficacious against all forms of dengue illness, ranging from febrile illnesses \nto severe forms such as DHF and DSS. Trials need to be large enough to address a \nvaccine\u2019s impact on the different clinical forms of dengue. Phase 4, or post-marketing, \ntrials will be particularly important for dengue for the same reason. L", "page": 152, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ularly important for dengue for the same reason. Likewise, long-\nterm evaluation of volunteers will be required to demonstrate lack of evidence for \nimmune enhancement/severe disease. Trials need to take place in multiple countries \n\u2013 particularly in both Asia and the Americas \u2013 due to the distinct epidemiological \ncharacteristics and the viruses circulating in each region. The greatest burden of disease \nis found in distinct age groups in different countries, and the methodology of capturing \nc", "page": 152, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ent countries, and the methodology of capturing \nclinical events may differ by age group and between countries. The epidemic peak \nvaries somewhat in timing and exact location from year to year even in endemic \ncountries; thus, long-term dengue surveillance data about the potential vaccine testing", "page": 152, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "141\nChapter 6. New avenues\nCHAPTER 6\nsite(s) is crucial and, even so, the unpredictability of timing and location adds a level \nof complexity to calculations of trial sample size. To facilitate the vaccine development \nprocess, WHO has developed guidelines for the clinical evaluation of dengue vaccines \n(12). The Paediatric Dengue Vaccine Initiative (PDVI) supports the establishment of field \nsites for the testing of vaccines.\n6.2.5 Vaccine utilization for dengue control\nAdditional work is requi", "page": 153, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "zation for dengue control\nAdditional work is required to bring a vaccine from licensing to programmatic use in \ndengue-endemic areas. Depending on cost-effectiveness and the outcome of financial \nand operational analysis, countries may decide to introduce dengue vaccines into the \nnational immunization programmes for routine administration. If the vaccine is to be used \nfor infants, the dengue vaccination will need to be carried out on a schedule compatible \nwith other vaccines. Interference bet", "page": 153, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "compatible \nwith other vaccines. Interference between dengue vaccine and other vaccines likely to \nbe given in the same time period must be ruled out. If the vaccine is to be delivered to \nolder age groups, proper contact points will need to be established to deliver the vaccine \neffectively and to ensure post-marketing surveillance. In addition, vaccine presentation, \npackaging and stability requirements should be compatible with large-scale use. WHO \nhas produced generic guidelines to guide n", "page": 153, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "e. WHO \nhas produced generic guidelines to guide national authorities in their decision-making \non the introduction of new vaccines (13). \nTo maximize the effect of vaccination, the potential impact of a vaccine on dengue \ntransmission needs to be studied (e.g. the role of herd immunity). A number of modelling \napproaches are being taken to address this and other similar issues, as well as the \ncharacteristics of the mosquito population transmitting the virus and climatographic \nparameters.\nGive", "page": 153, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ing the virus and climatographic \nparameters.\nGiven the complexity of dengue and dengue vaccines, it is imperative to continue \nscientific research that is directed at improving our understanding of the immune response \nin both natural DEN infections and vaccinees (e.g. defining neutralizing and potentially \nenhancing epitopes, improving animal models) alongside vaccine development and \nevaluation.\n6.3 Dengue antiviral drugs\n6.3.1\t Overview\nThe search for dengue antivirals is a new endeavour tha", "page": 153, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "earch for dengue antivirals is a new endeavour that is gaining momentum due \nto both increased interest in dengue and substantial progress in the structural biology \nof dengue virus. Furthermore, extensive drug discovery efforts in HIV and HCV have \ntaught us important lessons that encourage similar strategies to be adopted for dengue. \nSince HCV and dengue virus are members of the Flaviviridae family, the intensive work \non HCV antivirals \u2013 especially those that target the RNA-dependent RNA pol", "page": 153, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "cially those that target the RNA-dependent RNA polymerase \n\u2013 can benefit the search for dengue antivirals (14). The rationale for dengue antivirals \narises from clinical studies that have noted that the quantity of virus circulating in the \nblood of patients who develop DHF and DSS is higher by around 1\u20132 logs compared \nwith patients suffering from the milder dengue fever. Similar differences in viral load \nhave been observed in animal models of ADE (15,16,17). This observation suggests \nthat pr", "page": 153, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ADE (15,16,17). This observation suggests \nthat progress to serious dengue disease and adverse morbidity may be reversed by \nadministering potent and safe small molecule compounds that target essential steps in", "page": 153, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "142\nDengue: Guidelines for diagnosis, treatment, prevention and control\nvirus replication early during the disease, thereby lowering the viral load substantially. \nThis hypothesis requires field-testing when a suitable anti-dengue agent is discovered.\n6.3.2 Product development\nThe life cycle of dengue virus readily shows that the steps involved in virus entry, \nmembrane fusion, RNA genome replication, assembly and ultimate release from the \ninfected cell can be targeted by small molecules (18).", "page": 154, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ted cell can be targeted by small molecules (18). The importance of targets such \nas the viral protease and polymerase have been studied by reverse genetics using \ninfectious clones to validate them as targets for drug discovery. On the basis of success \nin the HIV and HCV fields in finding small molecules that target viral enzymes that \nare essential for virus replication in infected cells, academic institutions and non-profit \npharmaceutical enterprises and consortia are progressing in their s", "page": 154, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "terprises and consortia are progressing in their search for antiviral \ncompounds active against these targets in dengue virus. The field is also benefiting from \nnew insights afforded by x-ray crystallography and cryo-electron microscopy data. In \nthe past five years alone, seven new 3-D structures of dengue proteins have been solved \nand nine structures of other flavivirus proteins have become available. Based on these, \na number of in silico and high through-put screens have been and are being", "page": 154, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "d high through-put screens have been and are being undertaken, \nyielding several lead compounds so far (19). Currently the most advanced targets are \nthe NS3/NS2B protease and NS5 RNA-dependent RNA polymerase, which have \nundergone high through-put screening and lead compound optimization. New targets \u2013 \nincluding E, NS3 helicase, and NS5 methyltransferase \u2013 are being explored (20), and \nothers will soon be added to the list. Recent advances in understanding the mechanism \nof membrane fusion dur", "page": 154, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "nderstanding the mechanism \nof membrane fusion during DEN infection of target cells has opened up new possibilities \nfor designing novel antiviral strategies that target the fusion step as well (21).\nScreening efforts are continuing and will increase. They include the proprietary libraries \nof pharmaceutical and biotechnology companies, focused libraries of compounds \nsynthesized to specific targets (e.g. protease inhibitors), designed libraries based on \nstructural information, natural products", "page": 154, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "based on \nstructural information, natural products and approved drugs. Different approaches have \nbeen taken to screening compounds, such as high through-put screening of both target \nprotein activity and viral replication in cultured cells, high through-put docking in silico, \nand fragment-based screening using NMR and x-ray crystallography. Distinct classes of \ninhibitors are being explored, such as substrate- and transition-state-based as well as non-\nsubstrate-based inhibitors. Reporter repl", "page": 154, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "as non-\nsubstrate-based inhibitors. Reporter replicons based on yellow fever or DEN infectious \nclones have facilitated screening in cell culture for both primary and secondary screens \n(22,23). Early preclinical in vivo testing can be conducted in certain mouse models \nof dengue infection. For instance, tissue and cellular tropism of DEN in AG129 mice \n(mice of the 129 background lacking interferon a/b and g receptors) is similar to that \nin humans (24,25), and AG129 mice are being used as the", "page": 154, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "mans (24,25), and AG129 mice are being used as the first step in preclinical \ntesting of candidate antivirals (26). Alternative approaches, such as interfering with \nviral replication using peptide-conjugated phosphorodiamidate morpholino oligomers \n(P-PMOs), have also been proposed and are effective in cell culture (27,28). Initial \nstudies of such compounds in mice against the related West Nile virus have been \nreported (29). Other nucleotide-based approaches, including RNAi methodologies, \nha", "page": 154, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ased approaches, including RNAi methodologies, \nhave been investigated in the exploratory phase (30). In addition, cellular targets are \nunder consideration, as is the idea of incorporating multiple targets in one formulation so \nas to delay the possible development of resistance. A further approach is to target key \ndisease manifestations. As more is understood about the mechanism of severe dengue \ndisease, animal models that reproduce specific manifestations may be useful for testing \nanti-den", "page": 154, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "manifestations may be useful for testing \nanti-dengue drugs. For instance, the AG129 mouse demonstrates a vascular leak early-", "page": 154, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "143\nChapter 6. New avenues\nCHAPTER 6\ndeath phenotype when infected with DEN-2 strain D2S10 (31). It can also reproduce \nantibody-dependent enhancement of infection and disease (17) and is currently being \nused to test compounds that target disease phenotypes such as vascular leak.\n6.3.3 Challenges\nThere are numerous requirements for an anti-dengue drug (Box 6.2). The minimal target \nproduct profile includes oral route of administration, frequency of dosing of once per \nday, stability in the face", "page": 155, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "of dosing of once per \nday, stability in the face of heat and humidity, a long shelf-life, and low/reasonable \ncost of goods and ease of formulation to allow a reasonably priced product (18). \nWith respect to clinical efficacy, the drug must be active against all serotypes, reduce \nsymptoms, and reduce the incidence of severe disease. Furthermore, a safe drug may \nbe evaluated for prophylactic as well as paediatric use after proper trials. \nBox 6.2 The challenge of developing dengue antivirals", "page": 155, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "6.2 The challenge of developing dengue antivirals\n\t Development\t\n\t\n\t\n  \n\u2022 Several potential viral targets, of which the most advanced are  NS3/NS2B protease and NS5 polymerase;  \n\t \t\n\t\nwork in progress on E, NS3 helicase, and NS5 methyltransferase.\n  \n\u2022 Must be active against all serotypes.\n  \n\u2022 Must be effective in both primary and secondary DEN infections.\n  \n\u2022 Must be active orally, stable to heat and humidity, have a long shelf-life, and have low/reasonable  \n\t \t\n\t\nproduction costs.\n  \n\u2022 Exp", "page": 155, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "low/reasonable  \n\t \t\n\t\nproduction costs.\n  \n\u2022 Exploration of cellular targets?\n  \n\u2022 Good safety profile, including few or no secondary effects.\n  \n\u2022 Useful in infants, children and adults.\n\t Implementation\t\n\t\n\t\n  \n\u2022 Need for rapid point-of-care diagnostic tool to apply antiviral most effectively.\n  \n\u2022 Short window of viraemia.\n  \n\u2022 Possible development of resistance: use cocktails of multiple drugs to avoid this eventuality.\n  \n\u2022 Must be tested in acute DEN infection, and a prophylactic trial i", "page": 155, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "in acute DEN infection, and a prophylactic trial is not an option.\n6.3.4 Implementation\nOne of the biggest challenges in testing antivirals is that to be effective the drug(s) should \npresumably be delivered early after onset of symptoms. However, the vast majority of \ndengue patients present late during their illness, perhaps on days 3 or 4 of fever. Even \nduring clinical studies, patients do not present to study staff much earlier. In this respect, \na trial of dengue antivirals would have to c", "page": 155, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ect, \na trial of dengue antivirals would have to capture patients presenting to primary care \nfacilities, where it would be possible to enrol patients during the first two days after the \nonset of symptoms, whereas hospital admission is more likely to occur on days 3 or \n4 or later. However, the earlier the presentation with fever, the less likely it is that the \ndiagnosis will be dengue. Although prospective dengue diagnosis before treatment in a \nclinical study would be ideal, this would poten", "page": 155, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "a \nclinical study would be ideal, this would potentially be problematic as it would require \nrapid RT-PCR testing at or near the site of the study. The availability of new serological \nreagents such as NS1 antigen capture tests may make early point-of-care diagnosis", "page": 155, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "144\nDengue: Guidelines for diagnosis, treatment, prevention and control\npossible. It would also be ideal to test reactions between an anti-dengue drug and other \ndrugs often used to treat dengue patients, such as paracetamol.\nIt is likely that a multicentre trial of a candidate dengue antiviral drug would be indicated, \nwhich raises a series of issues. For instance, the treatment that dengue cases receive \nin hospitals is known to have a dramatic effect on the disease outcome, and the way \nclini", "page": 156, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "effect on the disease outcome, and the way \nclinicians treat dengue cases varies greatly both within and between institutions. In \naddition, getting physicians to document parameters and outcomes carefully in busy \nclinical situations is often difficult \u2013 though not impossible \u2013 and is clearly essential for \nany trial. A robust study design with a single protocol followed meticulously at all sites \nwould solve the problem but would be challenging to achieve.\nThe greatest burden of dengue in mos", "page": 156, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "g to achieve.\nThe greatest burden of dengue in most countries is in children, although in some areas \nolder age groups are also significantly affected. The target population for dengue drugs \nwould be all age groups but, because of the problematic nature of clinical trials in \nchildren, a drug trial may be better performed in the first instance in adults (>15 years \nof age). \nAlthough vaccines and drugs for dengue pose significant challenges during both \nproduct development and field-testing, tr", "page": 156, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ng both \nproduct development and field-testing, tremendous strides have been made recently in \nboth areas.\n6.4 REFERENCES\n1. Edelman R. Dengue vaccines approach the finish line. Clinical Infectious Diseases, \n2007, 45(Suppl 1):S56\u2013S60.\n2. Guy B, Almond JW. Towards a dengue vaccine: progress to date and remaining \nchallenges. Comparative Immunology, Microbiology and Infectious Diseases, 2008, \n2\u20133:239\u2013252.\n3. Hombach J. Vaccines against dengue: a review of current candidate vaccines at \nadvanced", "page": 156, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "review of current candidate vaccines at \nadvanced development stages. Revista Panamericana de Salud P\u00fablica, 2007, \n21:254\u2013260.\n4. Whitehead SS et al. Prospects for a dengue virus vaccine. Nature Reviews. \nMicrobiology, 2007, 5:518\u2013528.\n5. Anderson KB et al. Burden of symptomatic dengue infection in children at primary \nschool in Thailand: a prospective study. Lancet, 2007, 369:1452\u20131459.\n6. Clark DV. Economic impact of dengue fever/dengue hemorrhagic fever in Thailand \nat the family and populat", "page": 156, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "hagic fever in Thailand \nat the family and population levels. American Journal of Tropical Medicine and Hygiene, \n2005, 72:786\u2013791.\n7. Halstead SB, Suaya JA, Shepard DS. The burden of dengue infection. Lancet, 2007, \n369:1410\u20131411.", "page": 156, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "145\nChapter 6. New avenues\nCHAPTER 6\n8. Shepard DS et al. Cost-effectiveness of a pediatric dengue vaccine. Vaccine, 2004, \n22:1275\u20131280.\n9. Hombach Jet al. Scientific consultation on immunological correlates of protection \ninduced by dengue vaccines report from a meeting held at the World Health Organization \n17-18 November 2005. Vaccine, 2007, 25:4130\u20134139.\n10. Innis BL et al. Virulence of a live dengue virus vaccine candidate: a possible new \nmarker of dengue virus attenuation. Journal of Inf", "page": 157, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "marker of dengue virus attenuation. Journal of Infectious Diseases, 1998, 158:876\u2013\n880.\n11. Chanthavanich PC et al. Short report: immune response and occurrence of dengue \ninfection in thai children three to eight years after vaccination with live attenuated \ntetravalent dengue vaccine. American Journal of Tropical Medicine and Hygiene, 2006, \n75:26\u201328.\n12. Edelman R, Hombach J. Guidelines for the clinical evaluation of dengue vaccines \nin endemic areas: summary of a World Health Organization te", "page": 157, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "c areas: summary of a World Health Organization technical consultation. \nVaccine, 2008, 26(33):4113\u20134119.\n13. WHO. Vaccine introduction guidelines. Geneva, World Health Organization, \n2007 (Document WHO/IVB/05.18). \n14. Olsen DB et al. A 7-deaza-adenosine analog is a potent and selective inhibitor \nof hepatitis C virus replication with excellent pharmacokinetic properties. Antimicrobial \nAgents and Chemotherapy, 2004, 48(10):3944\u20133953.\n15. Goncalvez AP et al. Monoclonal antibody-mediated enhance", "page": 157, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "vez AP et al. Monoclonal antibody-mediated enhancement of dengue virus \ninfection in vitro and in vivo and strategies for prevention. Proceedings of the National \nAcademy of Sciences of the United States of America, 2007, 104:9422\u20139427.\n16. Halstead SB. In vivo enhancement of dengue virus infection in rhesus monkeys by \npassively transferred antibody. Journal of Infectious Diseases, 1979,140:527\u2013533.\n17. Balsitis SJ, Harris E. Animal models of dengue virus infection: applications, insights, \nand", "page": 157, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "ngue virus infection: applications, insights, \nand frontiers. In: Hanley KA, Weaver SC, eds. Frontiers in dengue virus research. \nNorwich, Horizon Scientific Press, 2009 (in press).\n18. Keller TH et al. Finding new medicines for flaviviral targets. Novartis Foundation \nSymposium, 2006, 277:102\u2013114.\n19. Johnston PA et al. HTS identifies novel and specific uncompetitive inhibitors of the \ntwo-component NS2B-NS3 proteinase of West Nile virus. Assay and Drug Development \nTechnologies, 2007, 5(6):737", "page": 157, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "and Drug Development \nTechnologies, 2007, 5(6):737\u2013750.\n20. Luzhkov VB et al. Virtual screening and bioassay study of novel inhibitors for \ndengue virus mRNA cap (nucleoside-2\u2019O)-methyltransferase. Bioorganic and Medicinal \nChemistry, 2007, 15:7795\u20137802.", "page": 157, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "146\nDengue: Guidelines for diagnosis, treatment, prevention and control\n21. Stiasny K, Kiermayr S, Heinz FX. Entry functions and antigenic structure of flavivirus \nenvelope proteins. Novartis Foundation Symposium, 2006, 277:57\u201365.\n22. Patkar CG, Kuhn RJ. Development of novel antivirals against flaviviruses. Novartis \nFoundation Symposium, 2006, 277:41\u201352.\n23. Ng CY et al. 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A dengue fever viremia model in mice shows reduction in viral \nreplication and suppression of the inflammatory response after treatment with antiviral \ndrugs.  Journal of Infectious Diseases, 2007,195:665\u2013674.\n27. Holden KL et al. Inhibition of dengue virus translation and RNA synthesis by a \nmorpholino oligomer to the top of the 3\u2019 stem-loop structure. Virology, 2006, 344:439\u2013\n452.\n28. Kinney RM et al. Inhibition of dengue virus serotypes 1 t", "page": 158, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "RM et al. Inhibition of dengue virus serotypes 1 to 4 in vero cell cultures with \nmorpholino oligomers. Journal of Virology, 2005, 79:5116\u20135128.\n29. Deas TS et al. In vitro resistance selection and in vivo efficacy of morpholino \noligomers against West Nile virus. Antimicrobial Agents and Chemotherapy, 2007, \n51:2470\u20132482.\n30. Stein DA, Shi PY. Nucleic acid-based inhibition of flavivirus infections. Frontiers in \nBioscience, 2008, 13:1385\u20131395.\n31. Shresta S et al. A murine model for dengue leth", "page": 158, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "1. Shresta S et al. A murine model for dengue lethal disease with increased vascular \npermeability. Journal of Virology, 2006, 80:10208\u201310217.", "page": 158, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "147\nChapter 6. New avenues\nCHAPTER 6", "page": 159, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "Neglected Tropical Diseases (NTD) \nTDR/World Health Organization\nHIV/AIDS, Tuberculosis and Malaria (HTM) \n20, Avenue Appia\nWorld Health Organization \n1211 Geneva 27\nAvenue Appia 20, 1211 Geneva 27, Switzerland \nSwitzerland\nFax: +41 22 791 48 69 \nFax: +41 22 791 48 54\nwww.who.int/neglected_diseases/en \nwww.who.int/tdr\nneglected.diseases@who.int \ntdr@who.int", "page": 160, "source": "dengue.pdf", "doc_title": "dengue"}, {"text": "Guideline \nfor the\npharmacological \ntreatment of \nhypertension \nin adults", "page": 1, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "Guideline \nfor the\npharmacological \ntreatment of \nhypertension \nin adults", "page": 3, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "Guideline for the pharmacological treatment of hypertension in adults\nISBN 978-92-4-003398-6 (electronic version)\nISBN 978-92-4-003397-9 (print version)\n\u00a9 World Health Organization 2021\nSome rights reserved. 