dengue case classification review 2014

Am. J. Trop. Med. Hyg., 91(3), 2014, pp. 621–634doi:10.4269/ajtmh.13-0676Copyright © 2014 by The American Society of Tropical Medicine and Hygiene

Comparing the Usefulness of the 1997 and 2009 WHO Dengue Case Classification:

A Systematic Literature Review

Olaf Horstick,* Thomas Jaenisch, Eric Martinez, Axel Kroeger, Lucy Lum Chai See, Jeremy Farrar, and Silvia Runge Ranzinger

Institute of Public Health, University of Heidelberg, Heidelberg, Germany; Department of Infectious Diseases, Section Clinical Tropical Medicine,Heidelberg University Hospital, Heidelberg, Germany; Instituto de Medicina Tropical, Pedro Kuori, La Habana, Cuba; Liverpool Schoolof Tropical Medicine, Liverpool, United Kingdom; Special Programme for Research and Training in Tropical Diseases, World Health

Organization, Geneva, Switzerland; Department of Paediatrics, Faculty of Medicine, University of Malaya, Kuala Lumpur,Malaysia; Wellcome Trust, Oxford, United Kingdom; Consultant in Public Health, Ludwigsburg, Germany

Abstract. The 1997 and 2009 WHO dengue case classifications were compared in a systematic review with 12 eligiblestudies (4 prospective). Ten expert opinion articles were used for discussion. For the 2009 WHO classification studiesshow: when determining severe dengue sensitivity ranges between 59–98% (88%/98%: prospective studies), specificitybetween 41–99% (99%: prospective study) - comparing the 1997 WHO classification: sensitivity 24.8–89.9% (24.8%/74%: prospective studies), specificity: 25%/100% (100%: prospective study). The application of the 2009 WHO classifi-cation is easy, however for (non-severe) dengue there may be a risk of monitoring increased case numbers. Warning signsvalidation studies are needed. For epidemiological/pathogenesis research use of the 2009 WHO classification, opinionpapers show that ease of application, increased sensitivity (severe dengue) and international comparability are advanta-geous; 3 severe dengue criteria (severe plasma leakage, severe bleeding, severe organ manifestation) are useful researchendpoints. The 2009 WHO classification has clear advantages for clinical use, use in epidemiology is promising andresearch use may at least not be a disadvantage.

INTRODUCTION

The World Health Organization (WHO), with its Spe-cial Program for Research and Training in Tropical Diseases(WHO/TDR), issued new dengue guidelines in 2009,1 includ-ing the 2009 WHO dengue case classification: dengue andsevere dengue (D/SD). Warning signs (WS) have been estab-lished for triage to help clinicians with symptomatic casesin need of closer surveillance and/or hospitalization (denguewith warning signs [D+WS]).Historically, the 1997 WHO dengue case classification

(dengue fever (DF), dengue hemorrhagic fever (DHF) anddengue shock syndrome (DSS) was developed in 1975 byexpert consensus based on studies on Thai children in the1950s and £60s, with modifications in 1986 and 1997.2 In thelast modification in 1997, four grades of DHF were defined(DHF1, −2, −3, and −4), with DHF1 and −2 being DHF andDHF3 and −4 being DSS.3

In this work, we will refer to the dengue case classifica-tion recommended by the WHO in 2009 as the D/SD clas-sification and the WHO 1997 classification as the DF/DHF/DSS classification.The reasons for developing D/SD were the shortcomings

of DF/DHF/DSS, which were established in many studiesand furthermore, summarized in a systematic review.2

DF/DHF/DSS (1) is poorly related to disease severity,(2) misdirects clinicians identifying severe disease, (3) isdifficult to use (tests required are often not available/difficultto apply), (4) does not help for triage in outbreaks, and(5) leads to different reporting globally as a result of thedifficulties in using the classification for reporting clinicians.The main emphasis of D/SD is, therefore, to help clini-

cians to identify and manage cases of severe dengue timely.

It helps to save resources and contributes to a reduction ofdengue mortality.Based on the largest prospective multicenter study, the

Dengue and Control (DENCO) study,4 D/SD describes den-gue as it currently occurs globally, focusing on severe dengue,defined as plasma leakage (shock or fluid accumulation withrespiratory distress, which includes the former DSS), severebleeding, or severe organ manifestation. With the improveddescription of dengue cases, case reporting is facilitated.WS have been empirically validated to some extent in theDENCO study. A larger study is currently under way toevaluate and define the predictive value of WS in outpatients(for the need of hospitalization) and inpatients (for severedisease).5 Furthermore, D/SD is based on best available evi-dence (evidence grade 1/2)6 on each step of the developmentfrom basic to implementation research.7

A discussion evolved internationally on the usefulnessand applicability of D/SD compared with DF/DHF/DSS,and in a relatively short period of time, numerous studieshave been published by many independent research groups.The objective of this study is to provide a systematic litera-ture review of the studies published, comparing D/SD andDF/DHF/DSS to facilitate the discussion about the usefulnessof the different classification systems.

METHODS

Reporting items for systematic reviews and meta-analyses(PRISMA) Statement for systematic reviews and meta-analyses8 were followed. This study defines (1) case definitionas the description of clinical and laboratory parameters todefine a dengue case compared with other febrile illnessesand (2) case classification as the different stages of the spec-trum of dengue severity, either D, including D+WS, or SD.Eligibility criteria included (1) research on dengue case

classification and/or dengue case definition, (2) comparisonof D/SD and DF/DHF/DSS, (3) any comparative/analytical

*Address correspondence to Olaf Horstick, INF 365, Institute ofPublic Health, University of Heidelberg, 69120 Heidelberg, Germany.E-mail: [email protected]

621

USUARIO

Resaltado

study design, and (4) published after the publication of thenew WHO dengue guidelines.1

All languages were included; the search was conductedin English only. Studies looking only at one classificationwere excluded for failing to compare the different models.Also excluded were studies not performed in dengue-endemiccountries. Studies without a defined methodology, includingexpert opinion and conference proceedings, were collectedand used for the discussion.The literature search and analysis were developed and

carried out through July 15, 2013 with two data extractors.The search terms derived from two major categories were(1) dengue disease (dengue) combined with (2) classificationand/or definition.The search strategy was applied to the following data-

bases: US National Library of Medicine and the NationalInstitutes of Health Medical Database (PubMed), the LatinAmerican and Caribbean Health Sciences Database (Lilacs),Excerpta Medica Database (EMBASE), and the CochraneDatabase of Systematic Reviews (CDSR). The WHO librarydatabase (WHOLIS) and Google Scholar were searched forgrey literature. Relevant literature was screened for addi-tional articles in the reference sections.Because of the limited search options available to this

field of research, a very broad search strategy was used, usinga reduced number of combinations to increase the number ofinitial hits.All results were screened for duplicates. In the next

stage, results were screened based on the title and abstractonly, and the full texts of potentially relevant studies weresubsequently assessed. Relevant information was tabulatedin evidence tables.Study designs were divided into the following categories:

(1) prospective studies of dengue cases, (2) studies analyz-ing post-hoc existing prospectively collected databases ofdengue cases, (3) studies reviewing retrospectively existingmedical charts of dengue cases, and (4) acceptability studies(mostly of qualitative design).No studies were excluded in the analysis for quality rea-

sons if the eligibility criteria were met, but limitations andpossible biases are reported in the results section. The analy-sis followed the categories according to the use of the caseclassification: (1) clinical use (establishing severe dengue dis-ease using WS for identifying severe dengue disease, detect-ing dengue, usefulness for triage, usefulness for outbreaks,and ease of application by clinicians), (2) use in surveillancedetecting dengue cases and detecting dengue outbreaks aswell as reporting of the different levels of severity of denguedisease (D/SD), and (3) use in research.

RESULTS

In total, 782 studies were identified during the electronicsearch that were potentially relevant to the research ques-tion, including duplicates. After the screening of titles andabstracts, 25 studies remained eligible.10–34 Eligible studiesare tabulated in Table 1. Ten studies22–31 were relevant tothe research question based purely on expert opinion, with-out stating a particular methodology as to how the resultswere derived. These studies were excluded from the analy-sis but reflected in the discussion for the purpose of high-lighting the different opinions. Three additional studies were

excluded after full assessment of the text, because they onlyassessed DF/DHF/DSS without comparison with D/SD32,33

or dealt with a particular subgroup of cases not representa-tive of dengue-endemic countries (dengue in travellers34).Of the remaining 12 studies,10–21 11 studies were from

published databases, and one study was from grey literature.No other studies were identified from the reference lists.Figure 1 summarizes the process of selection in a flowchart.All studies were published after 2009—the date set for

initiating the search. Most of the studies included (prospec-tive, post-hoc analysis of existing datasets or review ofexisting medical charts, and any qualitative design) wereperformed in Asia, with the exception of three studies: onestudy that included 18 study sites worldwide,10 one studyfrom Nicaragua,16 and one study from Peru.18 Studies10–13

are prospective studies published between 2010 and 2013.All other studies used datasets either prospectively devel-oped and compared post-hoc with the use of D/SD andDF/DHF/DSS or retrospectively derived from case notesof dengue-positive cases developed over time and withouta strict study protocol. One study10 also included the accept-ability of the different dengue case classifications with quali-tative methods.Sample sizes of the studies10–21 were relatively small, rang-

ing from 50 to 300 cases (mostly less than 100 cases), with theexception of three studies10,17,20 with more than 1,000 caseseach. Most of the studies included adults and children; onlythree studies were confined to pediatric centers.12,16,21

All studies were performed in hospital settings of eithersecondary or tertiary level hospitals. The study in ref. 10—with 18 study sites—had the biggest scale in case numbersand the most comprehensive scope with all levels ofhealthcare delivery systems included in Asian as well asLatin American countries.Studies often addressed multiple questions; the following

results are presented according to the categories describedin the methods sections. In general, the prospectively col-lected studies are largely in favor of the use of D/SD in theclinical setting; the retrospective studies have similar results,apart from the study in ref. 15Clinical use. Which classification describes the clinical

picture of dengue cases better? The studies dealing with thisquestion all agree that D/SD classifies dengue as it occursclinically. The study in ref. 10 in 18 countries with the biggestsample overall concludes that “13.7% of cases could notbe classified according to DF/DHF/DSS (missing data e.g.haematocrit, platelet counts, and tourniquet tests on > 50%of charts), compared to 1.6% for D/SD. 32.1% of severedengue cases could not be classified in the DF/DHF/DSSsystem.” The study in ref. 17, also in a large sample, recon-firms that “DF/DHF/DSS and D/SD were discordant indefining severe disease (p: 0.001).” D/SD describes severedisease, whereas DF/DHF/DSS describes severe disease lesswell. Similarly, findings in the study in ref. 19 are “a crosstabulation [that] showed DF cases were distributed in allof the severity groups stratified by D/D+WS/SD (53.8%Group D/45.4% Group D+WS/0.8% Group SD). Of theDHF cases, 23 (79%) were categorized as Group D+WS,and six (20.7%) as Group SD.”When looking at quality of studies, the studies in refs. 10,

17, and 19 of this systematic literature review provide proba-bly the best available quantitative evidence for this question.

622 HORSTICK AND OTHERS

Tabl

e1

Includedandexcludedstudies

Ref.

Authors

Year

Studytype

Focus

Large/

small*

Prospective/

retrospective

Country

Main

research

question

Methods

Results

Conclusion

Prospective

studies(follow-upofden

guecases)

10

Barniolan

dothers

2011

Mixed

methods,

threearms:

(1)quan

titative

(prospective

and

retrospective

chartreview

s),

(2)qualitative

(healthpersonnel

questionnaire),

and(3)focus

groups

Usefulnessan

dap

plicability

ofthenew

den

guecase

classification

Large

Prospective,

some

retrospective

data

Global:

18countries

Comparisonof

D/SD

and

DF/D

H/D

SS:

(1)clinical

applicability;

(2)triage

and

man

agem

ent

usefulness;

(3)user-

friendliness

andacceptance

(1)Prospective/

retrospective

med

ical

chartreview

s;(2)Self-ap

plied

questionnaires;

(3)focusgroups

13.7%

ofcasescould

notbeclassified

according

toDF/D

HF/D

SS(m

issingdata;e.g.,

hem

atocrit,p

lateletcounts,andtourniquet

testson>50%

ofcharts)compared

with

1.6%

forD/SD.W

SforSD

(necessary

for

theD+WScatego

ry)weredocumen

tedin

alargeproportion.T

herevisedclassification

also

provedto

bemore

sensitive

fortimely

recogn

itionofSD.32.1%

ofSD

casescould

notbeclassified

intheDF/D

HF/D

SS

system

.D/SD

was

easily

applicable

inclinical

practice,also

seen

tobeusefulfor

triage

andcase

man

agem

entbymed

ical

staffmore

freq

uen

tlythan

theDF/D

HF/D

SS

classification.C

oncernsin

questionnairesan

dfocusgroupsincluded

(1)hospitalization

ratesmightincrease

iftheWSarenot

precisely

defined

andwarrantsad

ditional

studies,(2)costim

plicationsifmore

patients

arebeingad

mitted,and(3)trainingneeds,

dissemination,andconcise

clinical

protocols.

Therevisedden

gue

classificationhas

ahighpotential

forfacilitating

den

guecase

man

agem

ent

andsurveillan

ce,b

eing

more

sensitive,especially

forsevere

disease,m

ore

accepted,anduserfriendly.

11

Basukian

dothers

2010

Prospective

study

ofden

guecases

SD

Medium

Prospective

Indonesia

Comparisonof

D/SD

and

DF/D

H/D

SS

Quan

titative

analysisof

prospectively

followed

up

den

guecases,

withclinical

andlaboratory

param

eters;

sensitivity

and

specificitytesting

Of145cases,usinganon-severitydefinition,

122cases(84.1%

)wereclassified

asnon-severe,ofwhichusingDF/D

HF/D

SS,

70(48.3%

)wereclassified

asDF,39(26.9%

)wereclassified

asDHFgrad

eI,13

(95)

were

classified

asDHFgrad

eII.23(15.95)were

classified

assevere,o

fwhich16

(11%

)wereclassified

asDHFgrad

eIIIan

d7(4.8%)wereclassified

asDHFgrad

eIV

.Withclinical

interven

tionsincluded

,eigh

tcases(6.6%)originally

classified

ashavingnon-SD

infectionwere

reclassified

ashavingsevere

infection

(sen

sitivity

=74%,specificity=100%

,likelihoodratio(−)=0.26).UsingD/SD,

117cases(80.7%

)wereclassified

asnon-severe,ofwhich79

(54.5%

)were

classified

asD–WS,38(26.2%

)were

classified

asD+WS,and28

(19.3%

)were

classified

asSD.U

singclinical

interven

tion,

fourcases(3.4%)that

wereoriginally

non-severewerereclassified

asSD

(sen

sitivity

=88%,specificity=99%,

likelihoodratio(+)=98.88,likelihood

ratio(−)=0.13).Binarylogisticregression:

SD

was

betterdetectingSD

(P=0.000,

Wald=22.446)than

DF/D

HF/D

SS

(P=0.175,Wald=6.339).

SD

may

bebetterat

detecting

SD

infectioncases

compared

with

DF/D

HF/D

SS.A

dditional

research

isneeded

with

larger

numbersofcases

inmultiple

centersusing

therevisedclinical

man

agem

entgu

idelines.

12

Jayaratne

andothers

2012

Prospective

study

ofden

guecases

WS

Medium

Prospective

SriLanka

(1)Usefulnessof

WSpredicting

SD;(2)

define

other

simple

laboratory

param

eters

usefulin

predictingSD

Quan

titative

analysisof

prospectively

collectedden

gue

caseswith

clinical

and

laboratory

param

eters.

In184casesin

twotertiary

centers,five

ormore

WSaresign

ifican

tly(P

=0.02)

associated

withthedevelopmen

tof

SD

(oddsratio=5.14,95%

confiden

ceinterval

=1.312–20.16).A

STlevelswere

sign

ifican

tlyhigher

(P=0.0001)combined

withab

dominalpain(m

ean=243.5,

SD

±200.7)

compared

withnon-abdominal

pain(m

ean=148.5,SD

±218.6).H

ighAST

levelswerealso

sign

ifican

tlyassociated

(P<0.0001)withSD

(oddsratio=27.26,

95%

confiden

ceinterval=1.632–455.2).

Lym

phocyte

counts<1,500cells/mm

3were

sign

ifican

tly(P

=0.005)

associated

withSD

Thepresence

offive

ormore

WSseem

sto

beapredictor

ofSD.L

ymphocyte

counts

<1,500cells/m

m3,platelet

counts<20,000/m

m3,and

raised

ASTlevelswere

associated

withSD

and

could

beusedto

help

identify

patientswhoare

likelyto

developSD.