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The responsibility for the interpretation and use of the material lies with the reader. \nIn no event shall WHO be liable for damages arising from its use.", "page": 4, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "Contents\nAcknowledgements\t\nv\nAcronyms and abbreviations\t\nvi\nExecutive summary\t\nvii\n1\t Introduction\t\n1\n2\t Method for developing the guideline \t\n3\n2.1\t\nGuideline contributors \t\n3\n2.2\t\nAnalytical framework and PICOs\t\n3\n2.3\t\nOutcome importance rating \t\n4\n2.4\t\nReviews of evidence \t\n4\n2.5\t\nCertainty of evidence and strength of recommendations \t\n5\n2.6\t\nDeciding upon recommendations\t\n6\n2.7\t\nFunding \t\n6\n3\t Recommendations\t\n7\n3.1\t\nBlood pressure threshold for initiation of pharmacological treatment\t\n7\n3.2", "page": 5, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "for initiation of pharmacological treatment\t\n7\n3.2\t\nLaboratory testing before and during pharmacological treatment\t\n8\n3.3\t\nCardiovascular disease risk assessment as guide to initiation of \t\n\t\n\t\nantihypertensive medications\t\n10\n3.4\t\nDrug classes to be used as first-line agents\t\n11\n3.5\t\nCombination therapy\t\n13\n3.6\t\nTarget blood pressure\t\n16\n3.7\t\nFrequency of re-assessment\t\n17\n3.8\t\nAdministration of treatment by nonphysician professionals\t\n19\n4\t Special settings\t\n21\n4.1\t\nHypertension in disaster, h", "page": 5, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "cial settings\t\n21\n4.1\t\nHypertension in disaster, humanitarian and emergency settings\t\n21\n4.2\t\nCOVID-19 and hypertension\t\n22\n4.3\t\nPregnancy and hypertension\t\n22\n5\t Publication, implementation, evaluation and research gaps\t\n24\n5.1\t\nPublication \t\n24\n5.2\t\nImplementation and dissemination \t\n24\n5.3\t\nEvaluation \t\n24\n5.4\t\nFuture updating of the guideline \t\n24\n5.5\t\nResearch gaps\t\n24\n6\t Implementation tools\t\n26\n6.1\t\nGuideline recommendations\t\n26\n6.2\t\nDrug- and dose-specific protocols\t\n28\nReferences\t\n30\nAn", "page": 5, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "and dose-specific protocols\t\n28\nReferences\t\n30\nAnnex 1: List of contributors\t\n37\nAnnex 2. Managing declarations of interest and conflicts of interest \t\n42\nAnnex 3: Treatment outcomes relevant to hypertension\t\n43\nAnnex 4: PICO questions \t\n44\nWeb Annex A: Summary of evidence\nWeb Annex B: Evidence-to-decision framework\niii", "page": 5, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "GUIDELINE FOR THE PHARMACOLOGICAL TREATMENT OF HYPERTENSION IN ADULTS\nFigures\nFig. 1\t\nAnalytic framework for antihypertensive medication treatment\t\n3\nFig. 2\t\nFramework for analysis\t\n9\nFig. 3\t\nAn approach for starting treatment with a single-pill combination \t\n26\nFig. 4\t\nAn approach for starting treatment not using a single-pill combination \n(i.e. with monotherapy or free combination therapy)\t\n27\nFig. 5\t\nAlgorithm 1\t\n28\nFig. 6\t\nAlgorithm 2\t\n29\nFig. A3.1\t Rating of outcomes\t\n43\niv", "page": 6, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": ". A3.1\t Rating of outcomes\t\n43\niv", "page": 6, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "Acknowledgements\nThe Guideline for the pharmacological treatment of hypertension in adults was prepared by the \nWorld Health Organization (WHO) Department of Noncommunicable Diseases. The departments of \nHIV, Hepatitis and Sexually Transmitted Infections (HHS), Mental and Substance use Disorders (MSD), \nMedicines and health products (MHP), the regional offices for Africa (AFRO), South East Asia (SEARO), \nEurope (EURO) and Eastern Mediterranean (EMRO), and the Pan American Health Organization/Reg", "page": 7, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "MRO), and the Pan American Health Organization/Regional \nOffice of the Americas (PAHO/AMRO) also contributed. These departments were represented on the \nWHO Steering Group for this guideline.\nResponsible technical officer: Taskeen Khan\nWHO Steering Group members: Bernadette Cappello (MHP), Neerja Chowdhury (MSD), Gampo Dorji \n(SEARO), Jill Farrington (EURO), Taskeen Khan (NCD), Pedro Ordunez (PAHO/AMRO), Steven Shongwe \n(AFRO), Slim Slama (EMRO), Cherian Varghese (NCD), Marco Vitoria (HHS), Temo", "page": 7, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "Cherian Varghese (NCD), Marco Vitoria (HHS), Temo Waqanivalu (NCD). \nGuideline Development Group: WHO would like to thank the members of the Guideline \nDevelopment Group (GDG) for their commitment, enthusiasm and expertise. GDG members were:\nShrish Acharya (WPRO), Akram Al-Makki (AMRO), Hind Mamoun Beheiry (EMRO), Beatriz Champagne \n(AMRO), Ugyen Choden (SEARO), Kenneth Connell (AMRO), Marie Therese Cooney (EURO), Donald \nDiPette (AMRO), Nnenna Ezeigwe (AFRO), Tom Gaziano (AMRO), Agaba Gidio (A", "page": 7, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "Ezeigwe (AFRO), Tom Gaziano (AMRO), Agaba Gidio (AFRO), Vilma Irazola \n(AMRO), Patricio Lopez Jaramillo (AMRO), Unab Khan (EMRO), Vindya Kumarapeli (SEARO), Andrew \nMoran (AMRO), Margaret Mswema Silwimba (AFRO), Brian Rayner (AFRO), K. Srinath Reddy (SEARO), \nNizal Sarrafzadegan (EMRO), Apichard Sukonthasan (SEARO), Paul Whelton (AMRO), Jing Yu (WPRO). \nMethodologist: M Hassan Murad (Professor of Medicine at the Mayo Clinic, Rochester, USA)\nSystematic Review Team: Reem Mustapha, Abdallah Al Alay", "page": 7, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "matic Review Team: Reem Mustapha, Abdallah Al Alayli, Romina Brignardello, Sara Jdiaa, Veena \nManja (University of Kansas Medical Center, Kansas, USA)\nExternal Review Group: WHO is grateful for the contributions of the following individuals who peer-\nreviewed the draft guideline:\nMabel Aoun, Antoinette P\u00e9ch\u00e8re Bertschi, Jennifer Cohn, Prabhdeep Kaur, Daniel T Lackland, Venus \nMushininga, Marcelo Orias, and Xin Hua Zhang.\nRebekah Thomas from the WHO Guidelines Review Committee Secretariat, and Na", "page": 7, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "HO Guidelines Review Committee Secretariat, and Nathan Ford, Chair of \nthe Guidelines Review Committee are gratefully acknowledged for their technical support throughout \nthe process. Thanks are also due to Alma Alic from the Department of Compliance, Risk Management \nand Ethics for her support in the assessment of declarations of interests. Sheila Nakpil from the \nDepartment of NCDs provided logistical support.\nWHO would like to recognize the voices of persons with lived experiences with hypert", "page": 7, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "ices of persons with lived experiences with hypertension whom we \nheard from through consultation during development of this guideline.\nACKNOWLEDGEMENTS\nv", "page": 7, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "GUIDELINE FOR THE PHARMACOLOGICAL TREATMENT OF HYPERTENSION IN ADULTS\nAcronyms and abbreviations\nACE1\nangiotensin-converting enzyme 1\nACE2\nangiotensin-converting enzyme 2\nACEi\nangiotensin-converting enzyme inhibitor\nARB\nangiotensin-II-receptor blocker\nBB\nbeta-blocker\nBP\nblood pressure\nCAD\ncoronary artery disease\nCCB\ncalcium channel blocker\nCKD\nchronic kidney disease\nCRE\nWHO Office of Compliance, Risk Management and Ethics\nCV\ncardiovascular\nCVD\ncardiovascular disease\nDBP\ndiastolic blood pressure", "page": 8, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "rdiovascular disease\nDBP\ndiastolic blood pressure\nDM\ndiabetes mellitus\nDOI\ndeclaration of interest\nECG\nelectrocardiogram\nEML\nEssential Medicines List\nERG\nExternal Review Group\nESRD\nend-stage renal disease\nGDG\nGuideline Development Group\nGRADE\nGrading of Recommendations Assessment, Development and Evaluation\nHCW\nhealth care worker (nonphysician)\nHIC\nhigh-income country\nHTN\nhypertension\nLIC\nlow-income country\nLMIC\nlow- and middle-income country\nLVH\nleft ventricular hypertrophy\nMACE\nmajor adverse c", "page": 8, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "left ventricular hypertrophy\nMACE\nmajor adverse cardiovascular event\nMI\nmyocardial infarction\nMIC\nmiddle-income country\nNCD\nnoncommunicable disease\nPEN\nWHO package of essential NCD interventions\nPICO \npopulation intervention comparator outcome \nQALY\nquality-adjusted life year\nRAAS\nrenin-angiotensin-aldosterone system\nSBP\nsystolic blood pressure\nACRONYMS AND ABBREVIATIONS\nvi", "page": 8, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "Executive summary\nMore people die each year from cardiovascular diseases than from any other cause. Over three \nquarters of heart disease and stroke-related deaths occur in low-income and middle-income countries. \nHypertension \u2013 or elevated blood pressure \u2013 is a serious medical condition that significantly increases the \nrisk of heart, brain, kidney and other diseases. Hypertension can be defined using specific systolic and \ndiastolic blood pressure levels or reported use of antihypertensive med", "page": 9, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "ure levels or reported use of antihypertensive medications. An estimated 1.4 billion \npeople worldwide have high blood pressure, but just 14% have it under control. However, cost-effective \ntreatment options do exist.\nIn this guideline, the World Health Organization (WHO) provides the most current and relevant \nevidence-based global public health guidance on the initiation of treatment with pharmacological \nagents for hypertension in adults. The recommendations target adult, non-pregnant patient", "page": 9, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "recommendations target adult, non-pregnant patients who were \nappropriately diagnosed with hypertension and counselled about life-style modifications. \nThe guideline provides new recommendations on the threshold for the initiation of pharmacological \ntreatment for hypertension, as well as recommendations on intervals for follow up, target blood \npressure to be achieved for control, and the cadre of health care workers who may initiate treatment. \nThe guideline provides the basis for deciding whe", "page": 9, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "The guideline provides the basis for deciding whether to initiate treatment with monotherapy, dual \ntherapy or single-pill combinations, as well as guidance for countries selecting medicines and algorithms \nfor hypertension control for their national guidelines for hypertension management.\nThe guideline was developed in accordance with the WHO Handbook for Guideline Development. In \nbrief, the WHO Steering Group, in collaboration with the Guideline Development Group, developed \nkey questions an", "page": 9, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "ine Development Group, developed \nkey questions and rated outcomes to identify those critical for the development of the guideline. \nConflicts of interest were handled in line with the current Compliance, Risk Management and Ethics \n(CRE) policy and all members of the GDG were asked to fill in the standard WHO Declaration of Interest \n(DOI) forms, which were reviewed. An overview of systematic reviews of the evidence was used to build \nsummary of findings tables according to the Grading of Recom", "page": 9, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "findings tables according to the Grading of Recommendations, Assessment, Development \nand Evaluations (GRADE) approach. The Guideline Development Group developed recommendations, \nconsidering the certainty of the evidence; the balance between desirable and undesirable effects; \nresource requirements and cost-effectiveness; health equity; acceptability, patient values and \npreferences, and feasibility.\nRecommendations \n1.\t RECOMMENDATION ON BLOOD PRESSURE THRESHOLD FOR INITIATION OF \nPHARMACOLOG", "page": 9, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "PRESSURE THRESHOLD FOR INITIATION OF \nPHARMACOLOGICAL TREATMENT\nWHO recommends initiation of pharmacological antihypertensive treatment of individuals \nwith a confirmed diagnosis of hypertension and systolic blood pressure of \u2265140 mmHg or \ndiastolic blood pressure of \u226590 mmHg.\nStrong recommendation, moderate- to high-certainty evidence\nWHO recommends pharmacological antihypertensive treatment of individuals with existing \ncardiovascular disease and systolic blood pressure of 130\u2013139 mmHg.\nStron", "page": 9, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "and systolic blood pressure of 130\u2013139 mmHg.\nStrong recommendation, moderate- to high-certainty evidence\nEXECUTIVE SUMMARY\nvii", "page": 9, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "GUIDELINE FOR THE PHARMACOLOGICAL TREATMENT OF HYPERTENSION IN ADULTS\nWHO suggests pharmacological antihypertensive treatment of individuals without \ncardiovascular disease but with high cardiovascular risk, diabetes mellitus, or chronic kidney \ndisease, and systolic blood pressure of 130\u2013139 mmHg.\nConditional recommendation, moderate- to high-certainty evidence \n2.\t RECOMMENDATION ON LABORATORY TESTING\nWhen starting pharmacological therapy for hypertension, WHO suggests obtaining tests to \nscre", "page": 10, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "ypertension, WHO suggests obtaining tests to \nscreen for comorbidities and secondary hypertension, but only when testing does not delay \nor impede starting treatment.\nConditional recommendation, low-certainty evidence\n3.\t RECOMMENDATION ON CARDIOVASCULAR DISEASE RISK ASSESSMENT \nWHO suggests cardiovascular disease risk assessment at or after the initiation of \npharmacological treatment for hypertension, but only where this is feasible and does not \ndelay treatment.\nConditional recommendation, lo", "page": 10, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "t \ndelay treatment.\nConditional recommendation, low-certainty evidence\n4.\t RECOMMENDATION ON DRUG CLASSES TO BE USED AS FIRST-LINE AGENTS\nFor adults with hypertension requiring pharmacological treatment, WHO recommends the \nuse of drugs from any of the following three classes of pharmacological antihypertensive \nmedications as an initial treatment: \n1. thiazide and thiazide-like agents\n2. angiotensin-converting enzyme inhibitors (ACEis)/angiotensin-receptor blockers (ARBs)\n3. long-acting dihydro", "page": 10, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "in-receptor blockers (ARBs)\n3. long-acting dihydropyridine calcium channel blockers (CCBs).\nStrong recommendation, high-certainty evidence\n5.\t RECOMMENDATION ON COMBINATION THERAPY\nFor adults with hypertension requiring pharmacological treatment, WHO suggests \ncombination therapy, preferably with a single-pill combination (to improve adherence and \npersistence), as an initial treatment. Antihypertensive medications used in combination \ntherapy should be chosen from the following three drug class", "page": 10, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "ould be chosen from the following three drug classes: diuretics (thiazide or \nthiazide-like), angiotensin-converting enzyme inhibitors (ACEis)/angiotensin-receptor \nblockers (ARBs), and long-acting dihydropyridine calcium channel blockers (CCBs).\nConditional recommendation, moderate-certainty evidence\n6.\t RECOMMENDATIONS ON TARGET BLOOD PRESSURE\nWHO recommends a target blood pressure treatment goal of <140/90 mmHg in all patients \nwith hypertension without comorbidities.\nStrong recommendation, m", "page": 10, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "on without comorbidities.\nStrong recommendation, moderate-certainty evidence\nviii", "page": 10, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "WHO recommends a target systolic blood pressure treatment goal of <130 mmHg in patients \nwith hypertension and known cardiovascular disease (CVD).\nStrong recommendation, moderate-certainty evidence\nWHO suggests a target systolic blood pressure treatment goal of <130 mmHg in high-risk \npatients with hypertension (those with high CVD risk, diabetes mellitus, chronic kidney \ndisease).\nConditional recommendation, moderate-certainty evidence\n7.\t RECOMMENDATIONS ON FREQUENCY OF ASSESSMENT\nWHO suggests", "page": 11, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "MENDATIONS ON FREQUENCY OF ASSESSMENT\nWHO suggests a monthly follow up after initiation or a change in antihypertensive \nmedications until patients reach target.\nConditional recommendation, low-certainty evidence\nWHO suggests a follow up every 3\u20136 months for patients whose blood pressure is under \ncontrol.\nConditional recommendation, low-certainty evidence\n8.\t RECOMMENDATION ON TREATMENT BY NONPHYSICIAN PROFESSIONALS\nWHO suggests that pharmacological treatment of hypertension can be provided by", "page": 11, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "ical treatment of hypertension can be provided by \nnonphysician professionals such as pharmacists and nurses, as long as the following \nconditions are met: proper training, prescribing authority, specific management protocols \nand physician oversight.\nConditional recommendation, low-certainty evidence\nix", "page": 11, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "1\t Introduction\nMore people die each year from cardiovascular diseases than from any other cause. Over three quarters \nof heart disease and stroke-related deaths occur in low-income and middle-income countries (1). Blood \npressure is the force exerted by circulating blood against the walls of the body\u2019s arteries, the major blood \nvessels in the body. Blood pressure is written as two numbers. The first number (systolic) represents the \npressure in blood vessels when the heart contracts or beats.", "page": 13, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "blood vessels when the heart contracts or beats. The second number (diastolic) represents \nthe pressure in the vessels when the heart rests between beats. Hypertension \u2013 or elevated blood \npressure \u2013 is a serious medical condition that significantly increases the risk of diseases of the heart, \nbrain, kidneys and other organs (2). Hypertension can be defined using specific systolic and diastolic \nblood pressure levels or reported use of antihypertensive medications. An estimated 1.4 billion peo", "page": 13, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "rtensive medications. An estimated 1.4 billion people \nworldwide have high blood pressure, but just 14% have it under control (2). However, cost-effective \ntreatment options do exist.\nA World Health Organization (WHO) guideline dealing specifically with raised blood pressure was last \npublished more than 20 years ago \u2013 in 1999 \u2013 and is now outdated. In 2007, a comprehensive guideline \non cardiovascular risk included some recommendations on hypertension but this also needs revision \nand updating", "page": 13, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "ension but this also needs revision \nand updating in the light of new evidence and practice (3). Guidance is particularly needed on some \ncontroversial issues, such as when to start treatment and whether laboratory testing and cardiovascular \nrisk assessment are needed prior to starting treatment. In the past decade, WHO has included diagnosis \nand management of hypertension in a total cardiovascular risk approach as part of the WHO package \nof essential noncommunicable disease (NCD) Interventio", "page": 13, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "ssential noncommunicable disease (NCD) Interventions (WHO PEN) 2007, 2010 and 2013. However, \nthis approach has not included the most recent advances in pharmacological treatment.\nThe WHO Essential Medicines List (EML) identifies all classes of antihypertensive drugs \u2013 angiotensin-\nconverting enzyme inhibitors (ACEi), calcium channel blockers (CCB), angiotensin receptor blockers \n(ARB) and thiazide diuretics \u2013 as essential. In June 2019, the EML included single-pill combination \nmedications for", "page": 13, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "included single-pill combination \nmedications for hypertension. This further supports the evaluation of all classes of antihypertensive \ndrugs as well as single-pill combinations in this current guideline.\nScope and objectives of the hypertension guideline\nThe 2021 WHO hypertension guideline aims to provide the most current and relevant evidence-\nbased global public health guidance on the initiation of treatment (with pharmacological agents) for \nhypertension in adults. The recommendations targe", "page": 13, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "hypertension in adults. The recommendations target the general adult, non-pregnant, hypertensive \npopulation. \nAlthough several countries and professional societies have guidelines on the topic of hypertension, \nthese are specific to the population of that particular country or the specific setting or constituency of \nthe professional society. Recent shifts in hypertension management, such as moving away from using \nbeta-blockers as a first-line agent or the increased research and adoption of c", "page": 13, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "agent or the increased research and adoption of combination therapies \nand single-pill combinations, are all additional reasons for new guidance. The Guideline for the \npharmacological treatment of hypertension in adults will be the first global guideline in the past two \ndecades on the topic and will have specific relevance to low- and middle-income countries (LMICs). \nThe guideline provides new recommendations on the threshold for the initiation of pharmacological \ntreatment for hypertension,", "page": 13, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "on of pharmacological \ntreatment for hypertension, recommendations on intervals for follow up, target blood pressure to be \nachieved for control, and the cadre of health care workers who may initiate treatment. It provides \nthe basis for deciding whether to initiate treatment with monotherapy, dual therapy, or single-pill \ncombination, as well as guidance for countries on selecting medicines for hypertension control in their \nnational guidelines for hypertension management.\nINTRODUCTION\n1", "page": 13, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "for hypertension management.\nINTRODUCTION\n1", "page": 13, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "GUIDELINE FOR THE PHARMACOLOGICAL TREATMENT OF HYPERTENSION IN ADULTS\nThis guideline will replace the guidance in the modules Evidence-based protocols and Risk-based CVD \nmanagement of the HEARTS technical package, as well as the guidance in the WHO PEN package \nregarding the threshold for initiation of treatment, and for the preferred pharmacological treatment for \nhypertension. \nThe guideline does not address measurement of blood pressure or diagnosis of hypertension. It \naddresses pharmacothe", "page": 14, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "agnosis of hypertension. It \naddresses pharmacotherapy in individuals with a \u201cconfirmed\u201d diagnosis of hypertension, such as \nhypertension diagnosed when blood pressure is found to be elevated on two different days.\nAlthough this guideline does not address modifiable risk factors for hypertension such as unhealthy \ndiet, physical inactivity, consumption of tobacco and alcohol, and being overweight or obese, a \ncomprehensive treatment plan for hypertension must include addressing these risk factor", "page": 14, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "rtension must include addressing these risk factors through life-\nstyle modifications and other interventions (2). \nNonpharmacological approaches to treatment or prevention of hypertension include:\n[\n[ reducing salt intake (to less than 5g daily)\n[\n[ eating more fruit and vegetables\n[\n[ being physically active on a regular basis\n[\n[ avoiding use of tobacco\n[\n[ reducing alcohol consumption\n[\n[ limiting the intake of foods high in saturated fats\n[\n[ eliminating/reducing trans fats in diet (2). \nTh", "page": 14, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "[ eliminating/reducing trans fats in diet (2). \nThe guideline does not address hypertensive crisis as it is focused on chronic blood pressure \nmanagement in regular care settings. \nThe objectives of the hypertension guideline are to:\n[\n[ provide a blood pressure threshold for the initiation of treatment for hypertension;\n[\n[ determine if laboratory tests or cardiovascular risk assessment are required prior to initiation of \ntreatment for hypertension;\n[\n[ determine the pharmacological agents wit", "page": 14, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "sion;\n[\n[ determine the pharmacological agents with which to initiate treatment; \n[\n[ determine the need to initiate treatment with monotherapy, dual therapy, or single-pill \ncombinations; \n[\n[ provide targets for blood pressure control in hypertension;\n[\n[ provide intervals for follow up for patients with hypertension; and\n[\n[ determine how nonphysician health care workers can participate in the management of \nhypertension.