(continued)

COMPARING THE 1997 AND 2009 WHO DENGUE CASE CLASSIFICATIONS 623

TABLE1

Continued

Ref.

Authors

Year

Studytype

Focus

Large/

small*

Prospective/

retrospective

Country

Main

research

question

Methods

Results

Conclusion

(oddsratio=3.367,95%

confiden

ceinterval

=1.396–8.123).P

latelet

counts<20,000cells/mm

3wereagain

sign

ifican

tlyassociated

(P<0.001)

withSD

(oddsratio=1.632–455.2,

95%

confiden


13

Prasadan

dothers

2013

Prospective

study

ofden

guecases

SD

Small

Prospective

India

Toassesstheaccuracy

andap

plicabilityof

therevisedWHO

classification(2009)

ofden

guein

children

seen

atatertiary

healthcare

facility

inIndia

Quan

titative

analysisof

prospectively

collectedden

gue

caseswith

clinical

and

laboratory

param

eters;

sensitivity

and

specificitytesting

56patientstested

positive

forden

gue;

5patients(8.9%)received

level1

treatm

ent,10

patients(17.8%

)received

level2,an

d41

patients(73.2%

)received

level3.42

(75%

)patientswereclassified

asDF,and13

patients(23.2%

)were

classified

asDHF/D

SS;o

nepatientwas

unclassifiab

le.1

patient(1.7%)was

classified

asD,9

patients(16%

)wereclassified

asD+WS,and46

patients(82.1%

)were

classified

asSD.M

anyofthesevere

man

ifestations(encephalopathy,shock,

mucosalbleed

,plateletcount<20,000,

respiratory

distress,liveren

zymes

>1,000U/L)wereseen

incasesclassified

asDF,w

hereasthesecasesweremostly

classified

asSD.S

ensitivity

was

24.8%

for

DF/D

HF/D

SSan

d98%

forSD.

SD

has

very

highsensitivity

for

iden

tifyingSD

andiseasy

toap

ply.

Analysisin

existingdataset

(prospectively

collectedden

guecaseswithpost-hocan

alysisorretrospective

analysisofexistingmed

ical

charts)

14

Chaterjian

dothers

2011

Post-hocan

alysis

usingan

existing

prospectively

collecteddataset

Early

den

gue

detection

Medium

Analysisusing

anexisting

prospectively

collected

dataset

Singapore

(1)Sen

sitivity/specificity

ofNS1stripwith

DF/D

HF/D

SSan

dD/SD

fordiagn

osis

ofacute

den

gue;

(2)sensitivity

ofthe

testsin

primary

compared

with

secondaryden

gue,

virusserotype,an

dclinical

characteristics

observed

inthe

earlystages

of

den

gueillness

Retrospective

quan

titative

analysisof

laboratory

andclinical

param

etersin

existingdataset;

sensitivity

and

specificitytesting

Of354casesdiagn

oseddefinitelyas

154den

gue

and200OFIcases,DF/D

HF/D

SScriteria

correctlydiagn

osed147(95.4%

)den

gue

casesan

dlabeled

128(64%

)as

den

gue

(sen

sitivity

of95.4%

andspecificityof

36.0%).D/SD

detected123(79.9%

)of

den

guecasesan

d86

(43.0%

)ofOFI

cases(sen

sitivity

of79.9%

andspecificity

of57.0%).TheNS1striphad

asensitivity

andspecificityof77.3%

and100%

,respectively,at15

minutesan

d80.5%

and100%

,respectively,at30

minutes.

Inconclusion,the1997

WHO

den

guecase

definitioncan

beusefulin

rulingout

den

gue,whereasthe

den

gueNS1Agstripcanbe

usedas

abed

sidediagn

ostic

testto

supportadiagn

osis

ofacute

den

gue,although

cautionisad

visedin

the

interpretationofthistestin

den

guehyp

eren

dem

icareas.

15

Kalayan

arooj

andothers

2011

Retrospective

applicationof

D/SD

onexisting

med

ical

charts

Case

management

Medium

Retrospective

analysis

usingexisting

med

ical

charts

Thailand

(1)Comparing

DF/D

HF/D

SSan

dD/SD

forclinical

man

agem

ent;

(2)assessing

fourcriteria

of

theDHFcase

definitionfor

possible

modification

Retrospective

quan

titative

analysisof

laboratory

andclinical

param

eters

inexisting

med

ical

charts;

sensitivity

and

specificity

testing

274confirm

edden

guepatientsan

d24

non-den

guefebrile

illnesses(N

D):

180DF(65.7%

),53

DHFgrad

eI(19.3%

),19

DHFgrad

eII(6.9%),19

DHFgrad

eII

(6.9%),an

d3DHFgrad

eIV

(1.1%);

85D

(31%

),160DW

(58.4%

),an

d29

SD

(1.1%).Therew

ereeigh

tDSS

patientswhohad

AST>1,000U

and

onepatientwhopresentedwith

encephalopathynotclassifiab

leby

DF/D

HF/D

SS.O

nenon-den

guepatient

whopresentedwithgastrointestinal

bleed

ingwas

classified

asSD.A

tleast

oneoftheWSwas

foundin

50%

of

ND

cases,53.3%

ofDF,83%

ofDHF

grad

eI,88.2%

ofDHFgrad

eII,100%

ofDHFgrad

eIII,an

d100%

ofDHF

grad

eIV

.Vomitingan

dab

dominal

pain

werethetw

omostcommonWSSfoundin

both

ND

andden

guepatients.B

leed

ing

and/orpositive

tourniquet

testwere

foundin

69.7%

ofDHFpatients.

Hem

oconcentrationcould

detectplasm

aleak

agein

44.7%,andCXR

added

up

eviden

ceofplasm

aleak

ageto

86.3%.

DF/D

HF/D

SSisrecommen

ded

foruse,compared

with

D/SD,b

ecau

sethelatter

createsdouble

theworkload

andneedsconfirm

atory

tests.DF/D

HF/D

SSneeds

modification:p

lasm

aleak

ageas

themajor

criteria,tourniquet

test

positive

orbleed

ing

symptomsas

minorcriteria,

andad

dunusual

den

gue

ascatego

ry.

(continued)


TABLE1

Continued

Ref.

Authors

Year

Studytype

Focus

Large/

small*

Prospective/

retrospective

Country

Main

research

question

Methods

Results

Conclusion

Ultrasonograp

hywas

themostsensitive

techniqueto

addeviden

ceofplasm

aleak

age

upto

100%

.Platelets£100,000cells/mm

3

werefoundin

93.5%

ofDHFpatients.

Intensive

monitoringan

dcarefulmed

ical

and

intraven

ousfluid

man

agem

entwereneeded

for94

DHFpatientscompared

with

189D+WSan

dSD

patients.

16

Narvaez

and

others

2011

Post-hocan

alysis

usingan

existing

prospectively

collecteddataset;

interrater

agreem

ent

SD;ap

plicability

Small

Retrospective

analysisof

anexisting

prospectively

collected

dataset

Nicaragua

Evaluating

DF/D

HF/D

SS

andD/SD

againstclinical

interven

tion

levelsfor

diagn

osing

severity

(data

from

5years

[2005–2010]of

ahospital-based

studyofped

iatric

den

gue)

Retrospective

quan

titative

analysisof

laboratory

andclinical

param

eters

inexisting

dataset;

sensitivity

and

specificity

analysisan

dinterrater

agreem

ent

when

applied

bydifferent

clinicians

Sen

sitivity

andspecificityofDF/D

HF/D

SSfor

thedetectionofsevere

casesofden

guewas

39.0%

and75.5%,respectively;sen

sitivity

andspecificityofD/SD

was

92.1%

and

78.5%,respectively.E

valuationof

physicians’clinical

diagn

osisresulted

inmoderateagreem

ent(k

=0.46,P

=0.001)

withthetrad

itionalclassificationand

substantialagreem

ent(k

=0.62,P

=0.001)

withtherevisedclassification.

D/SD

ismostusefulforthe

physicianforthedetection

ofsevere

casesofden

gue,

butitsuse

inpathophysiologicaland

epidem

iologicalstudies

needsad

ditionalevaluation

infuture

research.

17

Gan

and

others

2013

Post-hocan

alysis

usingan

existing

prospective

dataset

of

confirm

edden

guecases

DescribingSD

and

use/application

intheclinical

setting

Large

Retrospective

analysisof

anexisting

prospectively

collected

dataset

Singapore

EvaluatingD/SD

andDF/D

HF/

DSSusing

laboratory-

confirm

edad

ult

den

guecasesin

twoep

idem

ics

inSingapore:

2004

(predominan

tly

den

gueserotype1)

and2007

(predominan

tly

den

gueserotype2)

Retrospective

quan

titative

analysisof

laboratory

andclinical

param

eters

inexisting

dataset;

sensitivity

andspecificity

analysis

1,278den

gueconfirm

edcases.DHFoccurred

in14.3%,D

SSoccurred

in2.7%

,andSD

occurred

in16.0%.D

F/D

HF/D

SSan

dD/SD

werediscordan

tin

definingsevere

disease

(P=0.001).F

iveDSSpatients(15%

)wereclassified

asnon-SD

withoutWS.O

fSD

patients,107

did

notfulfillDHFcriteria

(14.9%

had

self-resolvingisolatedelevated

aminotran

sferases,18.7%

had

gastrointestinal

bleed

ingwithouthem

odyn

amiccompromise,

and56.1%

had

plasm

aleak

agewithisolated

tachycardia).Comparingagainstrequirem

ent

forintensive

care,includingthesingledeath

inthisseries,allsixhad

SD;o

nly

fourhad

DHF,b

ecau

setw

olacked

bleed

ing

man

ifestationsbuthad

plasm

aleak

age.

Increasinglengthofhospitalizationwas

notedam

ongsevere

caseswithboth

classifications,butthetren

dwas

only

statisticallysign

ifican

tforD/SD.L

engthof

hospitalizationwas

sign

ifican

tlylongerfor

severe

plasm

aleak

agecompared

with

severe

bleed

ingororgan

impairm

ent.

Req

uirem

entforhospitalizationincreased

usingD/SD

from

17.0%

to51.3%.

D/SD

isclinically

useful.It

retainscriteria

forplasm

aleak

agean

dhem

odyn

amic

compromisefrom

DF/D

HF/D

SSan

drefined

definitionsofsevere

bleed

ingan

dorgan

impairm

ent.Findings

from

ourretrospective

studymay

belimited

bythestudy

site—atertiary

referral

centerin

ahyp

eren

dem

iccountry—

andshould

be

evaluated

inawider

range

ofgeograp

hicsettings.

18

Siles

and

others

2013

Retrospective

analysisusing

existingmed

ical

charts

SD

Small

Retrospective

Peru

Toevaluatethe

usefulnessof

DF/D

HF/D

SS

andD/SD

Retrospective

quan

titative

analysisof

laboratory

andclinical

param

eters

inexisting

med

ical

charts;

sensitivity

and

specificity

analysis

Sen

sitivity

ofDF/D

HF/D

SSan

dD/SD

incapturingpatientswithlife-threaten

ing

disease

was

0%an

d59%,respectively,

andspecificityofthetw

oclassifications

was

98%

and41%,respectively.

DF/D

HF/D

SSmay

save

healthcare

resources

with

itsmore

stringent

definitionofaDHFcase,

whichrequires

themost

intensive

hospital

interven

tion;u

seofD/SD

guidelines

inthisoutbreak

facilitatedtheearly

admissionofthose

patients

withlife-threaten

ing

den

guedisease

for

appropriateclinical

man

agem

ent. (c

ontinued)


TABLE1

Continued

Ref.

Authors

Year

Studytype

Focus

Large/

small*

Prospective/

retrospective

Country

Main

research

question

Methods

Results

Conclusion

19

Tsaian

dothers

2012

Retrospective

analysisusing

existingmed

ical

charts

SD

Medium

Retrospective

Taiwan

Wecompared

differencesin

clinical/lab

oratory

featuresbetween

patientsseparately

classified

asDF/D

HFan

din

group

D/D

+WS/SD

Retrospective

quan

titative

analysisof

laboratory

andclinical

param

eters

inexisting

med

ical

charts

148ad

ultpatients(119

DF/29DHF;

64D/77groupD+WS/7

groupSD)were

included

.Compared

withDF,significan

tly

youngerage,lower

hospitalizationrate,

andhigher

plateletcountwerefoundin

groupD.C

ompared

withDHF,h

igher

plateletcountwas

foundin

groupD+WS.

Six

ofsevenpatients(86%

)classified

asgroupSD

fulfilledthecriteriaofDHF.

Across-tab

ulationshowed

that

DFcases

weredistributedin

alloftheseverity

groups

stratified

byD/D

+WS/SD

(53.8%

group

D/45.4%

groupD+WS/0.8%

groupSD).

OftheDHFcases,23

(79%

)were

catego

rizedas

groupD+WS,and6(20.7%

)werecatego

rizedas

GroupSD.A

llpatients

inGroupD

fellinto

thecatego

ryDF.

D/SD

effectivein

iden

tifying

SD

cases.Heterogeneity

inseverity

suggeststhat

careful

severity

ofdiscrim

inationin

patientsclassified

ingroup

D+WSisneeded

.Ourdata

suggestthat

itissafe

totreat

patientsclassified

asgroup

Donan

outpatientbasis.

20

Theinan

dothers

2013

Post-hocan

alysis

inexisting

prospectively

collecteddataset

WS

Large

Retrospective

Singapore

Perform

ance

of

WSforpredicting

DHFan

dSD

inad

ultden

gue

Retrospective

quan

titative

analysisof

laboratory

andclinical

param

eters

inexisting

prospectively

collected

dataset;

sensitivity

and

specificity

analysisin

relation

toWS

Of1,507cases,DHFoccurred

in298(19.5%

)an

dSD

occurred

in248(16.5%

)cases.

Ofthesecases,WSoccurred

before

DHF

in124an

dbefore

SD

in65

atmed

ianof

2daysbefore

DHForSD.T

hreemost

commonWSwerelethargy,abdominal

pain/ten

derness,an

dmucosalbleed

ing.

NosingleWSaloneorcombined

had

sensitivity

of64%

inpredictingsevere

disease.S

pecificitywas

0.90%

forboth

DHFan

dSD

withpersisten

tvo

miting,

hep

atomegaly,hem

atocritrise

andrapid

plateletdrop,clinical

fluid

accumulation,

andan

ythreeoffourWS.A

nyoneof

sevenWShad

96%

sensitivity

butonly

18%

specificityforSD.

NoWSwas

highly

sensitive

inpredictingsubsequen

tDHF

orSD

inourconfirm

edad

ultden

guecohort.

Persisten

tvo

miting,

hep

atomegaly,hem

atocrit

rise,rap

idplateletdrop,and

clinical

fluid

accumulation

aswellas

anythreeorfour

WSwerehighly

specific

forDHForSD.

21

Van

deWeg

andothers

2012

Post-hocan

alysis

inexisting

prospectively

collecteddataset

Disease

severity

Small

Retrospective

Indonesia

Toevaluate

DF/D

HF/D

SS

andD/SD

againstdisease

severity

Retrospective

quan

titative

analysisof

laboratory

andclinical

param

eters

inexisting

prospectively

collected

dataset;

sensitivity

andspecificity

analysis

D/SD,69patients(39.9%

)D

and104patients

(60.1%

)SD.D

F/D

HF/D

SS:24patients

(13.9%

)DFan

d149patients(86.1%

)DHF/D

SS.S

D:64severe

plasm

aleak

age,

6severe

bleed

ing,18

plasm

aleak

agean

dbleed

ing,an

d16

severe

organ

impairm

ent.

D:38patients(55.1%

)had

received

ITU

treatm

entcompared

with13

patients

(54.2%

)classified

asDF.S

D91

patients

(87.5%

)had

received

intensive

treatm

ent

interven

tion,a

slightlyhigher

number

than

116patients(77.9%

)in

theDHF/D

SSgroup.

D/SD

specificity,70.5%;sen

sitivity,

70.5%.D

F/D

HS/D

SSspecificity,25%;

sensitivity,89.9%

Tak

entogether,w

econclude

that,inboth

clinical

and

research

settings,the

perform

ance

ofD/SD

isan

improvemen

tto

DF/D

HF/D

SS,although

more

validated

anddetailed

classificationcriteria

need

tobedefined

.

Excluded

expertopinionstudiesrelevantto

thesubjectan

dusedin

thediscussion

22

Had

inegoro

2012

Review

Comparing

DF/D

HF/D

SS

andD/SD

for

clinical

application

N/A

N/A

Indonesia

Notspecified

Notspecified

Although

therevisedschem

eismore

sensitive

tothediagn

osisofSD

andben

eficialto

triage

andcase

man

agem

ent,thereremain

issues

withitsap

plicability.Itisconsidered

byman

yto

betoobroad

,req

uiringmore

specificdefinitionofWS.