\nTarget audience\nPrimary audience\nClinicians/health care providers at al", "page": 14, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "ry audience\nClinicians/health care providers at all levels of health care.\nSecondary audience \nNational NCD/CVD programme managers, health care academics, policy-makers setting practice \nrecommendations, students, and hypertension medicine manufacturers. \n2", "page": 14, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "2\t Method for developing the \nguideline \n2.1\t Guideline contributors \nIn order to develop the hypertension guideline, WHO established three groups: \n1.\t An internal WHO Steering Group to coordinate the guideline development process. \n2.\t A Guideline Development Group (GDG), composed of hypertension (HTN) physicians, \nnephrologists, cardiologists, pharmacists, nurses, researchers, academics, policy-makers and \nrepresentatives of patient groups, to review the evidence and develop recommendations.", "page": 15, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "review the evidence and develop recommendations. WHO \nselected the members of the GDG based on relevant expertise but it also considered appropriate \nrepresentation by region and sex. \n3.\t An External Review Group (ERG), composed of technical experts, representatives of HTN patient \ngroups and ministries of health from low-resource countries, to provide peer review of the \nguideline and ensure recommendations are aligned with current global needs. \nAnnex 1 lists the contributors in each group.", "page": 15, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "s. \nAnnex 1 lists the contributors in each group. Annex 2 describes the process for declaring and managing \nconflicts of interest. \n2.2\t Analytical framework and PICOs\nAn initial GDG meeting was held in Geneva in July 2019 to determine the scope and PICO (population, \nintervention, comparison, outcome) questions of the guideline. The GDG first developed an analytical \nframework (Fig. 1) that demonstrates the impact of interventions on intermediate and final outcomes \nand displays the order of th", "page": 15, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "e and final outcomes \nand displays the order of the key questions to better visualize and place them along the patient-flow \npathway. Following this, and a preliminary scoping review and discussion between the steering group \nand methodologist, PICO questions were developed. These were considered, deliberated on, further \nrefined and voted on during the meeting.\nFig. 1\t Analytic framework for antihypertensive medication treatment\nQ1: At what BP level should pharmacological \ntherapy be initiated?", "page": 15, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "evel should pharmacological \ntherapy be initiated?\nQ2: Are lab tests needed to start therapy?\nQ3: Is risk assessment needed to start therapy\nQ4: Monotherapy vs no therapy?\nQ5: Monotherapy vs other monotherapy?\nQ6: Monotherapy vs combination therapy?\nQ7: What choice of combination therapy?\nQ8: Single-pill combination vs free combination?\nQ9: Post-treatment target BP level?\nQ10: When should BP be re-assessed after \ntreatment initiation?\nQ11: Management by physician vs non-physician \nprovider?\nAdul", "page": 15, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "ment by physician vs non-physician \nprovider?\nAdults with \nadequately \ndiagnosed HTN \nwho have initiated \nlife-style \nmodification\nIntermediate \noutcomes\n[BP reduction\n[HTN control %\nFinal health \noutcomes\n[all-cause mortality\n[CV mortality\n[MI\n[CAD\n[stroke\n[ESRD\n[heart failure\nPharmacological \ntherapy\nSerious adverse effects\nMETHOD FOR DEVELOPING THE GUIDELINE\n3", "page": 15, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "GUIDELINE FOR THE PHARMACOLOGICAL TREATMENT OF HYPERTENSION IN ADULTS\n2.3\t Outcome importance rating \nMembers of the WHO Steering Group, in consultation with the GDG and methodologist, developed a \nlist of treatment outcomes most relevant to the care of individuals with HTN. The GDG then rated each \noutcome on a scale from 1 to 9 and indicated whether it considered each outcome critical (rated 7\u20139), \nimportant (rated 4\u20136) or not important (rated 1\u20133) for decision-making. The mean scores are prov", "page": 16, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "1\u20133) for decision-making. The mean scores are provided in \nAnnex 3. \n2.4\t Reviews of evidence \nThe WHO Steering Group, with the participation of the GDG, determined the scope of the guideline \nand identified eleven questions in the format of population, intervention, comparison, and outcomes \n(PICO) to guide the search for systematic reviews (Annex 4). Eleven overviews of reviews informed the \nguideline development process. A systematic search was carried out in PubMed, Embase, The Cochrane \nLib", "page": 16, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "s carried out in PubMed, Embase, The Cochrane \nLibrary, and Epistemonikos to identify existing systematic reviews that answered the PICO questions \npublished in 2015 or after. Suitable systematic reviews were then evaluated based on the following \ncriteria: \n[\n[ their methodology as appraised by the AMSTAR (Assessing the Methodological Quality of \nSystematic Reviews) tool;\n[\n[ how directly they matched the PICO questions;\n[\n[ whether they reported sufficient information to allow for an assessmen", "page": 16, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "d sufficient information to allow for an assessment of the certainty of the \nevidence (e.g. tables with characteristics of included studies, risk of bias assessments at the study \nlevel, results of meta analyses in forest plots);\n[\n[ whether they reported evidence in subgroups of interest (e.g. patients with diabetes mellitus \n(DM), cardiovascular disease (CVD), chronic kidney disease (CKD) etc); and \n[\n[ the date of the most recent review to ensure the most updated evidence was used. \nThe Syste", "page": 16, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "ure the most updated evidence was used. \nThe Systematic Review Team prioritized the most useful reviews for each question, comparison, \noutcome and subpopulation within questions, and included as many reviews as necessary to address \neach question comprehensively. (Web Annex A provides details of the search terms and strategy used.) \nNo reviews were updated.\nTwo questions (PICO 2 and 10, see Annex 4) were not addressed in an existing systematic review, and \nevidence from primary studies was ther", "page": 16, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "eview, and \nevidence from primary studies was therefore used. In this case, the Systematic Review Team reviewed \nthe list of studies used in existing guidelines, queried the GDG and content experts, and searched for \nprimary studies. \nA total of 159 systematic reviews and 17 additional primary studies were included. Most of these were \ntraditional systematic reviews in which the authors conducted pairwise meta-analysis, whereas nine \nanalysed individual patient data. The Systematic Review Team a", "page": 16, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "ividual patient data. The Systematic Review Team also identified several published network \nmeta-analyses. (See Web Annex A for full details.) \nMost of the included reviews were found to be of high certainty when assessed using the AMSTAR \ntool. Details of the selection process, and the reviews and studies included for each PICO question, are \npresented in Web Annex A.\nAnother overview of reviews was conducted to identify systematic reviews to inform other decision \ncriteria in the evidence-to-d", "page": 16, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "form other decision \ncriteria in the evidence-to-decision framework, including people\u2019s values, resources, acceptability, \nfeasibility and equity, presented in Web Annex A. This review was enriched by primary studies identified \nby GDG members. This review focused on evidence informing HTN management in low- and middle-\nincome settings.\n4", "page": 16, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "2.5\t Certainty of evidence and strength of recommendations \nThe GDG rated the certainty of evidence and developed the recommendations using the GRADE \n(Grading of Recommendations Assessment, Development and Evaluation) approach (4). When making \nrecommendations, GRADE defines the certainty of a body of evidence as \u201cthe extent of our confidence \nthat the estimates of an effect are adequate to support a particular decision or recommendation\u201d (5). \nMembers of the GDG, with the help of the methodolo", "page": 17, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "Members of the GDG, with the help of the methodologist, developed evidence profiles to summarize \nrelative and absolute estimates of effects, and an assessment of the certainty of the evidence. One \nevidence profile for each comparison within a PICO question was constructed, using the online \nGuideline Development Tool GRADEpro (https://gradepro.org). When there were systematic reviews \naddressing the relative effects in specific subpopulations, separate evidence profiles were constructed \nfor e", "page": 17, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "separate evidence profiles were constructed \nfor each subpopulation.\nAccording to the GRADE approach, the certainty of the evidence can be high, moderate, low, or very \nlow. Bodies of evidence from randomized controlled trials \u2013 which comprised almost the totality of those \nincluded in this guideline \u2013 start the assessment as high-certainty evidence but can be down-rated due \nto considerations of risk of bias, inconsistency, imprecision, indirectness, and publication bias. \nTable 1 presents an e", "page": 17, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "ness, and publication bias. \nTable 1 presents an explanation of the different levels of certainty of the evidence (5). \nTable 1 Certainty of evidence and its implications\nCertainty level\nDefinition\nHigh\nWe are very confident that the true effect lies close to that of the estimate \nof effect.\nModerate\nWe are moderately confident in the effect estimate. (The true effect is likely to \nbe close to the estimate of effect, but there is a possibility that it is substantially \ndifferent.)\nLow\nOur confid", "page": 17, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "at it is substantially \ndifferent.)\nLow\nOur confidence in the effect estimate is limited. (The true effect may be \nsubstantially different from the estimate of the effect.)\nVery low\nWe have very little confidence in the effect estimate. (The true effect is likely to be \nsubstantially different from the estimate of effect.)\nThe strength of the recommendations reflects the degree of confidence of the GDG that the desirable \neffects (e.g. beneficial health outcomes) of the recommendations outweigh", "page": 17, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "health outcomes) of the recommendations outweigh the undesirable effects \n(e.g. adverse effects). The strength of recommendations in this guideline was graded into two \ncategories: \nA strong recommendation is one for which the GDG was confident that the desirable effects of \nadhering to the recommendation outweigh the undesirable effects. \nA weak or conditional recommendation is one for which the GDG concluded that the desirable \neffects of adhering to the recommendation probably outweigh the u", "page": 17, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "ring to the recommendation probably outweigh the undesirable effects, but was not \nconfident about these trade-offs.\nMETHOD FOR DEVELOPING THE GUIDELINE\n5", "page": 17, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "GUIDELINE FOR THE PHARMACOLOGICAL TREATMENT OF HYPERTENSION IN ADULTS\n2.6\t Deciding upon recommendations\nThe GDG met virtually for four sessions in February 2021. Systematic reviews and GRADE tables were \npresented at the meeting. Formulation of recommendations and their strength were facilitated by the \nchair and supported by the methodologist, with the aim of achieving unanimous consensus. While the \nplan was to use a simple majority vote, full consensus was reached on all recommendations. \nTh", "page": 18, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "consensus was reached on all recommendations. \nThe GDG used evidence-to-decision tables to guide the process of developing recommendations. These \ntables addressed the certainty of evidence, the balance between desirable and undesirable effects, \nvalues, resource use and cost-effectiveness, equity, acceptability and feasibility. These tables are available \nin Web Annex B, and the full evidence profiles in Web Annex A. The WHO Steering Group noted \nremarks made by members of the External Review", "page": 18, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "d \nremarks made by members of the External Review Group and considered incorporating these into the \nfinal guideline. Some evidence-to-decision frameworks were consolidated to provide recommendations \nthat are more practical and implementable from an end-user perspective; hence, the 11 questions led to \neight recommendations.\n2.7\t Funding \nThe development of this guideline was financially supported by the US Centers for Disease Control and \nPrevention and the World Health Organization.\n6", "page": 18, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "ntion and the World Health Organization.\n6", "page": 18, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "3\t Recommendations\n3.1\t Blood pressure threshold for initiation of pharmacological treatment\n1.\t RECOMMENDATION ON BLOOD PRESSURE THRESHOLD FOR INITIATION OF \nPHARMACOLOGICAL TREATMENT\nWHO recommends initiation of pharmacological antihypertensive treatment of individuals \nwith a confirmed diagnosis of hypertension and systolic blood pressure of \u2265140 mmHg or \ndiastolic blood pressure of \u226590 mmHg.\nStrong recommendation, moderate- to high-certainty evidence\nWHO recommends pharmacological antihypert", "page": 19, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "evidence\nWHO recommends pharmacological antihypertensive treatment of individuals with existing \ncardiovascular disease and systolic blood pressure of 130\u2013139 mmHg.\nStrong recommendation, moderate- to high-certainty evidence\nWHO suggests pharmacological antihypertensive treatment of individuals without \ncardiovascular disease but with high cardiovascular risk, diabetes mellitus, or chronic kidney \ndisease, and systolic blood pressure of 130\u2013139 mmHg.\nConditional recommendation, moderate- to high", "page": 19, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "mHg.\nConditional recommendation, moderate- to high-certainty evidence\nImplementation remarks:\n[\n[\nInitiation of pharmacological hypertension (HTN) treatment should start no later than four \nweeks following diagnosis of HTN. If blood pressure level is high (e.g. systolic \u2265160 mmHg or \ndiastolic \u2265100 mmHg) or there is accompanying evidence of end organ damage, initiation of \ntreatment should be started without delay.\nEvidence and rationale\nThe GDG reviewed evidence from 14 relevant systematic revi", "page": 19, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "reviewed evidence from 14 relevant systematic reviews that summarized data from a large \nnumber of randomized trials involving over 120\u00a0000 adult participants (Web Annex A). Evidence \nsummaries are presented for the general population and for higher-risk populations (with diabetes (DM), \ncoronary artery disease (CAD), prior stroke) and were presented for various systolic blood pressure (SBP) \nthresholds (Web Annex A).\nThe anticipated benefits of a lower blood pressure (BP) target (140 SBP in the", "page": 19, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "a lower blood pressure (BP) target (140 SBP in the general population \nand 130 SBP in a high-risk population) were reduction in mortality, cardiovascular mortality, stroke, \nmyocardial infarction (MI) and heart failure events. The anticipated harms were mostly not serious \nside-effects, and some were a surrogate outcome, such as rise in creatinine that may not be clinically \nrelevant. On average, treatment was associated with a reduction in deaths and cardiovascular events \nthat ranged from 5 to", "page": 19, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "s and cardiovascular events \nthat ranged from 5 to 10/1000 and harms that ranged from 20 to 30/1000. The benefits were a \nreduction in severe events with significant morbidity and mortality whereas the harms were mostly not \nclinically significant. \nIn summary, the anticipated benefits were large and clearly outweighed the harms. The overall certainty \nvaried from moderate to high, depending on the BP level and agent used.\nRECOMMENDATIONS\n7", "page": 19, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "GUIDELINE FOR THE PHARMACOLOGICAL TREATMENT OF HYPERTENSION IN ADULTS\nEvidence-to-decision considerations\nThe value of antihypertensive therapy is well accepted by most patients, health care providers, health \nsystems, professional societies and government agencies. From a patient\u2019s perspective, preventing \ncardiovascular events is highly valued. However, some individuals who are eligible for antihypertensive \ntreatment may not present to care, may be lost to follow up, or are prescribed a treat", "page": 20, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "ay be lost to follow up, or are prescribed a treatment but fail to \ntake/adhere to the treatment. Treatment may be perceived as low value from the perspective of an \nasymptomatic patient unless the person is convinced of a trade-off between immediate inconvenience/\nside-effects and potential long-term health gains (6). The patient perception of an unfavourable cost-\nbenefit may be further exacerbated by the requirement for out-of-pocket payment for appointments or \nmedications. Therefore, the GD", "page": 20, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "or appointments or \nmedications. Therefore, the GDG considered that although there is important variability in stakeholder \nvalues, overall initiation of hypertension (HTN) medications is likely to be feasible and acceptable overall. \nGiven that the barriers to accessing HTN care in low-income settings include low patient health literacy, \nlack of financial protections, and limited resources (7), the GDG felt that health inequalities would \nprobably be reduced by HTN treatment. \nIn terms of cost", "page": 20, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "bly be reduced by HTN treatment. \nIn terms of costs and resource requirements, the GDG acknowledged variability, based on the structure \nof a country\u2019s public health system and its economic status. Other costs, including human resources \nand medications, were considered moderate, given the benefits. Multiple sources of cost effectiveness \nare available from various countries, such as Argentina, Nigeria, the USA and UK (8, 9, 10, 11, 12, 13), \nand for lower thresholds and higher-risk individuals", "page": 20, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "for lower thresholds and higher-risk individuals (14, 15, 16). Most cost-effectiveness estimates were \nclustered below USD 1000 per averted disability-adjusted life year (DALY) \u2013 well below the average 2017 \nGDP per capita for lower-middle income countries of USD 2188 (17), suggesting that pharmacological \ntreatment could be very cost-effective for this group of countries. HTN treatment (treating all with BP \n\u2265140/90 mmHg) has been shown to be cost-effective and a \u201cbest buy\u201d intervention by the", "page": 20, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "ost-effective and a \u201cbest buy\u201d intervention by the Kostova \nstudy (8). Treating high-risk/CVD patients with baseline 130\u2013139 mmHg has been shown to be cost \neffective, but not cost saving (SPRINT cost-effective analyses) (15); value depends on maintaining the \nintervention effect for more than five years.\n3.2\t Laboratory testing before and during pharmacological treatment\n2.\t RECOMMENDATION ON LABORATORY TESTING\nWhen starting pharmacological therapy for hypertension, WHO suggests obtaining tests", "page": 20, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "apy for hypertension, WHO suggests obtaining tests to \nscreen for comorbidities and secondary hypertension, but only when testing does not delay \nor impede starting treatment.\nConditional recommendation, low-certainty evidence\nImplementation remarks:\n[\n[\nSuggested tests include serum electrolytes and creatinine, lipid panel, HbA1C or fasting glucose, \nurine dipstick, and electrocardiogram (ECG). \n[\n[\nIn low-resourced areas or non-clinical settings, where testing may not be possible because of \na", "page": 20, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "s, where testing may not be possible because of \nadditional costs, and lack of access to laboratories and ECG, treatment should not be delayed, \nand testing can be done subsequently. \n[\n[\nSome medicines, such as long-acting dihydropyridine calcium-channel blockers (CCBs) are more \nsuitable for initiation without testing, compared to diuretics or angiotensin-converting enzyme \ninhibitors (ACEi)/angiotensin-II receptor blockers (ARBs).\n8", "page": 20, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "Evidence and rationale\nComparative studies that evaluate various testing strategies prior to the initiation of antihypertensive \ntreatment were not identified, despite a search of the literature. Therefore, indirect evidence was \nsought to evaluate this question. An analytic framework was developed to conceptualize the rationale \nfor obtaining diagnostic testing, such as laboratory tests and electrocardiogram (ECG), in this context \n(see Fig. 2). This framework identified the four most important", "page": 21, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "This framework identified the four most important reasons for obtaining testing, which are \nto diagnose secondary HTN, identify comorbidities (e.g. DM), identify end organ damage (e.g. chronic \nkidney disease (CKD) or left ventricular hypertrophy (LVH)), and for cardiac risk stratification. \nFig. 2 \tFramework for analysis\nPeople with \nhigh BP\nLaboratory tests\nECG\nTreatment\nPatient-important \noutcomes\nFollow-up tests\nPICO 2: No comparative studies \nDesirable effects of testing\nIdentification of:", "page": 21, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "s \nDesirable effects of testing\nIdentification of:\n\u2022 secondary HTN\n\u2022 comorbidities (e.g. DM)\n\u2022 end organ damage (e.g.  \nCKD, LVH)\nOpportunity to:\n\u2022 develop cardiac risk \nstratification\n\u2022 choose certain medications \nover others \ndirect evidence\nColor legend:\nindirect evidence\nUndesirable effects of \ntesting\n\u2022 incidental findings\n\u2022 cost\n\u2022 delay in starting treatment\nIn terms of secondary HTN, various studies suggest a prevalence of 5\u201310% among patients with a \ndiagnosis of HTN and a higher prevale", "page": 21, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "ents with a \ndiagnosis of HTN and a higher prevalence of 10\u201330% among patients with particularly high BP (e.g. \nover 175/115 mmHg) or BP that is resistant to treatment (18, 19, 20). Morbidities and end organ \ndamage that could be identified by testing patients with HTN are also common. One estimation \nindicates that 23%, 24% and 39% of patients with a diagnosis of HTN have one, two, three or more \ncomorbidities respectively. Common comorbidities among patients with HTN that can be discovered \nvi", "page": 21, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "among patients with HTN that can be discovered \nvia laboratory testing are hyperlipidaemia and diabetes, which have a prevalence of 56% and 27% \nrespectively (21). Testing at the point of starting HTN medications or for subsequent monitoring can \nalso identify patients who develop certain adverse events after treatment (e.g. hyperkalaemia and \nacute kidney injury), thus providing a rationale for testing. Testing also had the additional advantage of \nidentifying compelling indications for choosin", "page": 21, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "of \nidentifying compelling indications for choosing certain medications over others. For example, identifying \ndiabetes would favour the use of ACEis/ARBs, and identifying hyponatraemia would lead to not starting \ndiuretics. Overall, the desirable effects of testing were judged to be at least moderate.\nThe framework also identified the most undesirable effects of obtaining testing, which were delay \nof starting treatment, cost and incidental findings. Delay of treatment was judged to be the most", "page": 21, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "ings. Delay of treatment was judged to be the most \nimportant concern since it can lead to losing the patient for follow up and the potential for adverse \ncardiovascular (CV) outcomes. Incidental findings on testing were thought to be less important. The \nundesirable effects of testing were judged to have smaller magnitude. On balance, desirable effects are \nlikely to outweigh undesirable effects. The certainty of evidence across outcome was judged to be very \nlow due to serious concerns about t", "page": 21, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "ed to be very \nlow due to serious concerns about the indirectness of evidence.\nRECOMMENDATIONS\n9", "page": 21, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "GUIDELINE FOR THE PHARMACOLOGICAL TREATMENT OF HYPERTENSION IN ADULTS\nEvidence-to-decision considerations\nThere is uncertainty about patients\u2019 values and preferences regarding the issue of testing before starting \ntreatment for HTN. The cost of tests such as electrolytes, creatinine, lipid panel, glucose, HbA1C, \nurine dipstick, and ECG relative to overall costs of treatment and complications of HTN are small (22). \nHowever, in less well-resourced settings, this cost can have a large impact. Fur", "page": 22, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "d settings, this cost can have a large impact. Furthermore, if additional \ntests like ECG or 24-hour ambulatory BP monitoring were added, the cost can become a barrier (23). \nIt is unknown whether testing would lead to cost saving or be cost-effective. Testing was judged to be \nacceptable to most stakeholders, particularly patients and health care providers, and to a lesser extent \nto those governing health systems. Requiring testing before starting HTN medications can exacerbate \nhealth inequit", "page": 22, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "ing HTN medications can exacerbate \nhealth inequities and may not be feasible in low-resource settings.\n3.3\t Cardiovascular disease risk assessment as guide to initiation of \t \t\n\t\n\t\nantihypertensive medications\n3.\t RECOMMENDATION ON CARDIOVASCULAR DISEASE RISK ASSESSMENT\nWHO suggests cardiovascular risk assessment at or after the initiation of pharmacological \ntreatment for hypertension, but only where this is feasible and does not delay treatment.\nConditional recommendation, low-certainty evide", "page": 22, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "t.\nConditional recommendation, low-certainty evidence\nImplementation remarks:\n[\n[\nMost patients with SBP \u2265140 or DBP \u226590 mmHg are high risk and indicated for pharmacological \ntreatment; they do not require cardiovascular (CVD) risk assessment prior to initiating treatment. \nCVD risk assessment is most important for guiding decisions about initiating pharmacological \ntreatment for hypertension (HTN) in those with lower SBP (130\u2013139 mmHg). It is critical in \nthose with HTN that other risk factors", "page": 22, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "itical in \nthose with HTN that other risk factors must be identified and treated appropriately to lower \ntotal cardiovascular risk.\n[\n[\nMany CVD risk-assessment systems are available. In the absence of a calibrated equation for the \nlocal population, the choice should depend on resources available, acceptability and feasibility \nof application. \n[\n[\nWhenever risk assessment may threaten timely initiation of HTN treatment and/or patient follow \nup, it should be postponed and included in the follo", "page": 22, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": ", it should be postponed and included in the follow-up strategy, rather than taken as a first \nstep to indicate treatment.\nEvidence and rationale\nThe most direct evidence is derived from an individual patient data meta-analysis by Karmali that \ncompared the number of major adverse cardiovascular events (MACE) at five years when using a CVD \nrisk assessment strategy (based on age, sex, body mass index, blood pressure, previous antihypertensive \ntreatment, smoking, diabetes mellitus (DM), and hist", "page": 22, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "eatment, smoking, diabetes mellitus (DM), and history of CVD) vs BP levels alone for determining \nwhich patients receive treatment (24). This analysis suggested that risk assessment can potentially \nprevent 310 MACE events in 1000 people over five years, which the GDG considered to be a moderate-\nto-large benefit. However, this evidence was indirect for many reasons, including the effect being \ndependent on the BP at presentation (graphs diverge at higher level of BP\n, compared with starting \nme", "page": 22, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "at higher level of BP\n, compared with starting \nmedications without risk assessment) and the fact that these trials did not actually randomize patients \nto the two strategies sought in PICO question 3 (see Annex 4). Furthermore this evidence should not \nsuggest that people with intermediate risk would not have important treatment benefit. \nThere was no evidence of the undesirable anticipated effects of starting treatment based on \ncardiovascular risk assessment. However, delay in initiating care", "page": 22, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "risk assessment. However, delay in initiating care for HTN management and loss to follow \nup are important considerations, especially in low-resource settings.\n10", "page": 22, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "The GDG deduced that benefits of risk assessment may not all be attributable to risk assessment per \nse, but rather to the various treatments provided for risk factors identified during risk assessment. \nThe certainty of evidence across outcome was judged to be very low due to serious concerns about \nthe indirectness of evidence. Overall, the desirable effects of risk assessment at or after initiating HTN \nmedications outweighed the plausible undesirable effects, particularly when risk assessmen", "page": 23, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "esirable effects, particularly when risk assessment was \ndeemed not to delay the initiation of treatment.\nEvidence-to-decision considerations\nThere is important uncertainty over the value stakeholders place on conducting a CVD risk assessment \nprior to starting pharmacological treatment, and it was noted that patient perspectives may vary, \ndepending on the setting. In low-resource settings, patients may focus more on immediate treatment \nwithout having to bear additional costs for screening for", "page": 23, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "having to bear additional costs for screening for other risk factors and treating them. Studies \nhave also shown that in high-income countries (HICs) such as the United States, people of a lower \nsocioeconomic status have lower control of blood pressure and higher CVD risk over the years (25). \nThus, in low-resource settings, adding one more step before initiating treatment may increase inequities, \nas those patients who have limited access to health care services may suffer delays in treatment", "page": 23, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "ealth care services may suffer delays in treatment or even \nend up not receiving HTN treatment at all. \nIn terms of costs, there is no direct evidence of whether treatment of HTN with or without risk \nstratification is more cost effective. The cost of implementation of CVD risk assessment should also \naccount for capacity building of health care providers and the time taken to do so for each patient. \nCost of testing and delay in initiating care can be significant following a CVD risk stratifica", "page": 23, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "can be significant following a CVD risk stratification strategy \nin low-resource settings. Modelling by Gaziano et al. showed significant cost reduction using CVD risk-\nstratification before initiation of treatment in low-resource settings. However, screening costs, including \nthe cost of obtaining risk-factor information, productivity costs due to work loss, care costs and travel \ntime were not included in the analysis (26). \nA meta-analysis showed that proportional relative risk reduction in m", "page": 23, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "wed that proportional relative risk reduction in major CVD events from BP lowering \ndid not differ substantially with the presence or absence of previous CVD events, coronary heart disease, \nor cerebrovascular disease. Hence, the absolute benefit of blood pressure lowering would be greatest in \nthose with the highest absolute risk of CVD (27). \n3.4\t Drug classes to be used as first-line agents\nTo develop a recommendation that is practical and implementable by end-users, the evidence-to-decision", "page": 23, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "lementable by end-users, the evidence-to-decision \nframeworks of PICO questions 4 and 5 (see Annex 4) were used to develop one recommendation. \n4.\t RECOMMENDATION ON DRUG CLASSES TO BE USED AS FIRST-LINE AGENTS\nFor adults with hypertension requiring pharmacological treatment, WHO recommends the \nuse of drugs from any of the following three classes of pharmacological antihypertensive \nmedications as an initial treatment: \n1. thiazide and thiazide-like agents\n2. angiotensin-converting enzyme inhib", "page": 23, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "like agents\n2. angiotensin-converting enzyme inhibitors (ACEis)/angiotensin-receptor blockers (ARBs)\n3. long-acting dihydropyridine calcium channel blockers (CCBs).\nStrong recommendation, high-certainty evidence\nImplementation remarks:\n[\n[\nLong-acting antihypertensives are preferred.\n[\n[\nExamples of indications to consider specific agents include diuretics or CCBs in patients over \n65 years or those of African descent, beta-blockers in ischaemic heart disease, ACEis/ARBs in \npatients with severe", "page": 23, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "heart disease, ACEis/ARBs in \npatients with severe proteinuria, diabetes mellitus, heart failure or kidney disease.\nRECOMMENDATIONS\n11", "page": 23, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "GUIDELINE FOR THE PHARMACOLOGICAL TREATMENT OF HYPERTENSION IN ADULTS\nEvidence and rationale\nData from 32 systematic reviews were used to derive evidence on benefits and harms of various \nmedication classes (19 for comparisons against placebo and 13 for head-to-head comparisons). These \nreviews summarized the results of a many large randomized trials (Web Annex A). The anticipated \nbenefits were considered to be large. Mortality and major adverse cardiac events (MACE) reduction per \n1000 treated", "page": 24, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "cardiac events (MACE) reduction per \n1000 treated people for the various classes were 3 and 14 (low-dose thiazide), 12 and 39 (high-dose \nthiazide), 23 and 48 (ACEi), 8 and 23 (CCB), 2 and 8 (beta-blockers) and 14 and no data for MACE \n(ARBs) respectively. The anticipated adverse events were judged to be moderate. Compared to placebo, \n60 and 100 additional adverse events per 1000 treated people were observed for thiazides and beta-\nblockers respectively. Withdrawal from ACEi treatment and coug", "page": 24, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "pectively. Withdrawal from ACEi treatment and cough per 1000 treated people were 12 \nand 26 respectively. A systematic review of studies of pharmacotherapy for HTN in sub-Saharan Africa \nshowed a rate of side-effects of CCB of 6% (headache), 2% (dizziness) 2% (ankle oedema) (28). \nIn terms of the head-to-head comparisons among various classes, there was a smaller body of evidence, \nwith less data available on hard endpoints and patient-important outcomes. Comparisons showed \noverall minimal diff", "page": 24, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "outcomes. Comparisons showed \noverall minimal differences in SBP or DBP\n. For example, ACEis/ARBs vs CCBs differed by less than \n2 mmHg, and so did comparisons between ACEis/ARBs vs thiazide or ACEis vs ARB. There were more \nstroke events with beta-blockers than CCBs or ACEis/ARBs. \nThe anticipated benefits clearly outweighed the potential harms for three classes of medications: \nthiazide and thiazide-like agents, ACEis/ARBs, and long-acting dihydropyridine CCBs. The adverse \nevents of these thr", "page": 24, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "dropyridine CCBs. The adverse \nevents of these three classes were infrequent, usually mild, and can be managed or another agent can \nbe substituted. The amount of BP reduction appeared to be a more major determinant of reduction in \nCV events than the choice between these three classes of antihypertensive medications, as was shown \nin several landmark trials (ALLHAT, VALUE, CAMELOT trials) (29, 30, 31). This balance of benefits and \nharms was not as clear for beta-blockers as a first choice for", "page": 24, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "as clear for beta-blockers as a first choice for HTN management.\nIn terms of potential subgroups of patients that may benefit more from specific medication classes, \nALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) suggested greater \nBP reduction in individuals of African descent with chlorthalidone than lisinopril, and that stroke was \nsignificantly less likely with the diuretic than with the lisinopril in this group of patients than in those of \nCaucasian e", "page": 24, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "is group of patients than in those of \nCaucasian ethnicity (32). Other studies suggested benefit of diuretics or CCBs in patients over 65 years of \nage or of African descent, beta-blockers in patients with HTN who are post-myocardial infarction, ACEis/\nARBs in diabetes mellitus, heart failure or kidney disease (33, 34). Diuretics were likely to be the most \nefficacious medications, and CCBs the least efficacious medications for the prevention of heart failure.\nThe overall certainty of evidence v", "page": 24, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "heart failure.\nThe overall certainty of evidence varied from high to moderate for these three classes of medications \nwhen compared against placebo. It was noted that diuretic trials were older and practice patterns may \nhave changed over time, and that the severity and stage spectrum of diabetes mellitus and chronic kidney \ndisease varied in the available trials. In addition, evidence supporting the efficacy of antihypertensive \ndrug therapy is derived from trials conducted in adults at high ri", "page": 24, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "derived from trials conducted in adults at high risk for CVD/atherosclerotic CVD. Since \nCVD risk increases with higher levels of BP\n, and given that risk factors for CVD tend to track together, the \nassumption of greater benefits using CVD risk could be attributed to this.\n12", "page": 24, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "Evidence-to-decision considerations\nThe value of antihypertensive therapy is well accepted by most patients, health care providers, health \nsystems, professional societies and government agencies. From a patient\u2019s perspective, preventing \ncardiovascular events is highly valued. However, some individuals who are eligible for antihypertensive \ntreatment may evade efforts aimed at treatment or are prescribed a treatment but fail to take/adhere \nto the treatment. The asymptomatic nature of the disea", "page": 25, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "he treatment. The asymptomatic nature of the disease and concern about adverse events are the \nlikely driver for this perspective. Interviews of patients in England suggested greater acceptance of \nantihypertensive drug therapy with higher socioeconomic status. \nIn one study, as many as 35% of the Caucasians and 20% of the South Asians in the two lowest \nsocioeconomic categories told their interviewer that they would not accept antihypertensive drug \ntherapy (35). Shahaj et al. (6) synthesized s", "page": 25, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "rug \ntherapy (35). Shahaj et al. (6) synthesized six qualitative and 29 quantitative reviews and identified a \nrange of individual and social factors that affect treatment adherence, including familial (lack of support, \nneed for separate meals), and environmental (sense of security, local amenities, healthy food availability). \nA review by Fragasso et al. (36) suggested that quality of life on antihypertensive therapy is an important \nissue because clinicians are asked to initiate drug therapy", "page": 25, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "use clinicians are asked to initiate drug therapy in mostly asymptomatic patients who are \nnever happy to become, instead, symptomatic because of side-effects. Therefore, the GDG considered \nthat there is important variability in stakeholder values, but overall initiation of HTN medications is likely \nto be feasible and acceptable overall. Considering the ample literature on disparities in adherence to BP \nmedication regimes and cardiovascular outcomes based on race or socioeconomic status, trea", "page": 25, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "tcomes based on race or socioeconomic status, treatment was \njudged to reduce health inequities. \nIn terms of costs and resource requirements, thiazide-like agents, ACEis/ARBs and long-acting \ndihydropyridine CCBs are available as generic drugs, are simple to manufacture, and should be \navailable at low cost globally. Other costs related to workforce requirements, provision of infrastructure, \nlaboratory testing, lost work time etc. are real but modest. Numerous modelling studies demonstrate \nco", "page": 25, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "modest. Numerous modelling studies demonstrate \ncost effectiveness of antihypertensive therapy, which is especially beneficial in LMICs where large \nnumbers of adults have untreated HTN, as long as medications are available at low cost. Models were \navailable from many countries, including Bangladesh, Ghana and Nigeria (37, 38, 39, 40). \n3.5\t Combination therapy\nTo develop a recommendation that is practical and implementable by end-users, the evidence-\nto-decision frameworks of PICO questions 6,", "page": 25, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "dence-\nto-decision frameworks of PICO questions 6, 7 and 8 (see Annex 4) were used to develop one \nrecommendation. \n5.\t RECOMMENDATION ON COMBINATION THERAPY\nFor adults with hypertension requiring pharmacological treatment, WHO suggests \ncombination therapy, preferably with a single-pill combination (to improve adherence and \npersistence), as an initial treatment. Antihypertensive medications used in combination \ntherapy should be chosen from the following three drug classes: diuretics (thiazide", "page": 25, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "following three drug classes: diuretics (thiazide or \nthiazide-like), angiotensin-converting enzyme inhibitors (ACEis)/angiotensin-receptor \nblockers (ARBs), and long-acting dihydropyridine calcium channel blockers (CCBs).\nConditional recommendation, moderate-certainty evidence\nImplementation remarks:\n[\n[\nCombination medication therapy may be especially valuable when the baseline BP is \n\u226520/10 mmHg higher than the target blood pressure.\n[\n[\nSingle-pill combination therapy improves medication-ta", "page": 25, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "le-pill combination therapy improves medication-taking adherence and persistence and BP \ncontrol.\nRECOMMENDATIONS\n13", "page": 25, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "GUIDELINE FOR THE PHARMACOLOGICAL TREATMENT OF HYPERTENSION IN ADULTS\nEvidence and rationale\nThe GDG developed three PICO questions to address: monotherapy vs combination therapy as a first-\nline treatment for HTN, a comparison of the various combination therapies, and a comparison of single-\npill combinations vs multiple-pill combinations. These three questions were addressed separately in the \nevidence profiles and evidence-to-decision framework, but eventually led to one recommendation. The", "page": 26, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "k, but eventually led to one recommendation. The \nevidence base consisted of six, seven and eight systematic reviews respectively (Web Annex A).\nEvidence summaries demonstrate several comparisons of combination therapy to monotherapy. Data \non mortality, MACE and other hard endpoints were imprecise. Combination therapy lowered SBP more \nthan monotherapy did (e.g. standard dose CCB combined with ARB vs high dose CCB; or ACEi and ARB \ncombination vs either drug class alone) and had fewer adverse e", "page": 26, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "s either drug class alone) and had fewer adverse events (standard dose CCB combined \nwith ARB vs high dose CCB). Data on cardiovascular outcomes are limited from randomized trials. A \nlarge nonrandomized study from Italy (125\u00a0635 patients, age 40\u201385 years) evaluated those who started \nantihypertensive treatment with one drug vs a two-drug single-pill or free combination. Propensity score \nadjusted analysis suggests that an initial two-drug single-pill or free combination was associated with \nsig", "page": 26, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "-pill or free combination was associated with \nsignificant reductions in the risk of death (20%, 11\u201328%) and hospitalization for cardiovascular events \n(16%, 10\u201321%) compared with initial monotherapy (41). Combination antihypertensive therapy may be \nassociated with fewer side-effects due to use of lower doses of each drug.\nA comparison of the various combination therapies suggested overall effectiveness of combination \ntherapies that contained the three drug classes of diuretic, ACEi/ARB and CC", "page": 26, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "he three drug classes of diuretic, ACEi/ARB and CCB. Other desirable \neffects of a combination therapy are improved treatment adherence and persistence. However, many \nof these studies used a single-pill combination, thereby confounding the question of monotherapy \nvs combination therapy. A meta-analysis compared adherence and persistence between groups of \npatients taking antihypertensives as single-pill combinations vs free-equivalent components based \non 12 retrospective database studies. Adh", "page": 26, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "s based \non 12 retrospective database studies. Adherence, measured as the mean difference in medication \npossession ratio, was 8\u201314% higher with a single-pill combination. Persistence was also twice as likely \n(42). A second systematic review demonstrated that simplifying dosing regimens results in significant \nimprovements in medication adherence, ranging from 6% to 20% (43). \nThe desirable effects of greater adherence/persistence, improved BP control, and potentially improved \nclinical outcome", "page": 26, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "ontrol, and potentially improved \nclinical outcomes of combinations of the three classes of antihypertensive therapy compared outweigh \nthe undesirable effects such as side-effects, particularly when provided as a single-pill combination. The \noverall certainty in evidence was low across the outcomes of interest, noting that evidence was limited \nin terms of hard endpoints. \nEvidence-to-decision considerations\nIn terms of stakeholder values and preferences about monotherapy vs combination therap", "page": 26, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "references about monotherapy vs combination therapy or the \nvarious combination therapies, data were minimal. No important variability in values was expected \nwith regard to the critical outcomes. A systematic review demonstrated that simplifying dosing \nregimens results in significant improvements in medication adherence, ranging from 6% to 20% (43). \nConsidering the comparative ease of using a single-pill combination over multiple-pill combinations, and \nthe anticipated impact on adherence and", "page": 26, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "ions, and \nthe anticipated impact on adherence and persistence, the GDG judged that from a patient perspective \nthe single-pill option will be favoured by most.\nCombination therapy is accompanied initially by a moderate increase in resource requirements, such as \nprocurement, supply chain, and direct medication costs. Some combinations may be expensive, or not \nallow for exact dosing of both agents. However, the net benefit of improved BP control and reduction \nof major events associated with th", "page": 26, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "and reduction \nof major events associated with the hypertensive process compared to the increase in cost is large. \nBP control is also likely to be achieved sooner with combination therapy. Many modelling studies that \nevaluated combination vs monotherapy used a fixed dose (thereby not truly addressing the question). \nOne model from Japan used data from randomized trials and compared low-dose combination therapy \nof controlled-release nifedipine (20 mg/day) plus candesartan (8 mg/day) vs titrat", "page": 26, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "(20 mg/day) plus candesartan (8 mg/day) vs titrated monotherapy of \n14", "page": 26, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "candesartan. In the combination therapy group, higher efficacy and lower incremental treatment cost \n(dominance) were observed when compared to the monotherapy group (44). A retrospective cohort \nstudy that used the 2008\u20132012 BlueCross BlueShield of Texas claims suggests that mean annual drug \nutilization costs were highest for a single-pill combination strategy. However, disease-related inpatient \nservices utilization costs were lower compared with the up-titration strategy, which may offset in", "page": 27, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "ith the up-titration strategy, which may offset initial \ncosts (45). In one model from China, olmesartan/amlodipine as a single pill was dominant, compared \nwith olmesartan and amlodipine free combination and valsartan/amlodipine single-pill combination (46). \nIn a second study, there was a reduction in the cost of therapy of 33%, with a saving of USD 19 per \npatient/month after switching from free combination to the single-pill combination (47). \nSince single-pill combination therapy increases", "page": 27, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "Since single-pill combination therapy increases medication adherence and persistence, which could \nimprove HTN control rates and decrease major clinical events, the impact on health equities is expected \nto be favourable. In terms of acceptability, combination therapy, including in a single-pill form, can \ninitially be met with scepticism among stakeholders, including health care providers. However, this initial \nscepticism may improve once BP control improves. Despite effective, safe, afforda", "page": 27, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "control improves. Despite effective, safe, affordable, and available \npharmacological antihypertensive agents, the control rates of HTN are dismal worldwide, and over \nthe last 5 to 10 years have been decreasing in some HICs, and in LMICS, in tandem with increasing \nmajor cardiovascular events. Over 30% of the world population has HTN and only 13.8% of cases are \nconsidered controlled (48). One major reason for this poor level of control (one in seven) is that most \npatients only receive monothe", "page": 27, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "seven) is that most \npatients only receive monotherapy, whereas empirical evidence demonstrates that most patients require \ntwo drugs or more to achieve optimal and sustained control (44, 46, 49, 50, 51, 52). The rationale for \nrecommending a combination therapy, particularly in a single-pill approach, is based on the following \nconsiderations: \n[\n[ most individuals with HTN will eventually require two or more antihypertensive agents to achieve \nBP control; \n[\n[ the combination of two agents fro", "page": 27, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "BP control; \n[\n[ the combination of two agents from complementary classes yields greater BP-reduction efficacy \n(at least equal to the sum of the efficacy of each chosen agent); \n[\n[ lower doses of each agent are needed, which results in a reduction of side-effects and the fact \nthat use of complementary classes of antihypertensive agents may mitigate the side-effects of \neach agent; \n[\n[ adherence and persistence are increased; and \n[\n[ simplified logistics can lead to fewer stock-outs and a re", "page": 27, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "ed logistics can lead to fewer stock-outs and a reduced pharmacy inventory (53, 54). \nIn terms of feasibility, a study from India compared prices of antihypertensive single-pill combinations \nand equivalent single-agent pills in the private health care sector. The results suggested that \nmanufacturers have priced the combination higher than the price of its components. These data \ndemonstrate that the price of combination pills could be lowered to match the combined price of \nthe component, and", "page": 27, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "o match the combined price of \nthe component, and that manufacturing costs and market forces do not present a barrier to the \nimplementation of antihypertensive combination pills (55). Thus, the intervention is likely feasible \nto implement. The GDG acknowledged some challenges to single-pill combinations, such as limited \nflexibility in modifying the doses of individual components, and difficulty in attributing side-effects to \none of its components (56). \nAlthough randomized trials addressing", "page": 27, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "ents (56). \nAlthough randomized trials addressing this issue are not abundant, and those available are not \nsufficiently large or conducted for a long enough period to clearly address differences in major clinical \nevents, the initial combination treatment approach has been in place for over 15 years in large health \nsystems, such as the Kaiser Permanente system in the United States (57) and is a major component of \nthe WHO Global HEARTS Programme and the PAHO HEARTS in the Americas Initiative (", "page": 27, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "e and the PAHO HEARTS in the Americas Initiative (53). Recently, \ncombination antihypertensive medications in a single pill have been added to the WHO Essential \nMedicines List (49). This approach has demonstrated general acceptance by government, public, and \nprivate stakeholders and is demonstrating success in increasing HTN control rates worldwide.\nRECOMMENDATIONS\n15", "page": 27, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "GUIDELINE FOR THE PHARMACOLOGICAL TREATMENT OF HYPERTENSION IN ADULTS\n3.6\t Target blood pressure\n6.\t RECOMMENDATION ON TARGET BLOOD PRESSURES\nWHO recommends a target blood pressure treatment goal of <140/90 mmHg in all patients \nwith hypertension without comorbidities.\nStrong recommendation, moderate-certainty evidence\nWHO recommends a target systolic blood pressure treatment goal of <130 mmHg in \npatients with hypertension and known cardiovascular disease (CVD).\nStrong recommendation, moderate-", "page": 28, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "ar disease (CVD).\nStrong recommendation, moderate-certainty evidence\nWHO suggests a target systolic blood pressure treatment goal of <130 mmHg in high-risk \npatients with hypertension (those with high CVD risk, diabetes mellitus, chronic kidney \ndisease).\nConditional recommendation, moderate-certainty evidence\nEvidence and rationale\nThe evidence base consisted of five systematic reviews as well as a review of the SPRINT trial (58). \nEvidence profiles were constructed for various BP treatment tar", "page": 28, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "iles were constructed for various BP treatment targets, based on age and comorbidities \n(Web Annex A). \nThe desirable effects of lower target BP (per 1000 treated patients) were: a reduction in mortality \nof 27 (for SBP <120 vs <130\u2013139) and of 7 (for SBP 140/90 vs 150\u2013160/95\u2013105); a reduction in \ncardiovascular mortality of 40 (for SBP <130 vs <130\u2013149) and 6 (for SBP 140/90 vs 150\u2013160/95\u2013105); \nand a reduction in stroke of 17 (for SBP <130 vs <140). The increase in serious adverse events per 1", "page": 28, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "140). The increase in serious adverse events per 1000 \ntreated patients was 20 (for SBP <130 vs <140) and 5 (for SBP 140/90 vs 150\u2013160/95\u2013105). \nSummary results from a systematic review focusing on adults 65 years and older by Murad et al (59). \nsuggests that treatment to a lower BP target in individuals 65 years or older leads to a significant \nreduction in all-cause and CVD mortality, chronic kidney disease, myocardial infarction, or stroke \noutcomes. Similar conclusions were provided by anoth", "page": 28, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "tcomes. Similar conclusions were provided by another systematic review by Reboussin et al (60). \nNeither of these meta-analyses was able to account for the high risk of patients enrolled in the available \ntrials \u2013 at least in SPRINT and ACCORD (11, 61). Therefore, the GDG cautions against applying this \nevidence to lower-risk patients with raised BP or HTN \u2013 specifically, those not meeting trial eligibility \ncriteria for SPRINT, ACCORD or SPS3 (62). Network meta-analyses found a similar directio", "page": 28, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "2). Network meta-analyses found a similar direction of effect but \nmore optimistic beneficial effect sizes with intensive treatment (63, 64).\nIn patients with comorbidity (CAD, DM, CKD) there is consistent benefit with lower targets (variable \nthresholds); however, data in these subgroups were imprecise and the evidence was less certain. \nAdverse events such as dizziness in intensive control group and ischaemia in patients with coronary \nartery disease can shift the balance of benefits and harms", "page": 28, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "isease can shift the balance of benefits and harms in those aged 65 years or older. Concern \nabout lower adherence due to the need for extra patient and provider effort to reach lower targets \nshould also be balanced against intensive control. The overall certainty of the evidence was judged to \nbe moderate, with large benefits and moderate harms. The GDG made a judgement that the desirable \neffects outweigh the undesirable effects at a treatment goal of <140/90 mmHg in all patients with HTN \nwi", "page": 28, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "goal of <140/90 mmHg in all patients with HTN \nwithout comorbidities and of <130 mmHg in high-risk patients with HTN \u2013 those with high CVD risk, \ndiabetes, chronic kidney disease.\n16", "page": 28, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "Evidence-to-decision considerations\nFrom a patient perspective, HTN is often a silent disease and patients may not take antihypertensive \nmedications as directed because the positive effects of these medications are not as obvious as potential \nside-effects (61). Society and patients want to avoid premature mortality or disability. Serious adverse \nevents are also feared, but their duration and severity are often not well characterized in trials. Lower \ntargets are likely acceptable to other sta", "page": 29, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "Lower \ntargets are likely acceptable to other stakeholders, such as governments and providers, though there are \nusually several competing priorities and interests \u2013 especially the more acute demands of, and a higher \npriority placed on, acute conditions and health emergencies. Many well-known barriers to access to \nHTN care in low-income settings exist (6). Investment in the primary health care platform required for \neffective HTN management is often a challenge. Countries with low rates of HT", "page": 29, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "often a challenge. Countries with low rates of HTN control using more \nconservative BP thresholds may feel burdened by any request to set more ambitious BP treatment goals, \neven if only in selected high-risk patients. \nIntensive treatment for selected patients adds complexity for health workers; emphasis on team-based \ncare in low-resource settings means that simple, protocolized care is needed. Intensive treatment for \nsome patients complicates treatment protocols and may lead to decisional o", "page": 29, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "s treatment protocols and may lead to decisional overload, especially for health \nworkers with more limited training and/or autonomy. \nOn the other hand, strict BP targets in the general population with HTN are likely to be less acceptable \nto stakeholders. Most available evidence is derived from high-risk patients receiving intensive treatment \nand not the general population living with HTN. Treating HTN will reduce health inequity because \npreventing CV events reduces mortality across the popu", "page": 29, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "enting CV events reduces mortality across the population. Uncontrolled HTN might be over-\nrepresented in vulnerable populations. Therefore, improvement of HTN treatment and control through \nbetter treatment and a lower BP target could reduce long-standing inequality.\nRegarding costs, intensive treatment in the SPRINT trial meant one additional medication, one additional \noffice visit, and one additional laboratory test evaluation on average, and additional titration visits per \nparticipant over", "page": 29, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "additional titration visits per \nparticipant over 3.25 years, compared with standard treatment. In the United States, this translates \nto about USD 23\u00a0000 more per patient per year over their remaining lifetime (14, 15). Health care \ncosts are much less in countries other than the United States. Treating to lower BP targets will have \ndiminishing returns in progressively lower-risk patients as the magnitude of benefit becomes smaller. A \ncost-effectiveness study of screening and optimal manageme", "page": 29, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "ectiveness study of screening and optimal management of HTN, diabetes mellitus and chronic \nkidney disease in an Australian setting found that an intensive management of previously uncontrolled \nHTN compared with usual care resulted in an incremental cost-effectiveness ratio of AUD 2588. The \nstudy does not specify the target BP for the comparisons (65). A SPRINT trial health economic analysis \nprovided similar inferences (48, 50). \n3.7\t Frequency of re-assessment\n7.\t RECOMMENDATION ON FREQUENCY", "page": 29, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "y of re-assessment\n7.\t RECOMMENDATION ON FREQUENCY OF ASSESSMENT\nWHO suggests a monthly follow up after initiation or a change in antihypertensive \nmedications until patients reach target.\nConditional recommendation, low-certainty evidence\nWHO suggests a follow up every 3\u20136 months for patients whose blood pressure is under \ncontrol.\nConditional recommendation, low-certainty evidence\nRECOMMENDATIONS\n17", "page": 29, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "GUIDELINE FOR THE PHARMACOLOGICAL TREATMENT OF HYPERTENSION IN ADULTS\nThere was a minimal number of comparative studies that evaluated different follow-up lengths after \ninitiation of HTN medications. One randomized controlled trial compared a follow-up interval of three \nmonths to an interval of six months in family practice clinics in Canada. Participants (age 30\u201374 years) \nhad essential HTN that was controlled for at least three months before entry into the study. Mean BP\n, \ncontrol of HTN, p", "page": 30, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "entry into the study. Mean BP\n, \ncontrol of HTN, patient satisfaction and adherence to treatment were similar between the two groups \n(66). A retrospective population-based cohort study of family-practice clinics in the UK (67) studied \n88\u00a0756 adults with HTN (1986\u20132010). This study showed that in patients newly diagnosed with HTN, \nthose with >1.4 months prior to initiation of treatment had a hazard ratio of 1.12 (1.05\u20131.20) for a \nmajor adverse cardiovascular event (MACE) compared to those who", "page": 30, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "cardiovascular event (MACE) compared to those who started treatment at <1.4 months. \nFor patients who were initiated on treatment, those who waited >2.7 months before re-evaluation \nhad a hazard ratio of 1.18 (1.11\u20131.25) for MACE compared to those reassessed at <2.7 months. In \naddition, when reviewing protocols of large HTN trials that demonstrated important improvement in \ncardiovascular events with BP control, such as ACCORD and SPRINT, the initial length of time to follow \nup was one month", "page": 30, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "nitial length of time to follow \nup was one month (68, 69). This evidence indirectly suggests the appropriateness of this initial follow up \nin settings that conferred important benefit.\nThe anticipated desirable consequences of shorter follow up are better BP control and monitoring of \nside-effects, and perhaps improved adherence. Longer follow-up times are expected to lead to loss to \nfollow up. A systematic review of the impact of interventions to improve medication adherence in adults \npresc", "page": 30, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "s to improve medication adherence in adults \nprescribed antihypertensive medications suggested a decrease in adherence with an increase in time \nbetween intervention and follow up (70). The undesirable consequences of shorter follow up are the \nburden on patients and the health system. Certainty relating to these effects is very low.\nThe GDG found no evidence related to the question of the optimal follow-up time after the point that \nthe treated HTN patient achieves stable blood pressure control", "page": 30, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "HTN patient achieves stable blood pressure control.\nEvidence-to-decision considerations\nData on what patients consider significant in terms of the length of follow up after initiation of HTN \nmedications are lacking. Many patients, particularly those aged 65 years or older, or who live alone, \nare likely to be reassured by more frequent monitoring of BP\n, which can identify early signs of clinical \ndeterioration and provide a sense of security (71). However, younger asymptomatic patients may \nha", "page": 30, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "1). However, younger asymptomatic patients may \nhave the opposite perspective and find that frequent monitoring interferes with work and family \nresponsibilities. Telemonitoring may reduce the need for follow up, especially for patients living in \nareas remote from health care facilities. However, despite existing evidence on the effectiveness of \ntelemonitoring for patients with HTN, there is no empirical evidence of its long-term outcomes or \ngeneralizability to patients with various backgroun", "page": 30, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "eneralizability to patients with various backgrounds and educational levels (72).\t\nData on costs, resources and cost-effectiveness were unavailable. Frequent follow up is anticipated to \nbe associated with additional resource requirements, which may be offset by improved adherence, BP \ncontrol and improved outcomes that are important to patients. Burden on the health system may be \nreduced by involving nonphysician providers in follow up. \nThe WHO GDG considered a one-month follow up after initi", "page": 30, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "O GDG considered a one-month follow up after initiation of medications for HTN to be a \nreasonable approach, whereas intervals of 3 to 6 months can be applied when patients\u2019 BP is close to \nthe target and stable. Due to the lack of comparative data, these recommended intervals should be \nviewed as suggestions and may be modified, based on feasibility and other contextual factors. Such \nintervals were judged to be feasible and acceptable to key stakeholders. The impact of such follow-up \nlengths", "page": 30, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "akeholders. The impact of such follow-up \nlengths on health equity is unclear.\n18", "page": 30, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "3.8\t Administration of treatment by nonphysician professionals\n8.\t RECOMMENDATION ON TREATMENT BY NONPHYSICIAN PROFESSIONALS \nWHO suggests that pharmacological treatment of hypertension can be provided by \nnonphysician professionals such as pharmacists and nurses, as long as the following \nconditions are met: proper training, prescribing authority, specific management protocols \nand physician oversight.\nConditional recommendation, low-certainty evidence\nImplementation remarks:\n[\n[\nCommunity heal", "page": 31, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "vidence\nImplementation remarks:\n[\n[\nCommunity health care workers (HCWs) may assist in tasks such as education, delivery of \nmedications, blood pressure (BP) measurement and monitoring through an established \ncollaborative care model. The scope of hypertension care practised by community HCWs \ndepends on local regulations and currently varies by country.\n[\n[\nTelemonitoring and community or home-based self-care are encouraged to enhance the control \nof BP as a part of an integrated management sys", "page": 31, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "l \nof BP as a part of an integrated management system, when deemed appropriate by the treating \nmedical team and found feasible and affordable by patients.