Quan

titative

research

into

the

predictive

valueofthese

WSonpatientoutcomes

andthecost-effectiveness

ofthenew

classification

system

isrequired

toascertainwhether

thenew

classificationsystem

requires

additional

modificationorwhether

elem

entsofboth

classificationsystem

scan

becombined

. (continued)


TABLE1

Continued

Ref.

Authors

Year

Studytype

Focus

Large/

small*

Prospective/

retrospective

Country

Main

research

question

Methods

Results

Conclusion

23

Halstead

2012

Review

Comparing

DF/D

HF/D

SS

andD/SD

for

clinical

application

andpathogenesis

N/A

N/A

N/A

Todescribethe

usefulnessof

the1997

and

2009

case

classification

inrelationto

underlying

pathogenesis

Nonespecified

TheWHO

2009

case

classificationisnotuseful

forclinical

work

andespeciallynotfor

pathogenesisresearch

butmaybeuseful

forreporting.

Thedevelopmen

tofarobust

case

classificationis

thepriority.

24

Halstead

2013

Review

Comparingthe

DF/D

HF/D

SS

andD/SD

for

clinical

application

andpathogenesis

N/A

N/A

N/A

Wediscussthe

impactthat

the

widespread

adoptionofthe

2009

WHO

case

definitions

may

haveon

thedevelopmen

tofresearch

hyp

otheses

or

theconduct

of

research

on

den

guediseases

Nonespecified

Much

ofthefram

ework

forunderstan

dingthe

etiology

ofden

guedisease,thephen

omen

on

ofan

tibody-dep

enden

ten

han

cemen

tof

infection,andconceptsofTcell

immunopathology

has

developed

outof

studiesontheden

guevascularpermeability

syndrome.Asillustratedbelow,ifthefuture

pathogenesisresearch

isbased

onclinical

responsesincluded

inSD,such

patientswill

exhibitan

amixture

ofden

guedisease

syndromes

and/orcomplicationsof

treatm

ent,such

as(1)thedistinct

syndromes

contained

within

theclinical

catego

rysevere

bleed

ingan

d(2)inclusion

ofclinicalen

dpointsthat

may

confuse

naturalwithiatrogenicevolutionofdisease.

Pathogenesisresearch

should

beconducted

asmuch

aspossible

oncarefullydefined

catego

ries

ofhuman

disease

response,w

hichrequires

splitting,notlumping.

25

Horstick

and

others

2012

Review

Eviden

cebase

N/A

N/A

N/A

Reviewingthe

developmen

tofD/SD

Review

Step1:Systematicliterature

review

highligh

ted

theshortcomings

oftheDF/D

HF/D

SS:

(1)difficultiesin

applyingthecriteria

for

DHF/D

SS;(2)

thetourniquet

testhas

alow

sensitivity

fordistingu

ishingbetweenDHF

andDF;and(3)mostDHFcriteria

had

alargevariab

ilityin

freq

uen

cyofoccurren

ce.

Step2:Anan

alysisofregional

andnational

den

guegu

idelines:n

eedto

re-evaluatean

dstan

dardizegu

idelines;actual

ones

showed

alargevariationofdefinitions,an

inconsisten

tap

plicationbymed

ical

staff,an

dalack

of

diagn

osticfacilities

necessary

fortheDHF

diagn

osisin

frontlineservices.S

tep3:

Aprospective

cohortstudyin

seven

countries,acleardistinctionbetweenSD

(defined

byplasm

aleak

agean

d/orsevere

hem

orrhagean

d/ororgan

failure)an

d(non-severe)

den

guecanbemad

e.Step4:

Threeregional

expertconsensusgroupsin

theAmericas

andAsiaconcluded

that

den

gueisonedisease

entity

withdifferent

clinical

presentationsan

doften

,unpredictable

clinical

evolution.S

tep5:

Global

expertconsensusmeetingat

WHO

inGen

eva,Switzerlan

d—theeviden

cecollectedin

step

s1–4was

review

ed,anda

revisedschem

ewas

developed

andaccepted,

distingu

ishingD/SD.S

tep6:In

18countries,

theusefulnessan

dap

plicabilityofD/SD

compared

withtheDF/D

HF/D

SSschem

eweretested

,showingclearresultsin

favo

rof

therevisedclassification(note

ref.1).S

tep7:

Studiesareunder

way

onthepredictive

valueofWSforSD.

Thean

alysishas

shownthat

D/SD

isbetterab

leto

stan

dardizeclinical

man

agem

ent,raise

awaren

essab

out

unnecessary

interven

tions,

match

patientcatego

ries

withspecifictreatm

ent

instructions,an

dmak

ethekey

messagesof

patientman

agem

ent

understan

dab

leforall

healthcare

staffdealingwith

den

guepatients.

Furthermore,theeviden

ce-

based

approachto

develop

prospectively

theden

gue

case

classificationcould

be

amodel

approachforother

disease

classifications.

26

Lin

andothers

2013

Review

SD

N/A

N/A

N/A

Tocompare

theliterature

available

on

den

guecase

classification

N/A

D/SD

has

severalad

vantages.First,b

yem

phasizingden

gueas

atriphasicillness

rather

than

asthreedistinct

illnesses,

physiciansarereminded

toobservetheir

patientsclosely

onaday-to-day

basisforthe

D/SD

provides

practical

guidan

cean

dshowsbetter

catego

rizationin

accordan

cewithdisease

severity.

Therefore,m

ore

prospective

(continued)


TABLE1

Continued

Ref.

Authors

Year

Studytype

Focus

Large/

small*

Prospective/

retrospective

Country

Main

research

question

Methods

Results

Conclusion

appearance

ofWSuntilthecritical

phase

has

passed.S

econd,D

/SD

highligh

tsthat

patientswithoutWSmay

developSD,w

hich

canbefulm

inan

tan

dunpredictable.D

/SD

provides

practicalgu

idan

ceonhowto

man

agepatientsmore

appropriatelywhen

laboratory

dataareunavailable

aswellas

for

monitoringseverity,sothat

very

severe

cases

that

donotfulfilltheoriginal

criteriafor

DHFarenotmissed.U

singD/SD,p

hysicians

could

upgrad

ethecase

evaluationaccording

toclinicalseverity

ofdisease

man

ifestations.

datab

ases

needto

be

established

based

onD/SD,

whichwillenablenotonlythe

nationwideepidem

iologic

surveillance

ofseverecases

inendemiccountriesbut

also,internationalcomparison

ofdatato

improve

patient

managem

ent.

27

Srikiatkhachorn

andothers

2011

Review;expert

opinion

Comparing

DF/D

HF/D

SS

andD/SD

N/A

N/A

Thailand

Toevaluate

DF/D

HF/D

SS

andD/SD

None

The2009

clinical

classificationrepresentsa

sign

ifican

tdep

arture

from

theprior

classification.Incontrastto

theprevious

classification,w

hichdefines

DHFas

aclinical

entity

withplasm

aleak

ageas

the

cardinal

feature

that

differentiates

itfrom

DF,the2009

classificationlistsseveralclinical

man

ifestationsas

qualifiersforSD.T

he

improvemen

tin

den

gue-associated

mortality

overthepastdecad

eshas

beenbased

onthe

understan

dingofthenaturalhistory

of

plasm

aleak

agein

DHF,w

hichoccurs

aroundthetimeofdefervescen

cean

dcoincides

withthenad

iroftheplateletcount.

Delayed

detectionan

dtreatm

entofplasm

aleak

ageisthemajorcause

oforgan

failure,

listed

assevere

man

ifestationsin

the2009

classification.B

ylistingsevere

organ

invo

lvem

entas

acriterionforseverity

separatefrom

plasm

aleak

age,therevised

classificationplacesem

phasisonisolated

organ

failure

asacommonan

dsign

ifican

tcause

ofden

gueseverity.O

nthebasisofthe

statistics

from

theoutpatientdep

artm

entat

QueenSirikitNational

Institute

forChild

Healthin

Ban

gkokin

2008,thenew

case

definitionwould

havequalifiedan

additional

39,000

casesas

probab

leden

gue,whereas

only1m

600suspectedden

guecaseswere

detectedusingapositive

tourniquet

test

resultan

dleukopen

iaas

screen

ingtools.T

he

revisedclassificationalso

posessign

ifican

tproblemsforden

gueresearch.B

ecau

sethe

revisedclassificationisdesigned

primarilyas

acase-m

anagem

enttool,lessem

phasisis

placedontheunderlyingpathophysiology.

Despiteitslimitations,the

DHFcase

classificationhas

provedto

beusefulfor

advancingim

portan

tobservationsonden

gue

disease

pathogenesis,such

astheim

portan

ceof

secondaryden

guevirus

infectionto

theplasm

aleak

agephen

omen

on,

andhas

beeninstrumen

tal

inthedevelopmen

tof

treatm

entregimen

sthat

havesavednumerouslives.

28

Akbar

and

others

2012

Exp

ertopinion/

letter

tothe

publisher

regardingref.18

Comparing

DF/D

HF/D

SS

andD/SD

N/A

N/A

N/A

D/SD

compared

withDF/D

HF/D

SS

N/A

Webelieve

therevisedcase

classificationwith

itssimplified

structure

willfacilitate

effective

triage

andpatientman

agem

entan

dalso

allowcollectionofim

provedcomparative

surveillan

cedata.

Effortsarealso

beingdirected

todevelopmen

toftigh

ter

definitionsofsevere

phen

otypes

forbasic

science

research.

29

Farraran

dothers

2013

Exp

ertopinion/

letter

tothe

publisher

regardingref.15

Comparing

DF/D

HF/D

SS

andD/SD

N/A

N/A

N/A

D/SD

compared

withDF/D

HF/D

SS

N/A

Themainobjectives

oftheclassificationschem

eareto

improve

case

man

agem

entbytimely

iden

tificationofsevere

orpotentiallysevere

casesan

den

sure

that

scarce

resources

are

directedto

those

patientsmostin

need.D

/SD

presentssign

ifican

tim

provemen

tsoverthe

DF/D

HF/D

SSsystem

intw

okey

areas:(1)it

reflectsdisease

severity

inreal

time,an

d(2)it

allowsiden

tificationofahigher

proportionof

clinically

severe

cases.Unfortunately,

however,w

emustalso

recogn

izethat

weare

Classificationschem

esneedto

reflectthecontemporary

epidem

iology

ofthedisease,

beab

leto

assessseverity

inrealtime,an

dbeglobally

harmonized

.DF/D

HF/D

SS

was

toocomplicatedto

use

inclinicalorpublic

healthsettings

butwas

not

sufficientlyprecise

for

detailedpathogenesis

(continued)


TABLE1

Continued

Ref.

Authors

Year

Studytype

Focus

Large/

small*

Prospective/

retrospective

Country

Main

research

question

Methods

Results

Conclusion

nonearerto

elucidatingthemechan

isms

responsible

forthemicrovascular

deran

gemen

tsthat

arethehallm

arkofSD

or

understan

dingtheim

munecorrelates

of

protectionthan

weweremore

than

40years

ago.A

nother

long-established

dogm

athat

may

havecontributedto

thislack

of

progressisthebeliefthat

DFan

dDHFare

twoseparatedisease

entities

withdistinct

clinical

characteristics.Carefulobservational

studiesnowsuggestthat

themajorclinical

man

ifestations(altered

vascularpermeability,

thrombocytopen

ia,coagulation

deran

gemen

ts,h

epaticdysfunction)show

considerab

leoverlap

betweenthe

twosyndromes

andindicatethat

den

gue

virusinfectiondisruptsanumber

of

differentphysiologicalsystem

sto

varying

degrees

inindividual

patients,influen

cedby

both

hostan

dviralfactors,w

iththerelative

prominen

ceoftheresultingab

norm

alities

determiningthefinal

clinical

phen

otype.

studies.D/SD

brings

clarity,

clinicalan

dep

idem

iological

use,andthepotentialfor

developmen

tofmore

precise

definitionsof

clinical

phen

otypefor

pathogenesisstudies.

30

Horstick

and

others

2013

Exp

ertopinion/

letter

tothe

publisher

regardingref.20

WScomparing

DF/D

HF/D

SS

andD/SD

N/A

N/A

N/A

WSin

D/SD

compared

with

DF/D

HF/D

SS

None

WShavebeenin

use

inclinical

practicefora

longtime,despitetheknowledge

that

their

sensitivities

andspecificitiesarefarfrom

perfect.W

Shavebeenusedbycliniciansas

anad

ditional

tool,an

dtheirpower

has

been

described

usingafram

ework

ofrisk

increase

inthose

patientswithaWSpresent

overthose

patientswithnoWSpresent.The

WScurren

tlyproposedarebroad

clinical

sign

sthat

canoccurin

man

ydiseases.Their

usefulnessin

den

guehas

mostly

relied

on

expertopinion,w

iththeexceptionofafew

studiesthat

havetriedto

provideem

pirical

eviden

cefortheirusefulness.Hen

ce,a

prospective

studydesignisofparam

ount

importan

ceto

providehigh-qualitydata.

Studiesab

outWSneedto

be

prospective

andshould

includeprimarycare

toad

dressthequestionofhow

WScanbeusedin

the

context

ofSD.

31

Wiwan

ikitan

dothers

2013

Exp

ertopinion/

letter

tothe

publisher

regardingref.13

Comparing

DF/D

HF/D

SS

andD/SD

N/A

N/A

N/A

D/SD

comparison

withDF/D

HF/D

SS

Exp

ertopinion

D/SD

isexactlyusefulforgroupingofthe

patientforad

ditional

man

agem

ent.

However,w

hether

theclassificationis

usefulforpredictingofseverity

and

outcomeisstillcontroversial.

D/SD

canbeap

plicable,w

hich

does

notmeanthe

classificationiseasy.T

here

areman

yparam

etersto

be

collected,w

hichmight

taketime.

Other

(excluded

afterfullap

plicationofallinclusionan

dexclusioncriteriaas

assessed

from

thetext)

32

Gupta

and

others

2010

Prospectively

collected

den

guecases

DF/D

HF/D

SS

Small

Prospective

India

Inthisprospective

studyofden

gue

infectionduring

anep

idem

icin

Indiain

2004,

weap

plied

the

WHO

classification

ofden

gueto

assess

itsusefulnessfor

ourpatients

145clinically

suspected

casesofden

gue

infectionofall

ages;d

engu

econfirm

ationby

IgM

ELISA

and

HItest,and

DF/D

HF/D

SS

wereap

plied

toclassify

Of50

serologicallypositive

casesofden

gue

enrolled

inthestudy,only3met

the

WHO

criteria

forDHF,and1met

the

criteria

forDSS;h

owever,21(42%

)caseshad

oneormore

bleed

ing

man

ifestations.

ByusingWHO

criteriaofDHF

onIndianpatients,all

severe

casesofden

gue

cannotbecorrectly

classified

.Anew

definition

ofDHFthatconsiders

geograp

hican

dage-related

variationsinlaboratory

and

clinicalparam

etersis

urgentlyrequired.

33

Srikiatkhachorn

andothers

2010

Prospectively

collected

datab

ase,

retrospective

dataan

alysis

DF/D

HF/D

SS

Large

Retrospective

analysisin

anexisting

prospectively

collected

dataset

Thailand

AssessingifDHF

criteria

caniden

tify

SD

cases,as

determined

bythe

requirem

entfor

fluid

replacemen

tan

dbloodtran

sfusion;

sensitivity

and

Sen

sitivity

and

specificity

analysisfor

case

definitions

andseveral

criteria

Ourstudyshowed

that

DHFiscorrelated

stronglywiththeneedforinterven

tion.

DHFconstituted68%

ofden

guecases

that

received

sign

ifican

tinterven

tion.

However,42%

ofDHFcasesdid

not

requireinterven

tion.Incontrast,15%

ofDFan

d12%

ofOFIcasesdid

require

sign

ifican

tinterven

tion.T

hisfinding

Thecurren

tclassification

(DF/D

HF/D

SS)system

seem

sto

besuitab

le.