\n[\n[\nPhysician oversight can be done through innovative methods such as telemonitoring or similar \nto ensure access to treatment is not delayed.\nEvidence and rationale\nPICO question 11 (see Annex 4) addressed BP management by nonphysician health care workers \n(HCWs) as well as self-management by patients. The evidence base for this question co", "page": 31, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "y patients. The evidence base for this question consisted of \n11 systematic reviews (Web Annex A). The available evidence focused on evaluating care models in \nwhich BP control was managed by pharmacists, nurses, dietitians, and community HCWs. The outcome \nassessed in these studies were BP level and control. There was no data on cardiovascular events. \nAlthough the certainty of evidence was in general low, the magnitude of effect showed better control \nin 91\u2013264 more patients per 1000 (pharmaci", "page": 31, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "ontrol \nin 91\u2013264 more patients per 1000 (pharmacist studies) and an SBP/DBP reduction of 1\u20138 mmHg (nurse/\nHCW/dietitian studies). No study showed that nonphysician management was inferior to physician \nmanagement.\nA systematic review by Greer et al., showed that pharmacist-managed care led to better BP control \n(relative risk 1.44 or 170 more controlled per 1000) with no obviously reported difference in adherence, \nclinical events or quality of life (73). A systematic review by Anand has shown", "page": 31, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "life (73). A systematic review by Anand has shown that in LICs and MICs, \ntask sharing with pharmacists led to reductions of 8 mmHg SBP and 3.74 mmHg DBP\n. Similar results \nwere yielded by task sharing with nurses (5.34 mmHg lower), dieticians (4.67 mmHg lower), and \ncommunity HCWs (3.67 mmHg lower) (74). Data on undesirable effects (harms) were unavailable, which \nmay be due to publication bias, or reflect minimal harms.\nIn terms of self-management, a systematic review by Tucker (75) shows that", "page": 31, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "ent, a systematic review by Tucker (75) shows that self-monitoring by patients \nled to a 3.24 mmHg lower level SBP and 1.5 DBP\n, both statistically significant, and better BP control, \nas long as self-monitoring was remotely managed by a HCW. However, the study limitation was the \ninability to adequately blind participants to the intervention. There was minimal evidence about self-\ntitration on BP medications. \nThe GDG also concluded that since the evidence was from HICs, it may be less applicab", "page": 31, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "he evidence was from HICs, it may be less applicable to other \nsettings and that training of nonphysician HCWs varies considerably between countries. Overall the \ncertainty of evidence was low, with large anticipated desirable effects and a small magnitude of \nundesirable effects.\nRECOMMENDATIONS\n19", "page": 31, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "GUIDELINE FOR THE PHARMACOLOGICAL TREATMENT OF HYPERTENSION IN ADULTS\nEvidence-to-decision considerations\nThere is significant variability in patient and provider perspectives. Overall, society and patients want \nto reduce the risk of premature mortality or morbidity. Most of the available quantitative data were \nfocused on remote monitoring and not specifically on whether patients preferred BP being managed \nby physicians vs other providers, which was the primary question. Limited information p", "page": 32, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "ch was the primary question. Limited information provided mixed \nresults, with some patients appreciating some applications of self-care while others were concerned that \nbeing managed by others could harm the patient\u2013doctor relationship, but these comments were related \nto use of home-monitoring devices. In some studies in which BP was managed by nonphysicians, there \nwas good patient satisfaction and high retention, suggesting at least willingness, if not a preference, to \nhave BP managed by n", "page": 32, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "ess, if not a preference, to \nhave BP managed by nonphysicians (76, 77).Conversely, in-depth interviews with a sample of patients \nin the UK explored nurse and pharmacist prescribing and demonstrated that patients had concerns \nabout clinical governance, privacy and whether sufficient space was available to provide the service \nin community pharmacies. Participants had less concern about nursing management (78). Another \nstudy from Scotland explored patients\u2019 perspectives on pharmacist prescribi", "page": 32, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "red patients\u2019 perspectives on pharmacist prescribing and reported high \npatient satisfaction, but 65% stated that they would prefer to consult a doctor (79). Presumably, health \ninequities are reduced, since task shifting in the public sector increases access to those using public \nhealth vs private health. Increasing access in underserved areas can improve inequities.\nRegarding costs, Jacob et al. (80) synthesized data from 31 studies (24 from the US) and suggested that \nstudies that use commun", "page": 32, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "he US) and suggested that \nstudies that use community team approaches project a cost around USD 200/person/year to implement, \nbut with cost-savings for prevention of CVD outcomes such that net costs had a median cost of USD \n65/person/year, with 10 studies indicating negative or cost-savings overall. Most cost/quality-adjusted \nlife year (QALY) estimates were between USD 3888 and USD 24\u00a0000/QALY, with pharmacist-led \nprogrammes being more cost-effective than nurse-led ones. Only two were >USD 5", "page": 32, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "ffective than nurse-led ones. Only two were >USD 50\u00a0000/QALY out of \n28 studies. \nMost of the remaining cost data presented were related to self-monitoring and not to the question of \nphysician-led vs nonphysician-led care. However, if it is assumed that nonphysician salaries are lower, \nthen potentially costs will be lower, but that assumes that only limited effort by physicians is involved in \nany oversight of nonphysicians. Kulchaitanaroai et al. found similar results with a physician\u2013pharmac", "page": 32, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "al. found similar results with a physician\u2013pharmacist \ncollaborative system (81). \nThe two available analyses, by Jacob et al. and Kulchaitanaroai et al., focused on team-based \ninterventions as opposed to specifically physician vs other provider, and it is not clear if incremental cost-\neffectiveness ratios fit countries in all economic categories, nor whether the countries\u2019 willingness- to-\npay thresholds were analysed. All values appear to be below USD 50\u00a0000/QALY. For the US, the results \nwe", "page": 32, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "below USD 50\u00a0000/QALY. For the US, the results \nwere highly cost-effective, with most estimates well under USD 50\u00a0000/QALY but it remains unclear \nexactly how these may be translated to countries in lower economic categories. Even at USD 10\u00a0000/\nQALY, however, this would be acceptable for most MICs, though perhaps not for all LICs. However, if \nthe costs were the same or lower in programmes led by nurses or pharmacists compared to those led by \nphysicians then cost-saving was likely. \nThe GDG pr", "page": 32, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "hysicians then cost-saving was likely. \nThe GDG proposed four conditions that must be met for nonphysician-prescribing of antihypertensives. \nThese focused on the prescribers having proper training, prescribing authority in their locale, working \nwithin specific management protocols and having physician oversight. Community HCWs were \nsuggested as personnel who could assist with tasks such as education, delivery of medications, BP \nmeasurement and monitoring through an established collaborative", "page": 32, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "d monitoring through an established collaborative care model.\nTelemonitoring supervised by HCWs, and community- or home-based self-care, were considered as tools \nto enhance BP control as part of an integrated management system.\n20", "page": 32, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "4\t Special settings\n4.1\t Hypertension in disaster, humanitarian and emergency settings\nHypertension (HTN) is seen in a range of humanitarian crises and disaster settings (natural or \nhumanmade). This includes, but is not limited to, the wars in Syria and Iraq, the impact of the Great \nEast Japan Earthquake and Hurricane Katrina, and the living conditions of Palestinian refugees. The \nburden of HTN on those populations can be considerable (82). There are very little data on HTN control, \naccess t", "page": 33, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "ere are very little data on HTN control, \naccess to care and treatment, and patient understanding of HTN from Africa and Asia (except Japan), \ndespite protracted refugee situations on these continents. Violent and protracted\u00a0conflicts\u00a0are disastrous \nto civilian populations and their health care systems, and result in interruptions to treatment and care \n(83, 84). Armed conflicts are associated with increased short-term and long-term cardiac morbidity and \nmortality and increases in blood pressu", "page": 33, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "idity and \nmortality and increases in blood pressure (BP) (85). Following exposure to conflict, research in military \npopulations shows that post-traumatic stress disorder and severe injury are independent risk factors for \nthe development of HTN (86). The rates of treatment ranged from 53.4% to 98.1% of patients with \nHTN in this population (87, 88). \nThere are currently no data regarding target BP or the best antihypertensive agent to treat disaster-\nrelated HTN. Opinion-based recommendation i", "page": 33, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "aster-\nrelated HTN. Opinion-based recommendation is that the target BP control level should be less than \n140 mmHg for SBP and less than 90 mmHg for DBP\n. According to Kario et al, long-acting CCBs are \npreferred because they are metabolically neutral, and best at reducing BP variability, which is an \nindependent predictor of clinical outcomes, especially stroke. In addition, the BP-lowering effect of \nlong-acting CCBs is dose-dependent, and the degree of BP reduction that can be anticipated fro", "page": 33, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "degree of BP reduction that can be anticipated from these \nagents is known (89). Despite the challenges of working in humanitarian settings, several agencies have \nproduced guidelines for the identification and management of HTN. The WHO\u2019s Interagency Emergency \nHealth Kit has included a supplementary module with antihypertensive medications since 2017, but it \nis unclear how widely these are being used (90, 91). According to a personal communication from a \nphysician who treated HTN in Syrian r", "page": 33, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "tion from a \nphysician who treated HTN in Syrian refugees, the treatment was variable, and dependent on whatever \ndrug samples were available in the clinic. They had limited choices, including atenolol, lisinopril, and \nverapamil. Treatment was tailored to the patient\u2019s history. For example, patients with a history of \ncoronary artery disease received atenolol and lisinopril, patients with diabetes received lisinopril, and \npatients with migraine received verapamil. \nAssessment of HTN and approp", "page": 33, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "received verapamil. \nAssessment of HTN and appropriate resourcing to treat it should be a priority for agencies providing \nemergency and longer-term care for patients after or during humanitarian crises to prevent significant \nmortality and morbidity. Further studies are needed to accurately estimate prevalence of HTN in crisis-\naffected populations throughout the world and to evaluate the best treatment approach for this \npopulation. \nHumanitarian crises and disaster settings (natural or human", "page": 33, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "ian crises and disaster settings (natural or humanmade) can affect health care and services \nin many different ways. A list of potential barriers that can affect the management of individuals with \nhypertension is as follows: \n[\n[ significant decline of living standards \n[\n[ loss/destruction of health care facilities \n[\n[ flight of medical personnel causing shortage of medical care providers\n[\n[ severe shortage of medicines\n[\n[ lack or absence of essential supplies, equipment and materials\n[\n[ c", "page": 33, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "essential supplies, equipment and materials\n[\n[ compromise of the provision of primary and secondary health care\n[\n[ interruption of water, food and electricity\n[\n[ lack of morbidity and mortality data due to destruction of information systems and data collection\n[\n[ high psychological stress burden on both general population and health care personnel.\nSPECIAL SETTINGS\n21", "page": 33, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "GUIDELINE FOR THE PHARMACOLOGICAL TREATMENT OF HYPERTENSION IN ADULTS\n4.2\t COVID-19 and hypertension\nAlmost all available evidence suggests that hypertension increases the risk of severe COVID-19, defined \nas admission to intensive care, clinically defined severity or a combination of these; or mortality. It was \nsometimes unclear, however, whether this risk was independent of other risk factors (92). Initial reports \nhave identified higher rates of HTN among severely ill, hospitalized COVID-19", "page": 34, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "of HTN among severely ill, hospitalized COVID-19 patients, with overall \nHTN rates of 50\u201356% (93, 94). It had been unclear if this relationship was causal or confounded by age \nand other comorbidities associated with HTN, including obesity, diabetes and chronic kidney disease. \nConcerns regarding use of angiotensin-converting enzyme inhibitors (ACEis) in these patients were \nraised due to identification of angiotensin-converting enzyme 2 (ACE2), the monocarboxypeptidase \nthat inactivates angiot", "page": 34, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "the monocarboxypeptidase \nthat inactivates angiotensin II and thereby counters the activation of the classic renin\u2013angiotensin\u2013\naldosterone system (RAAS), as the functional receptor for the severe acute respiratory syndrome \ncoronavirus 2 (SARS-CoV-2) (95, 96). The WHO conducted a rapid review of evidence related to the use \nACEis or ARBs in COVID patients which identified 11 observational studies. No studies were found that \nwere designed to directly assess whether ACEis or ARBs increase the r", "page": 34, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "rectly assess whether ACEis or ARBs increase the risk of acquiring COVID-19. After \nadjustment for confounders, history of ACEi or ARB use was not found to be associated with increased \nseverity of COVID-19 illness. There were no studies that addressed the potential benefits and harms of \ninitiating ACEis or ARBs as treatment for patients with COVID-19 (97). Accordingly, discontinuation of \nACEis or ARBs may yield worse outcomes than continuation of their use in patients with a diagnosis \nof COV", "page": 34, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "of their use in patients with a diagnosis \nof COVID-19. In contrast to the uncertainty about the potential benefit of initiating RAAS blocker use \nin patients with COVID-19, there is a clear potential for harm in withdrawing these agents in high-risk \nCOVID-19 patients with established myocardial injury, HTN or heart failure (96). Most of the world\u2019s \nprofessional societies either recommend or strongly encourage continuing ACEis/ARBs in COVID-19-\ninfected patients (98). Further research that wi", "page": 34, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "-\ninfected patients (98). Further research that will address key unanswered questions about the role of the \nRAAS in the pathogenesis and possible treatment of COVID-19 and other coronavirus-based diseases is \nurgently needed. Prospective studies \u2013 in particular, ongoing randomized, placebo-controlled trials such \nas the Ramipril for the Treatment of COVID-19 (RAMIC) trial (ClinicalTrials.gov number,\u00a0NCT04366050) \nmay provide clearer insight regarding the effect of ACEis or ARBs in patients with", "page": 34, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "rding the effect of ACEis or ARBs in patients with COVID-19.\n4.3\t Pregnancy and hypertension\nHypertension, including chronic HTN, gestational HTN, pre-eclampsia, and eclampsia, is a very common \nmedical condition in pregnancy (99). Due to the adverse consequences of increased morbidity \nand mortality to both the women and fetus, HTN in pregnancy must be diagnosed, treated (when \nappropriate), and followed up diligently. It is important to note that up to 10% of pregnancy-related \ndeaths are attr", "page": 34, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "at up to 10% of pregnancy-related \ndeaths are attributed to HTN, and its presence in pregnancy leads to long-term adverse cardiovascular \nconsequences. Unfortunately, hypertensive disorders of pregnancy are markedly increasing (100, \n101). For instance, in the United States between 1998 and 2006, hypertensive disorders in pregnancy \nincreased from 6.7% to 8.3%, chronic HTN in pregnancy increased from 1.1% to 1.7%, and pre-\neclampsia/eclampsia from 0.9% to 1.2%. The potential serious consequences", "page": 34, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "m 0.9% to 1.2%. The potential serious consequences of HTN and pregnancy \nand the contraindication in pregnancy of some of the commonly prescribed pharmacological \nantihypertensive medications discussed below should be discussed with women who are or could \nbecome pregnant.\nThe normal haemodynamic state of pregnancy is one of systemic vasodilation accompanied by an \nincrease in cardiac output and decrease in total peripheral resistance. This results in a normal decrease in \nBP in the second trime", "page": 34, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "ts in a normal decrease in \nBP in the second trimester. HTN in pregnancy is generally diagnosed when BP is \u2265140 mmHg and/or \u226590 \nmmHg on at least two occasions, at least six hours apart. Chronic HTN is defined as a diagnosis of HTN \nbefore 20 weeks gestation, while gestational HTN is defined as a diagnosis of HTN at 20 weeks or later. \nPre-eclampsia and eclampsia are pregnancy-specific medical conditions requiring immediate and specific \nmedical management.\n22", "page": 34, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "management.\n22", "page": 34, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "While BP treatment thresholds for HTN in pregnancy continue to change, it is generally recommended \nfor both chronic and gestational HTN that pharmacologic treatment be initiated when the SBP is \n\u2265160 mmHg and/or the DBP is \u2265105 mmHg. In chronic HTN, frequently the woman has already been \ndiagnosed with HTN prior to the pregnancy and thus may already be on chronic antihypertensive \npharmacological therapy. In this case, the current regimen may be continued, with the caveat that the \nmedication r", "page": 35, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "continued, with the caveat that the \nmedication regimen may have to be changed to preferred medications, and certain antihypertensive \nmedications that are contraindicated in pregnancy must be discontinued. The recommended treatment \nBP goal/target also has been subject to debate and is changing. For instance, achieving a lower BP target \n(DBP of 85 mmHg vs 100 mmHg) has recently been shown to decrease the maternal development \nof severe HTN while not increasing maternal or fetal risk. If targe", "page": 35, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "le not increasing maternal or fetal risk. If target organ damage is present, initiating \nantihypertensive pharmacological treatment at a DBP of \u226590 mmHg should be considered.\nAs with most, if not all, other medical conditions requiring pharmacological treatment during \npregnancy, the treatment considerations in HTN are no different from those of non-pregnant adults. \nThus, since medications are not studied specifically for efficacy and safety in pregnancy, medication \nselection is usually based", "page": 35, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "pregnancy, medication \nselection is usually based on long-term clinical use and experience. This usually means older medications \nthat have had a substantial long-term track record of efficacy and safety are to be considered. For \nthe pharmacological treatment of HTN in pregnancy, preferred medications include methyldopa, \nbeta-blockers (particularly labetalol), CCBs (particularly nifedipine and, as an alternative, verapamil), \nand the direct-acting vasodilators (particularly hydralazine). There", "page": 35, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "ing vasodilators (particularly hydralazine). There is evidence to suggest that among \nthese agents, beta-blockers and CCBs appear to be more effective than methyldopa in decreasing the \ndevelopment of severe HTN later in the pregnancy. The use of thiazide diuretics has been debated, \nparticularly if the individual is already chronically on a thiazide prior to the pregnancy. In this situation \nthe thiazide diuretic may be continued during the pregnancy. \nThere are clear contraindications to the u", "page": 35, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "nancy. \nThere are clear contraindications to the use of some antihypertensive medications during pregnancy. \nThese include all the renin\u2013angiotensin system inhibitors, such as the ACEis, the ARBs and, although \nnot used any more, the direct-acting renin inhibitors, due to direct adverse effects on the fetus, and \nthe mineralocorticoid receptor antagonist spironolactone due to fetal anti-androgen effects. The use \nof the beta-blocker atenolol is also contraindicated due to the observation of intr", "page": 35, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "lso contraindicated due to the observation of intrauterine fetal growth \ninhibition (102).\nIn summary, HTN in pregnancy, manifested by the various hypertensive pregnancy disorders, is a very \ncommon medical condition. HTN pregnancy disorders have serious maternal and fetal consequences. \nThere are currently several preferred oral antihypertensive pharmacological agents available to \ntreat chronic HTN and gestational HTN during pregnancy. In addition, there are antihypertensive \npharmacological a", "page": 35, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "ion, there are antihypertensive \npharmacological agents that are contraindicated in pregnancy. There is evidence to support the \npharmacological treatment of HTN in pregnancy at given BP thresholds without and with the presence \nof end organ damage to decrease the likelihood of the development of severe HTN later in the \npregnancy. Even with the effective lowering of BP during the pregnancy and in the immediate post-\npartum period, the presence of hypertensive disorders of pregnancy significantl", "page": 35, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "f hypertensive disorders of pregnancy significantly increases long-term CV \nrisk, including future HTN, coronary disease, and stroke.