(continued)


Identifying dengue (case definition). Only one study dealtwith the question of whether the case definitions for D aremore useful to detect dengue compared with DF.14 Theresults—retrospectively based on 164 dengue cases com-pared with 200 other febrile illnesses (OFIs)—show for DF(as defined by the DF/DHF/DSS classification) a sensitivityof 95.4% and a specificity of 36.0% and for D (as defined bythe D/SD classification) a sensitivity of 79.9% and specificityof 57.0%. The study acknowledges that D/SD was not primar-ily designed for detecting dengue. When using an NS1 test, thesensitivity and specificity for both dengue case classificationsimprove considerably (Table 1).Identifying severe disease (case classification). Several studies

looked at sensitivity and specificity of D/SD and DF/DHF/DSS for identifying severe dengue. Sensitivity for detection ofsevere disease has been calculated by five studies,11,13,16,18,21

with results in the range from 59% to 98% for SD (as definedby the D/SD classification). The prospective studies11,13 esti-mate sensitivity at 88% and 98%, respectively. Specificity isestimated between 41% and 99% (99% for the prospectivestudy presenting values11). Sensitivity and specificity forDHF (as defined by the DF/DHF/DSS classification) rangebetween 24.8% and 89.9% and between 25% and 100%,respectively (sensitivity of 24.8% and 74% for the prospec-tive studies and 100% specificity for the prospective studypresenting data) (Table 2).In summary, comparing DF/DHF/DSS with D/SD, it seems

that, in most studies, D/SD turned out to be better in termsof sensitivity and specificity for distinguishing D and SD,which is summarized in the study in ref. 10 (here derivedfrom qualitative data: “the revised classification also provedto be more sensitive for timely recognition of severe disease”).WS for SD disease. Several studies looked at the value

of WS as predictors of severe disease. The study in ref. 11suggests that having at least five WS may be a good pre-dictor of severe disease; in particular, lymphocyte counts< 1,500 cells/mm3, platelet counts < 20,000/mm3, and raisedAST levels were associated with SD. However, in the studyin ref. 20, the three most common WS were lethargy,abdominal pain/tenderness, and mucosal bleeding. Also, nosingle WS alone or combined had a sensitivity of more than64% in predicting severe disease.20 Specificity was 90% forboth DHF and SD with persistent vomiting, hepatomegaly,hematocrit rise, and rapid platelet drop.20

In practice, however, it seems that WS are significantevents that are well-documented in medical charts,10 butusing WS as compulsory hospitalization criteria may wellincrease workload.Usefulness for triage and in outbreaks. The study in ref. 10

finds—with focus groups and questionnaires among clini-cians in 18 countries—that D/SD “was easily applicable inclinical practice, also seen to be useful for triage and casemanagement by medical staff, more frequently than theDF/DHF/DSS classification.” The study in ref. 15 analysesmedical charts of 274 confirmed dengue cases. When usingDF/DHF/DSS, more intensive treatment (with careful moni-toring and intravenous rehydration) was needed in 94 casescompared with 189 cases when using D+WS and SD ascriteria. Similarly, the study in ref. 17 calculates the require-ment for hospitalization increasing from 17.0% to 51.3%using D/SD. This finding is in agreement with the findingsin the study in ref. 18: “DF/DHF/DSS may save health care

TABLE1

Continued

Ref.

Authors

Year

Studytype

Focus

Large/

small*

Prospective/

retrospective

Country

Main

research

question

Methods

Results

Conclusion

specificityan

alysisof

each

componen

tof

DF/D

HF/D

SS

showstheheterogeneity

inseverity

ineach

disease

catego

ry.Inthisstudy,10

(76%

)of

13den

guecaseswithdocumen

tednarrow

pulsepressure

wereclassified

asDHFby

thecase

definitions.Twoofthreepatients

withDFwithhyp

otensionhad

sign

ifican

them

orrhagean

drequired

bloodtran

sfusion.

Significan

tdiscordan

cebetweenthe

grad

ingofDHFcasesbytheexpertan

dstrict

WHO

criteria

was

also

noted.

34

Wietenan

dothers

2012

Prospectively

collected

den

guecases

Comparing

DF/D

HF/D

SS

andD/SD

innon-endem

icsetting

Small

Prospective

TheNetherlands

withglobal

travelers

Theaim

ofthisstudy

was

toassessthe

applicabilityan

dben

efitsofD/SD

inclinical

practicefor

returningtravelers

Specificityan

dsensitivity

and

assessingthe

usefulnessin

predictingthe

clinical

course

ofthedisease

DF/D

HF/D

SS,compared

withD/SD,h

ada

marginally

higher

sensitivity

fordiagn

osing

den

gue.D/SD

had

aslightlyhigher

specificityan

dwas

lessrigid.D

+WSwas

admittedmore

often

than

those

patients

whohad

noWS(relativeratio=8.09;

95%

confiden


Ethnicity,age,hyp

ertension,d

iabetes

mellitus,orallergieswerenotpredictive

oftheclinicalcourse

Forreturned

travelers,D/SD

did

notdifferin

sensitivity

andspecificityfrom

DF/D

HF/D

SSto

aclinically

relevantdegree.

Thegu

idelines

did

not

improve

iden

tificationof

severe

disease.

Thetable

showsincludedandexcludedstudiesaccordingto

thestudytype.Large,>500cases;medium,100–499cases;sm

all,<100cases.AST=aspartate

transaminase;NS1=nonstructuralprotein

1;CXR

=chestX

ray;N

/A=notapplicable;IT

U=intensive

therapyunit;IgM

=im

munoglobulinM;ELISA

=enzyme-linkedim

munosorbentassay;HI=hemagglutinationinhibition;OFI=otherfebrile

illnesses.


resources with its more stringent definition of a DHF caserequiring the most intensive hospital intervention.” How-ever, the same study points out that “the use of D/SDguidelines in this outbreak facilitated the early admissionof those with life threatening dengue disease for appropriateclinical management.”Ease of application by clinicians. Only two studies assessed

the ease of application by health personnel, with positiveresults overall for the D/SD classification: the study in ref. 10shows, with questionnaires and focus groups, that D/SD waseasily applicable in clinical practice more frequently thanthe DF/DHF/DSS classification; the former was also seen

to be useful for triage and case management by medicalstaff. The study in ref. 16 analyzed with interrater agree-ment methods how clinicians agreed with each other whenclassifying the same cases according to either D/SD orDF/DHF/DSS; the former had substantial agreement (k = 0.62,P = 0.001), and the latter had moderate agreement (k = 0.46,P = 0.001).Use in surveillance and research. No study examined the

use of D/SD compared with DF/DHF/DSS in the contextof dengue surveillance and/or reporting; the study in ref. 10argued that, with the improved description of cases andespecially, the improved sensitivity for severe cases, data

Figure 1. Flowchart of the systematic search for literature.

Table 2

Reported sensitivities and specificities for dengue severity

Ref. Authors Place Pro/Retro Sample size

D/SD (%) DF/DHF/DSS (%)

CommentsSensitivity Specificity Sensitivity Specificity

11 Basuki and others Indonesia Pro 145 88 99 74 100 Using a “clinical intervention tool”13 Prasad and others India Pro 56 98 NR 24.8 NR Comparing with “treatment levels”16 Narvaez and others Nicaragua Retro 544 92.1 78.5 39.0 75.5 Comparing with “clinical intervention levels”18 Siles and others Peru Retro 92 59 41 0 98 Comparing with “hospital level of care”21 Van de Weg

and othersIndonesia Retro 173 70.5 79.5 89.9 25 Comparing with “intensive

treatment intervention”

NR = not reported; Pro = prospective; Retro = retrospective.


collection for epidemiological returns should be improved.However, the study in ref. 16 concludes that the use inepidemiology needs to be evaluated.No study addressed whether D/SD has advantages or

disadvantages for research. The study in ref. 16 states thatits use in pathophysiological and epidemiological studies needsadditional evaluation.Because there were no studies identified that formally

evaluated D/SD compared with DF/DHF/DSS in these areas,we refer to the discussion section below, where expert opinions/viewpoints were also included.Additional results. Most studies conclude that additional

research needs to address unsolved questions, especially inlarger studies (locally adapted case definitions for diagnosingdengue in the absence of confirmatory laboratory testingand the predictive value of WS in outpatients and inpa-tients) and different settings.11,12

It has also been emphasized that training needs to beaddressed as well as the development of local clinical proto-cols for dengue.