\nSPECIAL SETTINGS\n23", "page": 35, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "GUIDELINE FOR THE PHARMACOLOGICAL TREATMENT OF HYPERTENSION IN ADULTS\n5\t Publication, implementation, \nevaluation and research gaps\n5.1\t Publication \nThis guideline is available to download from the WHO website. Given that an overview of published \nsystematic reviews was used for the development of the guideline, all reviews are already published and \navailable online. \n5.2\t Implementation and dissemination \nWHO regional and country offices, through their contacts with ministries of health, will", "page": 36, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "ugh their contacts with ministries of health, will encourage \nimplementation at country level. WHO will provide technical assistance if substantial country adaptation \nis required. The HEARTS technical package, which is currently being implemented in 18 countries \nand has significant partner endorsement, membership and engagement, will be the platform used to \nimplement and disseminate this guideline. The package will be revised to include the implementation \ntools from this guideline. Separate", "page": 36, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "plementation \ntools from this guideline. Separate implementation aspects are being considered as implementation or \nderivative tools for nonphysician treatment and the treatment of hypertension in areas of humanitarian \ncrises, following publication of the guideline. Implementation support will be extended to countries \nthrough all three levels of WHO.\n5.3\t Evaluation \nWHO will monitor uptake and implementation of the guideline in national policies and programmes by \nreviewing the number of coun", "page": 36, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "es and programmes by \nreviewing the number of countries that have adapted or endorsed the guideline nationally. \n5.4\t Future updating of the guideline \nThe guideline is expected to be valid for a period of five years. This period reflects the fact that new \nresearch findings are likely to become available in the meantime but also represents a feasible time \nframe, considering the costs, time and other resources that are needed for the updating process. If the \nevidence base or user needs change", "page": 36, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "ocess. If the \nevidence base or user needs change before the five-year mark, consideration will be given to producing \nupdates sooner.\n5.5\t Research gaps\nSeveral research gaps were identified by the GDG according to the theme of the PICOs. \nThresholds to determine initiation of therapy and targets to achieve for control\n[\n[ More evidence is required regarding treatment of those in the SBP 130\u2013139 range who fall into \none or more of the following subgroups: diabetes, chronic kidney disease, heart", "page": 36, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "subgroups: diabetes, chronic kidney disease, heart failure, 65 years \nor older.\n[\n[ There is a need for better outcomes data from, for example, trials that include heart failure and \ncognitive impairment among outcomes.\n[\n[ Clinical significance of adverse events registered in clinical trials needs greater clarity. \n[\n[ There is a need to quantify the difference in estimates between blinded, placebo-controlled trials \nand unblinded, active control trials using a standard framework.\n24", "page": 36, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "l trials using a standard framework.\n24", "page": 36, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "[\n[ There is a need for periodic analysis of trials in order to capture effects of changes over time in \nbackground epidemiology of CVD, non-BP treatments, competing risks, etc.\n[\n[ More evidence is needed in LICs, MICs and other non-North American/European countries.\n[\n[ An assessment of the feasibility, resource needs, and costs of intensive treatment in real clinical \npractice is needed. The resource commitment required for more intensive treatment in LMICs \nneeds to be quantified.\n[\n[ The op", "page": 37, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "tment in LMICs \nneeds to be quantified.\n[\n[ The opportunity cost of directing resources towards achieving SBP <130 in high-risk individuals \nneeds to be established.\n[\n[ Research is needed on the feasibility, acceptability, and efficacy of intensive treatment, especially \nin high-risk populations in LICs and MICs.\nLaboratory tests to determine initiation of treatment\n[\n[ A greater understanding of the essential tests to be performed in all patients to reduce costs and \nimprove outcomes is requir", "page": 37, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "ts to reduce costs and \nimprove outcomes is required.\nRole of cardiovascular risk in hypertension treatment\n[\n[ An exploration is needed of key operational aspects of the implementation of a risk-based \napproach to CVD prevention and BP-lowering pharmacological treatment in primary health care \nsettings.\nMonotherapy versus combination therapy\n[\n[ A comparison is required of long-term data about hard clinical endpoints between monotherapy \nand combination therapy.\n[\n[ There is a need for research", "page": 37, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "bination therapy.\n[\n[ There is a need for research studies on real-world experiences, designed and statistically powered, \nto determine if there is a difference in clinical outcomes, such as reduction in MACE, mortality, \nand serious adverse events, between single-pill combinations vs multiple-pill combinations.\n[\n[ Health economic analyses are needed to quantify cost-effectiveness and budget implications of \nimplementing incremental initial combination therapy compared with initial monotherapy.", "page": 37, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "ination therapy compared with initial monotherapy.\nFrequency of re-assessment\n[\n[ Criteria establishing the clinical definition of stable BP control will be needed to guide the \nselection of patients for less frequent follow-up visits.\n[\n[ Research is needed for early and accurate identification of patients less likely to achieve BP control \nand less likely to follow up as requested by their health care provider.\n[\n[ Better evidence is needed on the timing, frequency, and intensity of interventi", "page": 37, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "the timing, frequency, and intensity of interventions that improve \ntreatment adherence.\nTeam-based care for hypertension\n[\n[ Evidence is needed that remote monitoring and use of community HCWs/navigators can assist in \nthe management of BP\n.\n[\n[ Evidence of the feasibility, costs, and effectiveness of community/home-based monitoring of BP is \nneeded.\nPUBLICATION, IMPLEMENTATION, EVALUATION AND RESEARCH GAPS\n25", "page": 37, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "GUIDELINE FOR THE PHARMACOLOGICAL TREATMENT OF HYPERTENSION IN ADULTS\n6\t Implementation tools\n6.1\t Guideline recommendations\nGraphic summaries of the guideline recommendations are presented below in an algorithmic approach \n(Figs 3 and 4). This maps the recommendations to a patient-care pathway.\nFig. 3\t An approach for starting treatment with a single-pill combination \nTreat adults with BP \u2265140 mmHg or \u226590  \n(SBP \u2265130 mmHg for those with CVD, DM, CKD). \nStart two-drug combination therapy, prefer", "page": 38, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "CKD). \nStart two-drug combination therapy, preferably in a single-pill combination \n(ACE/ARB, dihydropyridine CCB, thiazide-like agents). \nTreatment targets: <140/90 mmHg \n(SBP <130 mmHg for high-risk patients with CVD, DM, CKD).\nFollow up monthly after initiation or a change in antihypertensive \nmedications until patient reaches BP target. \nFollow up every 3\u20136 months for patients with BP under control.\nPharmacological treatment to be initiated under the following circumstances:\n[\n[\nA diagnosis", "page": 38, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "under the following circumstances:\n[\n[\nA diagnosis of HTN has already been made.\n[\n[\nInitiation of pharmacological HTN treatment should start no later than four weeks after diagnosis of HTN. \n[\n[\nIf BP level is high or there is accompanying evidence of end organ damage, initiation of treatment should \nbe started without delay.\n[\n[\nPatient should be counselled about starting medication therapy.\n[\n[\nBasic laboratory testing (electrolytes, creatinine, lipogram, glucose, HbA1C, urine dipstick, and E", "page": 38, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "e, lipogram, glucose, HbA1C, urine dipstick, and ECG) to \noccur as long as it does not delay treatment. \n[\n[\nA CV risk assessment can be conducted immediately (as long as it does not delay initiation of treatment) \nor at a later visit.\n[\n[\nConsider using diuretics or CCB in patients 65 years or older, or those of African or Afro-Caribbean descent, \nbeta-blockers (BBs) post MI, ACEis/ARBs in those with DM, heart failure or CKD.\n26", "page": 38, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "Fig. 4 \tAn approach for starting treatment not using a single-pill combination (i.e. with monotherapy or \nfree combination therapy)\nPharmacological treatment to be initiated under the following circumstances:\n[\n[\nA diagnosis of HTN has already been made.\n[\n[\nInitiation of pharmacological HTN treatment should start no later than four weeks after diagnosis of HTN. \n[\n[\nIf BP level is high or there is accompanying evidence of end organ damage, initiation of treatment should \nbe started without dela", "page": 39, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "ation of treatment should \nbe started without delay.\n[\n[\nPatient should be counselled about starting medication therapy.\n[\n[\nBasic laboratory testing (electrolytes, creatinine, lipogram, glucose, HbA1C, urine dipstick, and ECG) to \noccur as long as it does not delay treatment. \n[\n[\nA CV risk assessment can be conducted immediately (as long as it does not delay initiation of treatment) \nor at a later visit.\n[\n[\nConsider using diuretics or CCB in patients 65 years or older, or those of African or", "page": 39, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "atients 65 years or older, or those of African or Afro-Caribbean descent, \nbeta-blockers (BBs) post MI, ACEis/ARBs in those with DM, heart failure or CKD.\nTreat adults with BP \u2265140 mmHg or \u226590  \n(SBP \u2265130 mmHg for those with CVD, DM, CKD). \nStart with medications from any of the following three classes of pharmacological \nantihypertensive medications as an initial treatment: \n1) thiazide and thiazide-like agents, 2) ACEi/ARB, and 3) long-acting dihydropyridine CCB.\nTreatment targets: <140/90 mmH", "page": 39, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "ihydropyridine CCB.\nTreatment targets: <140/90 mmHg \n(SBP <130 mmHg for high-risk patients with CVD, DM, CKD).\nFollow up monthly after initiation or a change in antihypertensive medications \nuntil patient reaches target. \nFollow up every 3\u20136 months for patients with BP under control.\nIMPLEMENTATION TOOLS\n27", "page": 39, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "GUIDELINE FOR THE PHARMACOLOGICAL TREATMENT OF HYPERTENSION IN ADULTS\n6.2\t Drug- and dose-specific protocols\nTwo examples of suggested drug and dose-specific protocols are presented below (Figs 5 and 6). These \nshould be viewed as examples and other approaches are possible.\nAlgorithm 1: Initiation of treatment with a single-pill combination\n[\n[ Beginning treatment with two antihypertensive drugs from different classes is recommended \nwhen baseline BP is \u226520/10 mmHg above goal, and should be cons", "page": 40, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "e BP is \u226520/10 mmHg above goal, and should be considered when baseline BP is \n\u2265140/90 mmHg.\n[\n[ Drugs affecting the renin\u2013angiotensin system (ACEis, ARBs, and aliskiren) have been associated \nwith serious fetal toxicity, including renal and cardiac abnormalities and death; they are \ncontraindicated for use during pregnancy.\nFig. 5 Algorithm 1\nStart ARB\u2013CCB at \nhalf-maximal doses \n(Example*: Telmisartan 40\u2013 \nAmlodipine 5 mg** \nonce a day).\nRecheck BP in 4\u20136 weeks; \nif BP is at goal, follow up \nin", "page": 40, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "BP in 4\u20136 weeks; \nif BP is at goal, follow up \nin 3\u20136 months.\nRecheck BP in 4\u20136 weeks; \nif BP is at goal, follow up \nin 3\u20136 months.\nRecheck BP in 4\u20136 weeks; \nif BP is at goal, follow up \nin 3\u20136 months.\nRecheck BP in 4\u20136 weeks; \nif BP is at goal, follow up \nin 3\u20136 months.\nIf  BP is not at goal, \nincrease ARB\u2013CCB (double \nthe dose to Telmisartan 80\u2013 \nAmlodipine 10 mg \nonce a day).\nIf BP is not at goal, \nadd a thiazide/thiazide-like \ndiuretic at half-maximal \ndose (hydrochlorothiazide \n25 mg or ch", "page": 40, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "lf-maximal \ndose (hydrochlorothiazide \n25 mg or chlorthalidone \n12.5 mg once a day).\nIf BP is not at goal, increase \nthe thiazide/thiazide-like \ndiuretic (double the dose to \nhydrochlorothiazide 50 mg or \nchlorthalidone 25 mg \nonce a day).\nIf  BP is not at goal, \nrefer to a specialist.\nNOTE: Monitor potassium and \nkidney function when starting or \nchanging the dose of ACEi/ARB \nor thiazide/thiazide-like diuretic, if \ntesting is readily available and does \nnot delay treatment.\nThis protocol is co", "page": 40, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "and does \nnot delay treatment.\nThis protocol is contraindicated for women who are or could become pregnant. Neither an ACEI or ARB \nshould be given to pregnant women.\n*\t The medications mentioned serve as examples and can be replaced with any two medications from any of the \nthree drug classes (ACEis/ARBs, CCBs or thiazide/thiazide-like diuretics). Start two individual pills or, if available, \nboth in a single-pill combination (fixed-dose combination).\n**\t Can be replaced with other individual p", "page": 40, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "tion).\n**\t Can be replaced with other individual pills or, if available, other single-pill combinations (fixed-dose \ncombinations).\n28", "page": 40, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "Algorithm 2: Initiation of treatment not using a single-pill combination (i.e. with monotherapy \nor free combination therapy)\n[\n[ A CCB, rather than a thiazide-type diuretic or ACEi/ARB, was selected as first-line medication \nif one agent is used, to avoid the need for electrolyte measurements or to alleviate concerns \nregarding potential change in GFR.\n[\n[ Drugs affecting the renin-angiotensin-aldosterone system (ACEis, ARBs, and aliskiren) have been \nassociated with serious fetal toxicity, inc", "page": 41, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "been \nassociated with serious fetal toxicity, including renal and cardiac abnormalities and death; they \nare contraindicated for use during pregnancy.\nFig. 6 Algorithm 2\nIf BP is not at goal, increase \nthe ARB (double the dose to \nTelmisartan \n80 mg once a day).\nRecheck BP in 4\u20136 \nweeks; if BP is at \ngoal, follow up in \n3\u20136 months.\nIf BP is not at goal, \nadd an ARB at half maximal \ndose (for example \nTelmisartan \n40 mg once a day).\nRecheck BP in 4\u20136 \nweeks; if BP is at \ngoal, follow up in \n3\u20136", "page": 41, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "4\u20136 \nweeks; if BP is at \ngoal, follow up in \n3\u20136 months.\nIf BP is not at goal, \nincrease the CCB (double the \ndose to Amlodipine 10 mg \nonce a day).\nRecheck BP in 4\u20136 \nweeks; if BP is at \ngoal, follow up in \n3\u20136 months.\nStart a CCB at half maximal \ndose  (Amlodipine 5 mg* \nonce a day).\nRecheck BP in 4\u20136 \nweeks; if BP is at \ngoal, follow up in \n3\u20136 months.\nRecheck BP in 4\u20136 \nweeks; if BP is at \ngoal, follow up in \n3\u20136 months.\nIf BP is not at goal, \nadd a thiazide/thiazide-like \ndiuretic at half", "page": 41, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": ", \nadd a thiazide/thiazide-like \ndiuretic at half maximal dose \n(hydrochlorothiazide 25 mg \nor chlorthalidone 12.5 mg \nonce a day). \nIf BP is not at goal, increase \nthe thiazide/thiazide-like \ndiuretic (double the dose to \nhydrochlorothiazide 50 mg or \nchlorthalidone 25 mg \nonce a day).\nIf  BP is not at goal, \nrefer to a specialist.\nNOTE: Monitor potassium and kidney function \nwhen starting or changing dose of ACEi/ARB or \nthiazide/thiazide-like diuretic, if testing is readily \navailable and doe", "page": 41, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "diuretic, if testing is readily \navailable and does not delay treatment.\nThis protocol is contraindicated for women \nwho are or could become pregnant. Neither \nan ACEI or ARB should be given to pregnant \nwomen.\n*\t Can be replaced with a thiazide/thiazide-like \ndiuretic or an ACEi or ARB. An ACEi or ARB \nis preferred for patients with proteinuria.\nIMPLEMENTATION TOOLS\n29", "page": 41, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "GUIDELINE FOR THE PHARMACOLOGICAL TREATMENT OF HYPERTENSION IN ADULTS\nReferences\n(1)\t\nCardiovascular diseases (CVDs). Key facts. 17 May 2017 [website] (https://www.who.int/news-\nroom/fact-sheets/detail/cardiovascular-diseases-(cvds), accessed 31 March 2021).\n(2)\t\nHypertension. Key facts. 13 September 2019 [website] (https://www.who.int/news-room/fact-\nsheets/detail/hypertension, accessed 31 March 2021).\n(3)\t\nPrevention of cardiovascular disease: guidelines for assessment and management of total", "page": 42, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "guidelines for assessment and management of total \ncardiovascular risk. Geneva: World Health Organization; 2007. \n(4)\t\nHultcrantz M, Rind D, Akl EA, Treweek S, Mustafa RA, Iorio A, et al. The GRADE Working Group \nclarifies the construct of certainty of evidence. J Clin Epidemiol. 2017;87:4-13. doi: 10.1016/j.\njclinepi.2017.05.006. \n(5)\t\nBalshem H, Helfand M, Sch\u00fcnemann HJ, Oxman AD, Kunz R, Brozek J. GRADE guidelines: \n3. Rating the quality of evidence. J Clin Epidemiol. 2011;64(4):401-406. doi:", "page": 42, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "idence. J Clin Epidemiol. 2011;64(4):401-406. doi: 10.1016/j.\njclinepi.2010.07.015. \n(6)\t\nShahaj O, Denneny D, Schwappach A, Pearce G, Epiphaniou E, Parke H, et al. Supporting \nself-management for people with hypertension: a meta-review of quantitative and qualitative \nsystematic reviews. J Hypertens. 2019;37(2):264-279. doi: 10.1097/HJH.0000000000001867.\n(7)\t\nMeiqari L, Nguyen T-P-L, Essink D, Zweekhorst M, Wright P\n, Scheele F. 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Obstet Gynecol. 2015;125(1):5-12. doi: 10.1097/\nAOG.0000000000000564.\n(102)\t Abalos E, Duley L, Steyn DW, Gialdini C. An", "page": 48, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "(102)\t Abalos E, Duley L, Steyn DW, Gialdini C. Antihypertensive drug therapy for mild to moderate \nhypertension during pregnancy. Cochrane Database of Syst Rev. 2018;10(10):CD002252. doi: \n10.1002/14651858.CD002252.pub4.\n36", "page": 48, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "Annex 1: List of contributors\nThe World Health Organization (WHO) would like to thank the members of the Guideline Development \nGroup, the scientists who provided systematic reviews and the external peer reviewers for their \ncontributions to the development of these recommendations. Professor K Srinath chaired the meeting \nwith the assistance of the deputy chair, Professor Nizal Sarafzadeggan.\nWHO Steering Group\nName\nDepartment/Office\nBernadette Cappello\nDepartment of Essential Medicines and Pro", "page": 49, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "Cappello\nDepartment of Essential Medicines and Products\nNeerja Chowdhury\nDepartment of Mental Health \nGampo Dorji\nRegional Office of South East Asia (SEARO)\nJill Farrington\nRegional Office of Europe (EURO)\nTaskeen Khan\nDepartment of Noncommunicable Diseases\nPedro Ordunez\nPan American Health Organization/Regional Office of the Americas \n(PAHO/AMRO)\nSteven Shongwe\nRegional Office for Africa (AFRO) \nSlim Slama\nRegional Office of the Eastern Mediterranean (EMRO)\nCherian Varghese\nDepartment of Noncom", "page": 49, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "anean (EMRO)\nCherian Varghese\nDepartment of Noncommunicable Diseases\nMarco Vitoria\nDepartment of HIV/AIDS\nTemo Waqanivalu\nDepartment of Noncommunicable Diseases\nGuideline Development Group\nName\nAffiliations\nExpertise\nRegion\nShrish Acharya\nConsultant Physician and Head of Internal \nMedicine, Colonial War Memorial Hospital, \nFiji\nChair, National Medicine and Therapeutics \nCommittee, Ministry of Health, Fiji\nInternal medicine\nClinical practice \nguideline development\nWPRO\nAkram \nAl-Makki\nDirector of", "page": 49, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "eline development\nWPRO\nAkram \nAl-Makki\nDirector of Graduate Medical Education, \nMedical Director of Acute (Inpatient) Dialysis \nUnit, Indiana University, IN, USA \nHealth-Arnett, Affiliate Faculty of Pharmacy \nPractice, Purdue University, College of \nPharmacy\nHTN management \nin disaster and \nhumanitarian settings, \npharmacology of \nhypertensive medicines \nand HTN management, \nNephrology\nAMRO\nHind Mamoun \nBeheiry\nAssociate Professor of Physiology, Dean \nFaculty of Nursing Sciences, International", "page": 49, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "Dean \nFaculty of Nursing Sciences, International \nUniversity of Africa (IUA), Sudan\nNursing and HTN, \nguideline development, \naccess to HTN care in \nlow-resource settings, \npathophysiology of HTN, \nHTN management and \nprevention at community \nlevel\nEMRO\nANNEXES\n37", "page": 49, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "GUIDELINE FOR THE PHARMACOLOGICAL TREATMENT OF HYPERTENSION IN ADULTS\nBeatriz \nChampagne\nCLAS Coalici\u00f3n Latinoam\u00e9rica Saludable/\nCoalition for Americas\u2019 Health @CLASenLA\nAdvocacy, coalition \nbuilding, policy change, \npatient perspectives, \nimplementation \nresearch, behavioural \nsciences\nAMRO\nUgyen Choden\nChief Analyst, Department of Financial \nRegulation and Supervision, Royal Monetary \nAuthority, Bhutan\nPatient perspective, \ndrafting guidelines, \npolicies and \nimplementing policies\nSEARO\nKennet", "page": 50, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "policies and \nimplementing policies\nSEARO\nKenneth \nConnell\nDeputy Dean of Internationalization \n& Recruitment and Lecturer in Clinical \nPharmacology, The UWI, Cave Hill Campus\nConsultant Internist, Queen Elizabeth \nHospital, Barbados \nGovernor of the American College of \nPhysicians Caribbean Chapter\nInternal medicine, HTN \n& ethnicity, medical \neducation\u00a0\nAMRO\nMarie Therese \nCooney\nClinical Professor, University College Dublin, \nIreland \nConsultant Physician in Geriatric and \nGeneral Medicine,", "page": 50, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "tant Physician in Geriatric and \nGeneral Medicine, St Vincent\u2019s University \nHospital, Ireland\t\nCardiovascular \nrisk estimation, \ncardiovascular disease \nprevention, frailty and \nmulti-morbidity\nEURO\nDonald \nDiPette\nDistinguished Health Sciences Professor, \nUniversity of South Carolina and University \nof South Carolina School of Medicine, \nColumbia, SC, USA \nClinical pharmacology \nand pharmacology \nof HTN medications, \nHTN management, \npathophysiology of \nHTN, health care and \npolicy making inclu", "page": 50, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "logy of \nHTN, health care and \npolicy making including \nprimary care\nAMRO\nNnenna \nEzeigwe\nConsultant Public Health Physician; Director/\nNational Coordinator, Non-Communicable \nDiseases (NCDs), Federal Ministry of Health, \nAbuja, Nigeria\nPublic health, policy-\nmaking, programme \nimplementation\nAFRO\nTom Gaziano\nAssociate