DISCUSSION

Limitations. Because D/SD was only introduced in 2009,the number of studies available is surprising, probably under-lining the importance of this question. Nevertheless, thenumber of studies available for answering the study questionwas limited, and therefore, all available data in this study,including lower-quality studies and retrospective studies,had to be considered in this review. Only very few prospec-tive studies are available, and even fewer qualitative studieshave been reported. Regarding the quality of retrospectivestudies, it is often unclear if all data are available retrospec-tively to conduct such studies. Also, almost all studiesreviewed are on a secondary or tertiary level of care and notprimary care. Most studies are not in resource-poor settings.Furthermore, sample sizes are mostly small, and data fromAsian countries prevail.Publication bias is another concern, especially for the

expert opinion papers; therefore, they have been excludedfrom the analysis and are mentioned only in the discussion.Relative value of the two dengue case classifications. The

first question is which purpose does the classification serve:clinical care, surveillance, or research (see also ref. 29). Inthis section, we will consider these three main areas of appli-cation of the dengue case classification.For the clinical use of D/SD, the three prospective studies

dealing with this question confirm that D/SD has advan-tages in defining the severity of dengue cases.10,11,13 Theevidence is even stronger when considering sample size. Thestudy in ref. 10 is, by far, the biggest study in this context,conducted globally in 18 different dengue-affected coun-tries, and the study in ref. 11 is a medium-sized study. Thesensitivity and specificity analyses11,13,16,18,21 are equallyin favor of D/SD. However, this finding is no surprise,because the classification has been designed4 “to developa revised evidence-based classification that would betterreflect clinical severity.”The ability to distinguish D and SD—as it currently occurs

globally—is probably the biggest advantage of D/SD.Expert opinion underlines this finding. The studies in

refs. 26 and 29 argue—mainly with reference to the study

by Alexander and others4 and the study in ref. 10—thatD/SD offers a better categorization than the DF/DHF/DSS classification.In a letter responding to study,13 it has been queried

whether the classification is useful for predicting dengueseverity and also, if the application of the classification canbe considered to have an easy application.31

Clinical use of the classification also includes the use ofWS. It would be beneficial to have robust and validatedWS, but the level of evidence for most WS as establishedin D/SD is not very high, because large quantitative studiesare needed to establish the validity of single parametersand/or combinations of parameters in predicting the prog-ress to SD. This finding has been acknowledged by thetwo quantitative studies dealing with this question12,20 andthe expert opinions: responding to the study in ref. 20, ithas been mentioned that convincing studies about WSneed to be prospective and should include primary care.30

The WS, as defined in the D/SD framework, were consid-ered to require more specific definitions.22 Currently, largeglobal prospective studies are under way to help improvethe knowledge of the value of WS (International ResearchConsortium on Dengue Risk Assessment, Managementand Surveillance study (IDAMS) at http://ichgcp.net/clinical-trials-registry/NCT01550016 and Laboratory Diagnosis andPrognosis of Severe Dengue study at http://ichgcp.net/clinical-trials-registry/NCT01421732).The dengue case definition is important for diagnosing a

dengue case, especially when diagnosing without laboratoryconfirmation in resource-poor settings.14 The D/SD frame-work uses the same criteria for case definitions as definedby the DF/DHF/DSS framework (which is based on expertopinion), with some modifications also driven by expertopinion. However, it is well-known that using only clinicalcriteria for discriminating between different febrile illnessesis difficult or impossible. Similar to the WS, this questioncan only be addressed with large prospective global studies,which are under way (IDAMS study above).This finding leads to the question of whether a clinically

based dengue diagnosis and the application of WS can beuseful for triage. Some studies, based on qualitative argu-ments10 and expressing the viewpoints of clinicians, come toa positive answer; others refer to the fact that the ease ofapplication is also documented in studies.16 One retro-spective study argues that the caseload for hospitalizationincreases dramatically.15 However, the same study acknowl-edges that only 68% of cases with SD disease can be clas-sified with the DF/DHF/DSS framework. In other words,32% of cases are not classifiable and maybe missed, reflectingthe low sensitivity of DHF. This result has been summarizedin the study in ref. 18, which acknowledges that the work-load may potentially increase with the broad use of WS butthat cases with severe disease are correctly identified. Itseems that the application of the WS in the algorithm needsadjustment to the locally available resources, which was men-tioned in the WHO guidelines1: “depending on the clinicalmanifestations and other circumstances, patients may . . . bereferred for in-hospital management (Group B).” Whetherincreased admissions with early treatment may reduce severe/fatal illnesses needs to be analyzed as well.The expert opinion papers vary on this issue. One study22

supports the view that D/SD is beneficial for triage; another


study31 reports the excellent experience of using D/SD forgrouping of patients for additional management.It would be useful to see more studies using the algo-

rithms for treatment as suggested in the WHO guidelines1

and the Clinical Handbook on Dengue Management,9 withlocal adaptations in prospective studies—maybe in outbreaksituations—and use of qualitative methods to assess theusefulness of D/SD in real-life circumstances.No quantitative studies assessed the use of the D/SD versus

the DF/DHF/DSS classification in dengue surveillance andcase reporting. However, the difficulties in applying DF/DHF/DSS led to the development of multiple local adapta-tions and put global comparability at risk. Studies assessingthe use of D/SD in clinical settings argued that the improveddescription of dengue as it occurs globally, leading to morespecific categorizations according disease severity, shouldlead to improved reporting. Likewise, the opinion-basedpapers in this systematic review argue that D/SD23 “maybeuseful for surveillance and reporting” and provide the oppor-tunity of improved international comparison of data.26 How-ever, to confirm this answer, additional research is warranted.For the use of the D/SD classification as an outcome in

basic research or pathogenesis research, no quantitative datawere available.A viewpoint/opinion paper24 argues that “pathogenesis

research should be conducted as much as possible on care-fully defined categories of human disease response. Thisrequires splitting, not lumping.” This work was respondedto by a group of authors29 arguing that “DF/DHF/DSS wastoo complicated to use in clinical or public health settings,yet was not sufficiently precise for detailed pathogenesisstudies” and that “D/SD brings clarity, clinical and epide-miological utility, and the potential for development of moreprecise definitions of clinical phenotype for pathogenesisstudies.” Therefore, D/SD, with its three severity markers—severe plasma leakage, severe bleeding, and severe organmanifestation—can be further refined for basic research.Two other views were expressed: (1) quantitative studies

confirmed that the DF/DHF/DSS framework does not reflectlevels of severity10,17,19; and (2) critical evaluation of D/SD islimited to the use in basic research; however, this critical eval-uation is not based on specific studies, but is based on expertopinion only.23,24,27

Some studies suggest solutions—based on their analysis—to reclassify the dengue disease classifications (for example,introducing subgroups for dengue with organ failure). How-ever, it has to be underlined that these suggested solutionsare based on each individual study presenting individualsolutions15,17 and not the result of the highest available evi-dence for the particular study question, the latter being oneof the strengths of D/SD.25

In conclusion, this systematic review confirms—almost5 years after its introduction—that the D/SD classificationis able to detect disease severity with high sensitivity, thusassisting clinical management and potentially, contributing toreducing dengue mortality.The limitation of not having more appropriate studies avail-

able is also a result of this study, with the urgent call for studiesto be designed prospectively and include primary care.Diagnosis of dengue by clinical parameters only continues

to be a challenge. It is recommended to await the findingsof the ongoing large clinical studies for a possible adap-

tation of case definitions and WS. Furthermore, it is rec-ommended to study the performance of D/SD for triage,especially in outbreak situations. For surveillance and globalreporting, a unified classification system with accurate infor-mation on disease severity would be advantageous.For pathogenesis research, the D/SD classification may open

new opportunities, with a fresh look at underlying pathologynow that the spectrum of disease is better described.

Received November 21, 2013. Accepted for publication February 19,2014.

Published online June 23, 2014.

Financial support: No funds were received for this systematic review.T.J., A.K., and S.R.R. are partly funded by European Union GrantFP7-281803 IDAMS. JF is funded by the Wellcome Trust.

Authors’ addresses: Olaf Horstick, Institute of Public Health, Uni-versity of Heidelberg, Heidelberg, Germany, E-mail: [email protected]. Thomas Jaenisch, Department of Infectious Dis-eases, Section Clinical Tropical Medicine, University HospitalHeidelberg, Heidelberg, Germany, E-mail: [email protected]. Eric Martinez, Instituto de Medicina Tropical, PedroKuori, La Habana, Cuba, E-mail: [email protected]. Axel Kroeger,Community Medicine, Liverpool School of Tropical Medicine,Liverpool, United Kingdom, and Special Programme for Researchand Training in Tropical Diseases, World Health Organization,Geneva, Switzerland, E-mail: [email protected]. Lucy Lum ChaiSee, Department of Paediatrics, Faculty of Medicine, University ofMalaya, Kuala Lumpur, Malaysia, E-mail: [email protected] Farrar, Wellcome Trust, Oxford, United Kingdom, E-mail:[email protected]. Silvia Runge Ranzinger, Consultant, PublicHealth,Ludwigsburg,Germany,E-mail: [email protected].

This is an open-access article distributed under the terms of theCreative Commons Attribution License, which permits unrestricteduse, distribution, and reproduction in any medium, provided theoriginal author and source are credited.

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