Professor, Harvard Medical School\nCenter for Health Decision Science, Harvard \nTH Chan School of Public Health\nClinical Director, iHeart Champion Program\nDirector, Global Cardiova", "page": 50, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "iHeart Champion Program\nDirector, Global Cardiovascular Health Policy \nand Prevention Unit\nCardiovascular Medicine Division, Brigham & \nWomen\u2019s Hospital\nImplementation of HTN \ntreatment guideline, \ncost-effectiveness, \nglobal health policy, \nepidemiology, screening \nstrategies\nAMRO\nAgaba Gidio \nConsultant Physician (endocrinologist)/Head \nAdult Diabetes Clinic\nMulago National referral Hospital, Kampala \nUganda\nEndocrine HTN, HTN in \npatients with Diabetes\nAFRO\nVilma Irazola\nDirector, Instituto", "page": 50, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "h Diabetes\nAFRO\nVilma Irazola\nDirector, Instituto de Efectividad Clinica \ny Sanitaria (IECS); Institute for Clinical \nEffectiveness and Health Policy (IECS)\nDeputy Director of the Master\u2019s Degree \nProgram in Clinical Effectiveness, University \nof Buenos Aires\nSenior Researcher, National Scientific Council \n(CONICET), Argentina\nImplementation science, \nNCDs epidemiology, \nprevention and \nmanagement; \ncardiovascular health, \nglobal health, \nhealth policy \nAMRO\n38", "page": 50, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "policy \nAMRO\n38", "page": 50, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "Patricio Lopez \nJaramillo\nDirector, Masira Research Institute, \nUniversidad de Santander (UDES) \nScientific Director, Centro Integral \npara la Prevencion de la Enfermedades \nCardiometabolicas (CIPCA), Bucaramanga, \nColombia\nEndocrinology, clinical \nmanagement of HTN, \nresearch\nAMRO\nUnab Khan\nDiplomate, American Board of Family \nMedicine and Adolescent Medicine\nAssociate Professor and Chair, Department \nof Family Medicine, Aga Khan University, \nKarachi, Pakistan\nNCDs, educational \nprogrammes for", "page": 51, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "rachi, Pakistan\nNCDs, educational \nprogrammes for \nprimary care physicians, \nworkplace/employee \nwellness and safety, \nprogram implementation \nresearch\nEMRO\nVindya \nKumarapeli\nConsultant Community Physician, Director \n(Non-Communicable Diseases), Ministry of \nHealth, Sri Lanka\nAccess to HTN care in \nlow-resource settings, \npublic health, policy-\nmaking, programme \nimplementation, primary \nhealth care\nSEARO\nAndrew \nMoran\nDirector, Global Hypertension Control, \nResolve to Save Lives, an initiative", "page": 51, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "ion Control, \nResolve to Save Lives, an initiative of Vital \nStrategies\nAssociate Professor of Medicine, Columbia \nUniversity Irving Medical Center, New York, \nNY, USA\nHTN, primary care, \nhealth economic \nevaluation, HTN program \nevaluation\nAMRO\nMargaret \nMswema \nSilwimba\nClinical Pharmacist and Head of \nPharmaceutical services, Premium \nDepartment (UTH)\nPart-time Lecturer (Faculty of Pharmacy) \nLusaka Apex Medical University, Zambia\nHTN pharmaceuticals, \npharmacy education\nAFRO\nBrian Rayner\nEme", "page": 51, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "uticals, \npharmacy education\nAFRO\nBrian Rayner\nEmeritus Professor and Senior Research \nScholar, Division of Nephrology and \nHypertension, Department of Medicine, \nUniversity of Cape Town, Cape Town, \nSouth Africa\nGuidelines, resistant HTN \nespecially in individuals \nof African descent, \ngenetics of HTN, diabetic \nkidney disease\nAFRO\nK Srinath \nReddy\nPresident, Public Health Foundation of India\nCardiology, prevention \nand control of NCDs, \nepidemiology, health \nsystems and policy, \nuniversal heal", "page": 51, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "ology, health \nsystems and policy, \nuniversal health \ncoverage, public health\nSEARO\nNizal \nSarrafzadegan\nDistinguished Professor of Medicine \nand Cardiology, Director of Isfahan \nCardiovascular Research Institute, a WHO \nCollaborating Centre in Iran\nAffiliate Professor, School of Population \nand Public Health, Faculty of Medicine, \nUniversity of British Columbia, Vancouver, \nCanada\nCardiology, \nepidemiology, \nprevention and \ncontrol of NCDs, public \nhealth, programme \nimplementation and \nevaluat", "page": 51, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "ic \nhealth, programme \nimplementation and \nevaluation, global health\nEMRO\nApichard \nSukonthasan\nCardiac Specialist and Head of Medicine \nDepartment, Bangkok Hospital Chiang Mai\nGuideline development, \ncardiovascular disease \nprevention, HTN \nmanagement\nSEARO\nANNEXES\n39", "page": 51, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "GUIDELINE FOR THE PHARMACOLOGICAL TREATMENT OF HYPERTENSION IN ADULTS\nPaul Whelton\nShow Chwan Chair in Global Public Health, \nDepartment of Epidemiology, Tulane \nUniversity School of Public Health and \nTropical Medicine, Tulane, USA\nEpidemiology \nand prevention of \ncardiovascular and \nrenal disease, research, \nguidelines development, \nglobal health, \nhealth policy\nAMRO\nJing Yu\nMD, PhD, Professor of Internal Medicine, \nChief of Cardiology, Director, Center of \nHypertension, Director, Department o", "page": 52, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "r, Center of \nHypertension, Director, Department of \nCardiology, Lanzhou University Second \nHospital, China\nChairman of Hypertension League in Gansu, \nNingxia and Qinghai Region of China\nAcute and chronic \ncomplications of HTN, \naccess to HTN care in \nlow-resource settings, \npharmacology of \nhypertensive medicines, \ncardiovascular \ncomplications\nWPRO\nConsultant and Systematic Review Team\nMethodologist: M Hassan Murad (Professor of Medicine at the Mayo Clinic, Rochester, USA)\nSystematic Review Te", "page": 52, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "Mayo Clinic, Rochester, USA)\nSystematic Review Team: Reem Mustapha, Abdallah Al Alayli, Romina Brignardello, Sara Jdiaa, Veena \nManja (University of Kansas Medical Center, Kansas, USA)\nExternal Review Group\nName\nAffiliation\nRegion\nMabel Aoun\nHead of the Department of Nephrology, Saint-Georges Hospital \nAjaltoun\nAssistant Professor, Medical School, Saint-Joseph University of \nBeirut, Lebanon\nEMRO\nAntoinette P\u00e9ch\u00e8re \nBertschi\nHead Hypertension Unit and Centre, Service of Nephrology and \nHypertens", "page": 52, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "t and Centre, Service of Nephrology and \nHypertension, University Hospital of Geneva, Switzerland\nEURO\nJennifer Cohn\nSenior Vice President, Cardiovascular Health\nAssistant Professor, Division of Infectious Diseases, University of \nPennsylvania, PA, USA\nAMRO\nPrabhdeep Kaur\nScientist E and Head of Division of Noncommunicable Diseases, \nICMR-National Institute of Epidemiology, Chennai, India\nSEARO\nDaniel T Lackland\nProfessor of Epidemiology and Neurology\nDirector, Division of Translational Neurosci", "page": 52, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "ology\nDirector, Division of Translational Neurosciences and Population \nStudies, Medical University of South Carolina, Charleston, SC, USA\nAMRO\nVenus Mushininga\nProgram Manager, Non Communicable Diseases, Ministry of Health \nand Child Care, Harare, Zimbabwe\nAFRO\nMarcelo Orias\nChief of Nephrology at Sanatorio Allende\nProfessor in Internal Medicine at National University of C\u00f3rdoba, \nAssociate Professor of Internal Medicine, Yale University, CT, USA\nAMRO\n40", "page": 52, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "A\nAMRO\n40", "page": 52, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "Xin Hua Zhang\nProfessor of Medicine\nVice-Director of Beijing Hypertension League Institute, Beijing, \nChina\nPresident, World Hypertension League, WHL Global Office\nDirector, WHL Asia-Pacific Regional Office\nWPRO\nOverall coordination and writing of the guideline \nThe guideline process was coordinated by the WHO Department of Noncommunicable Diseases. The \nfirst draft was written by Taskeen Khan. Drafts were reviewed by the Guideline Development Group and \nExternal Review Group, and subsequently r", "page": 53, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "oup and \nExternal Review Group, and subsequently revised by Taskeen Khan.\nANNEXES\n41", "page": 53, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "GUIDELINE FOR THE PHARMACOLOGICAL TREATMENT OF HYPERTENSION IN ADULTS\nAnnex 2. Managing declarations of \ninterest and conflicts of interest \nThe steering group followed the current Compliance, Risk Management and Ethics (CRE) policy. \nAll members of the Guideline Development Group (GDG) were asked to fill in the standard WHO \nDeclaration of Interest (DOI) forms, which were reviewed. The WHO Secretariat reviewed the curriculum \nvitae of each potential participant and conducted internet searches (", "page": 54, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "tial participant and conducted internet searches (PubMed, Open Payments Data, \nGoogle Scholar) for information on potential financial and academic conflicts of interest related to the \nsubject of the meeting. All DOIs are on file at the WHO Department of Noncommunicable Diseases. \nThe WHO Steering Group published the names and brief biographies of potential GDG members on the \nWHO website for more than two weeks, together with a description of the objective of the meeting, for \npublic review and", "page": 54, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "e objective of the meeting, for \npublic review and comment. There were no concerns raised about any members.\nNone of the declared interests was judged sufficient to affect any of the experts\u2019 objective judgement \nduring the guidelines development process or on the recommendations, or therefore to preclude their \nfull participation in the development of the guidelines.\nDuring the course of the development of the guideline, one GDG member\u2019s status of conflict of interest \nchanged as she accepted a", "page": 54, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "of conflict of interest \nchanged as she accepted a temporary appointment as a staff member at WHO. She was removed from \nfurther GDG engagements immediately upon accepting appointment.\nAll members of the GDG and all meeting observers were required to sign a confidentiality agreement \nbefore participating in the meeting.\nAll members of the External Review Group (ERG) were asked to fill in the standard WHO DOI forms, \nwhich were reviewed. None of the declared interests was judged sufficient to aff", "page": 54, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "he declared interests was judged sufficient to affect any of the \njudgement during the review process, or therefore to preclude their participation as expert reviewers.\n42", "page": 54, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "Annex 3: Treatment outcomes \nrelevant to hypertension\nMembers of the WHO Steering Group, in consultation with the GDG and methodologist, developed a \nlist of treatment outcomes most relevant to the care of individuals with hypertension. The GDG then \nrated each outcome on a scale from 1 to 9 and indicated whether it considered each outcome critical \n(rated 7\u20139), important (rated 4\u20136) or not important (rated 1\u20133) for decision-making (Fig. A3.1).\nFig. A3.1\t Rating of outcomes\nImportance of outcome", "page": 55, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "ig. A3.1\t Rating of outcomes\nImportance of outcomes for decision making\n8.6\n8.4\n8.1\n8.0\n7.9\n7.8\n7.6\n6.9\n6.9\n6.8\n6.8\n6.3\n6.0\n4.4\nLimited importance\nImportant\nCritical\nAny adverse events (eg, edema) \nStroke \nMI \nCAD \nCV death \nHeart failure \nESRD \nAdherence \nAdverse events leading to discontinuation of BP meds \nAll-cause mortality \nSerious adverse events (eg, syncope) \nTime to BP control \nPatient satisfaction \nPill/medication burden \nANNEXES\n43", "page": 55, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "GUIDELINE FOR THE PHARMACOLOGICAL TREATMENT OF HYPERTENSION IN ADULTS\nAnnex 4: PICO questions \nThe eleven questions in population, intervention, comparison, and outcomes (PICO) format used to \nguide the systematic reviews. In addition, relevant subgroups (s) were identified.\n1\t\nAt what level of blood pressure should pharmacological therapy be started to \nprevent cardiovascular events?\nP\nAdult men and women\nI\nSpecific systolic and diastolic blood pressure thresholds:*\nsystolic (mmHg): \u2265120, \u2265130,", "page": 56, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "pressure thresholds:*\nsystolic (mmHg): \u2265120, \u2265130, \u2265140, \u2265150\ndiastolic (mmHg): \u226580, \u226590\nC\nPlacebo or systolic or diastolic blood pressure threshold that is higher than intervention \nthresholds\nO\nDeath (all-cause mortality), cardiovascular death (death from MI, sudden cardiac death or \nstroke), stroke, myocardial infarction, end-stage renal disease, cognitive impairment/dementia, \nheart failure events and adverse events\ns\nBased on different effect modifiers such as: estimated cardiovascular risk", "page": 56, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "t modifiers such as: estimated cardiovascular risk; pre-existing CAD, \nstroke, diabetes, age, sex, chronic kidney disease and race/ethnicity\n*\t Each BP threshold in the intervention category (I) will be compared with a higher threshold. For example, I \n(<140) will be compared to C (\u2265140)\n2\t\nIs any laboratory testing necessary prior to initiation or during titration of \npharmacological treatments\nP\nAdult men and women requiring antihypertensive treatment\nI\nInitiation or titration of antihypertens", "page": 56, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "eatment\nI\nInitiation or titration of antihypertensives without lab tests\nC\nInitiation or titration of antihypertensives with lab tests\nO\nDeath (all-cause mortality), cardiovascular death (death from MI, sudden cardiac death or \nstroke), stroke, myocardial infarction, end-stage renal disease and heart failure events, cognitive \nimpairment/decline\nBP control\nTime to control BP\nAdherence\nAdverse effects\nPatient satisfaction\ns\nIndividual drugs and doses\nPatients with no comorbidities\nBaseline blood", "page": 56, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "ses\nPatients with no comorbidities\nBaseline blood pressure\nType of lab test (ECG, blood, etc)\n44", "page": 56, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "3\t\nShould cardiovascular risk assessment be used to guide initiation of \nantihypertensive medications?\nP\nAdult men and women without pre-identified CVD\nI\nInitiating antihypertensives drug therapy based on a formal CVD risk estimation\nC\nInitiating antihypertensives drug therapy without formal CVD risk assessment (i.e. using only \nBP threshold)\nO\nDeath (all-cause mortality), cardiovascular death (death from MI, sudden cardiac death or \nstroke), stroke, myocardial infarction, end-stage renal diseas", "page": 57, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "oke, myocardial infarction, end-stage renal disease heart failure events, cognitive \nimpairment/dementia, and adverse events\nProportion of people prescribed with antihypertensives\nBP levels\ns\nBP levels\n4\t\nIn adults with hypertension requiring pharmacological treatment, which drugs \nshould be used as first-line agents?\u00a0\nP\nAdult men and women with hypertension requiring pharmacological treatment\nI\nBB, CCB, diuretics, ACEi, or ARB\nC\nPlacebo\nO\nDeath (all-cause mortality), cardiovascular death (death", "page": 57, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "(all-cause mortality), cardiovascular death (death from MI, sudden cardiac death or \nstroke), stroke, cognitive impairment/dementia, myocardial infarction, end-stage renal disease \nand heart failure events\nAdverse effects such as bradycardia, acute kidney injury, angioedema, asthma, electrolyte \nabnormalities or hypotension\nBP reduction and control (if data on CVD events are absent)\ns\nBased on different effect modifiers such as: estimated cardiovascular risk; pre-existing CAD, \nstroke, diabetes,", "page": 57, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "ascular risk; pre-existing CAD, \nstroke, diabetes, age, sex, chronic kidney disease and race/ethnicity, level of baseline BP\n5\t\nIn adults with hypertension requiring pharmacological treatment, which drugs \n(BB, CCB, diuretics, ACEi, or ARB vs BB, CCB, diuretics, ACEi, or ARB in head-to-\nhead studies) should be used as first-line agents?\u00a0\nP\nAdult men and women with HTN requiring pharmacological treatment\nI\nBB, CCB, diuretics, ACEi, or ARB\nC\nBB, CCB, diuretics, ACEi, or ARB (head-to-head studies)", "page": 57, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "B, diuretics, ACEi, or ARB (head-to-head studies)\nO\nDeath (all-cause mortality), cardiovascular death (death from MI, sudden cardiac death or \nstroke), stroke, cognitive impairment/dementia, myocardial infarction, end-stage renal disease \nand heart failure events\nAdverse effects such as bradycardia, acute kidney injury, angioedema, asthma, electrolyte \nabnormalities or hypotension\nBlood pressure reduction and control (if data on CVD events are absent)\ns\nBased on different effect modifiers such a", "page": 57, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "sent)\ns\nBased on different effect modifiers such as: estimated cardiovascular risk; pre-existing CAD, \nstroke, diabetes, age, sex, chronic kidney disease and race/ethnicity, level of baseline blood \npressure\nANNEXES\n45", "page": 57, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "GUIDELINE FOR THE PHARMACOLOGICAL TREATMENT OF HYPERTENSION IN ADULTS\n6\t\nIn adults with hypertension requiring pharmacological treatment, which drugs \n(monotherapy using BB, CCB, diuretics, ACEi or ARB vs combination therapy using \nBB, CCB, diuretics, ACEi or ARB) should be used as first-line agents?\u00a0\nP\nAdult men and women with HTN requiring pharmacological treatment\nI\nBB, CCB, diuretics, ACEi, or ARB\nC\nCombination therapy\nO\nDeath (all-cause mortality), cardiovascular death (death from MI, sudde", "page": 58, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "ality), cardiovascular death (death from MI, sudden cardiac death or \nstroke), stroke, cognitive impairment/dementia, myocardial infarction, end-stage renal disease \nand heart failure events\nAdverse effects such as bradycardia, acute kidney injury, angioedema, asthma, electrolyte \nabnormalities or hypotension\nBP reduction and control (if data on CVD events are absent)\ns\nBased on different effect modifiers such as: estimated cardiovascular risk; pre-existing CAD, \nstroke, diabetes, age, sex, chro", "page": 58, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "re-existing CAD, \nstroke, diabetes, age, sex, chronic kidney disease and race/ethnicity, level of baseline BP\n7\t\nIn adults with hypertension requiring pharmacological treatment, which \ncombination therapy of two or more drugs (BB, CCB, diuretics, ACEi, or ARB) vs \ndifferent combination therapy of two or more drugs (BB, CCB, diuretics, ACEi, or \nARB) should be used as first-line agents?\nP\nAdult men and women with HTN requiring pharmacological treatment\nI\nCombination therapy of two or more drugs (", "page": 58, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "tment\nI\nCombination therapy of two or more drugs (BB, CCB, diuretics, ACEi, or ARB)\nC\nDifferent combination therapy of two or more drugs (BB, CCB, diuretics, ACEi, or ARB)\nO\nDeath (all-cause mortality), cardiovascular death (death from MI, sudden cardiac death or \nstroke), stroke, cognitive impairment/dementia, myocardial infarction, end-stage renal disease \nand heart failure events\nAdverse effects such as bradycardia, acute kidney injury, angioedema, asthma, electrolyte \nabnormalities or hypote", "page": 58, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "dema, asthma, electrolyte \nabnormalities or hypotension\nBP reduction and control (if data on CVD events are absent)\ns\nBased on different effect modifiers such as: estimated cardiovascular risk; pre-existing CAD, \nstroke, diabetes, age, sex, chronic kidney disease and race/ethnicity, level of baseline BP\n46", "page": 58, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "8\t\nIn adults with hypertension requiring pharmacological intervention, is use of \na single-pill combination of antihypertensive drugs associated with improved \noutcomes?\nP\nAdult men and women with HTN requiring pharmacological intervention\nI\nSingle-pill combination (FDC) of antihypertensive drugs \u2013 five classes (any two or more from the \nfive)\nC\nPharmacological interventions that do not involve use of single-pill combinations\nO\nDeath (all-cause mortality), cardiovascular death (death from MI, su", "page": 59, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "ortality), cardiovascular death (death from MI, sudden cardiac death or \nstroke), stroke, myocardial infarction, end-stage renal disease and heart failure events.\nAdverse effects\nPatient satisfaction\nAdherence\nBP level/change\nNumber of antihypertensive medications\ns\nBased on different effect modifiers such as: estimated cardiovascular risk; pre-existing CAD, \nstroke, diabetes, age, sex, chronic kidney disease and race/ethnicity, level of baseline BP\n9\t\nWhat target blood pressure should pharmacol", "page": 59, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "BP\n9\t\nWhat target blood pressure should pharmacological treatment aim to achieve?\nP\nAdult men and women\nI\nSpecific systolic and diastolic blood pressure targets:\nsystolic (mmHg): <120, <130, <140, <150\ndiastolic (mmHg): <70, <80, <90\nC\nSystolic or diastolic blood pressure targets that are higher than the intervention targets\nO\nDeath (all-cause mortality), cardiovascular death (death from MI, sudden cardiac death or \nstroke), stroke, myocardial infarction, end-stage renal disease heart failure e", "page": 59, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "nfarction, end-stage renal disease heart failure events, cognitive \nimpairment/dementia, and adverse events\ns\nBased on different effect modifiers such as: estimated cardiovascular risk; pre-existing CAD, \nstroke, diabetes, age, sex, chronic kidney disease and race/ethnicity\n10\t In adults with hypertension given pharmacological treatment, when should blood \npressure be reassessed?\nP\nAdult men and women with HTN receiving a pharmacological intervention\nI\nSpecific interval\nC\nAlternative interval\nO", "page": 59, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "tion\nI\nSpecific interval\nC\nAlternative interval\nO\nDeath (all-cause mortality), cardiovascular death (death from MI, sudden cardiac death or \nstroke), stroke, myocardial infarction, end stage renal disease and heart failure events\nAdverse effects\nBP control\nAdherence\nPatient satisfaction\ns\nTitration phase vs controlled HTN follow up, level of initial BP, other conditions, remote \nmonitoring vs clinical visit\nANNEXES\n47", "page": 59, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "GUIDELINE FOR THE PHARMACOLOGICAL TREATMENT OF HYPERTENSION IN ADULTS\n11\t Can pharmacological management of hypertension be provided by nonphysician \ncare providers?\nP\nAdult men and women\nI\nPharmacological management by nonphysician care providers\nC\nPharmacological management by medically qualified practitioners (doctors)\nO\nDeath (all-cause mortality), cardiovascular death (death from MI, sudden cardiac death or \nstroke), stroke, myocardial infarction, end-stage renal disease and heart failure e", "page": 60, "source": "hypertension.pdf", "doc_title": "hypertension"}, {"text": "ction, end-stage renal disease and heart failure events\nBP control\nAdherence\nSerious adverse effects\nPatient satisfaction\ns\nInitiation vs follow up\nSelf-care vs CHW vs nurse vs pharmacist vs physician assistant vs in or out of clinic\nLevels of care\nRural vs urban settings\nEthnicity\n48", "page": 60, "source": "hypertension.pdf", "doc_title": "hypertension"}]