Hiv Staging

WHO CASE DEFINITIONS
OF HIV FOR SURVEILLANCE

AND REVISED CLINICAL
STAGING AND IMMUNOLOGICAL
CLASSIFICATION
OF HIV-RELATED DISEASE
IN ADULTS AND CHILDREN
Strengthening health services to fght HIV/AIDS
HIV/AIDS Programme
WHO Library Cataloguing-in-Publication Data
WHO case defnitions of HIV for surveillance and revised clinical staging and immunological classifcation of HIV-related
disease in adults and children.
1.HIV infections - diagnosis. 2.HIV infections - classifcation. 3.Disease progression. 4.Epidemiologic surveillance -
standards. 5.Disease notifcation - standards. I.World Health Organization.
ISBN 978 92 4 159562 9 (NLM classifcation: WC 503.1)
World Health Organization 2007
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WHO CASE DEFINITIONS
OF HIV FOR SURVEILLANCE
AND REVISED CLINICAL
STAGING AND IMMUNOLOGICAL
CLASSIFICATION
OF HIV-RELATED DISEASE
IN ADULTS AND CHILDREN
3
Abbreviations 4
Introduction................................................................................................................................. 5
Background................................................................................................................................. 6
SurveillanceandcasereportingforHIV...................................................................................... 7
WHOcasedefnitionforHIVinfection.......................................................................................... 8
WHOcasedefnitionforadvancedHIV(infectionordisease)(includingAIDS)......................... 9
PrimaryHIVinfection................................................................................................................. 10
ClinicalandimmunologicalclassifcationforHIVandrelateddisease......................................11
Table1. WHOclinicalclassifcationofestablishedHIVinfection.......................................... 12
Table2. WHOimmunologicalclassifcationforestablishedHIVinfection............................. 15
Annex1. PresumptiveanddefnitivecriteriaforrecognizingHIV-related
clinicaleventsamongadults(15yearsorolder)andamongchildren
(youngerthan15years)withconfrmedHIVinfection.............................................. 19
Annex2. PresumptivediagnosisofsevereHIVdiseaseamongHIV-seropositive
HIV-exposedchildren............................................................................................... 39
References................................................................................................................................. 40
CONTENTS
4
WHO CASE DEFI NI TI ONS OF HI V FOR SURVEI LLANCE AND REVI SED CLI NI CAL STAGI NG AND
I MMUNOLOGI CAL CLASSI FI CATI ON OF HI V-RELATED DI SEASE I N ADULTS AND CHI LDREN
AbbREVIATIONS
ADS acquiredimmunodefciencysyndrome
ART antiretroviraltherapy
CD4+ T-lymphocytebearingCD4receptor
CDC UnitedStatesCentersforDiseaseControlandPrevention
DNA deoxyribonucleicacid
HV humanimmunodefciencyvirus
PMTCT preventionofmothertochildtransmission(ofHIV)
RNA ribonucleicacid
WHO WorldHealthOrganization
EA EnzymeImmunoassay
ELSA Enzyme-Linkedimmunosorbentassay
S/R Test SimpleorRapidHIVantibodytest
5
INTRODUCTION
With a view to facilitating the scaling up of access to antiretroviral therapy, and in line with a
public health approach
i
, this publication outlines recent revisions WHO has made to case
defnitionsforsurveillanceofHIVandtheclinicalandtheimmunologicalclassifcationforHIV-
relateddisease.HIVcasedefnitionsaredefnedandharmonizedwiththeclinicalstagingand
immunologicalclassifcationstofacilitateimprovedHIV-relatedsurveillance,tobettertrackthe
incidence, prevalence and treatment burden of HIV infection and to plan appropriate public
health responses. The revised clinical staging and immunological classifcation of HIV are
designed to assist in clinical management of HIV, especially where there is limited laboratory
capacity.Thefnalrevisionsoutlinedherearederivedfromaseriesofregionalconsultationswith
Member States in all WHO regions held throughout 2004 and 2005, comments from public
consultationandthedeliberationsofaglobalconsensusmeetingheldinApril2006.
In most countries, reporting of acquired immunodefciency syndrome (AIDS) cases has been
incompleteandchildrenarerarelyincluded.Further,timelyandappropriateuseofantiretroviral
therapydelaysandmaypreventthedevelopmentofAIDSaspreviouslydefned.Theadvances
inantiretroviraltherapy(ART)thereforemeanthatpublichealthsurveillanceofAIDSalonedoes
not provide reliable population-based information on the scale and magnitude of the HIV
epidemic. Data on adults and children diagnosed with HIV infection are more useful for
determiningpopulationsneedingpreventionandtreatmentservices.
SimplifedHIVcasedefnitionsareprovidedbasedonlaboratorycriteriacombinedwithclinical
orimmunologicalcriteria.TheclinicalstagingofHIV-relateddiseaseforadultsandchildrenand
thesimplifedimmunologicalclassifcationareharmonizedtoauniversalfour-stagesystemthat
includes simplifed standardized descriptors of clinical staging events. The revised HIV case
defnitionsandtheclinicalandimmunologicalclassifcationsystemproposedareintendedfor
conductingpublichealthsurveillanceandforuseinclinicalcareservices.WHOrecommends
thatnationalprogrammesreviewandstandardizetheirHIVandAIDScasereportingandcase
defnitionsinthelightoftheserevisions.
i Thepublichealthapproachtoantiretroviraltherapyisdefnedinthefollowingarticle:TheWHOpublic-healthapproachtoan-
tiretroviraltreatmentagainstHIVinresource-limitedsettings.C Gilks, S Crowley, R Ekpini, et al. Lancet(Vol.368,August2006,
505510).
6
In 1986, WHO developed a provisional clinical AIDS case defnition for adults and children
(Banguidefnition)[1]toreportAIDScasesinresource-constrainedsettings[2, 3].Thedefnition
was formalized in 1986 and modifed in 1989 (for adults and adolescents only) to include
serological HIV testing and then modifed again in 1994 to accommodate 1993 revisions to
European and United States Centers for Disease Control and Prevention defnitions [3-12].
European and United States Centers for Disease Control and Prevention defnitions include
specifccasedefnitionsforchildren.StudiesinAfricansettings[13-15]suggestthattheoriginal
WHOclinicalcasedefnitionsforAIDSinchildrenarenotverysensitiveorspecifc.AIDScase
reportinginmiddle-andlow-incomecountrieshasbeenincompleteandofvariableaccuracy,
which has hampered its utility. Underreporting and delays in notifcation are frequent and
exacerbated by weak heath information systems and the lack of diagnostic capacity. In high-
income countries, AIDS case reporting combined with active AIDS case-fnding has allowed
AIDS notifcation and AIDS specifc mortality to be monitored. However, the widespread
availability of successful antiretroviral therapy means that both new AIDS cases and AIDS
mortalityhavebeendecliningincountrieswithhighcoverageofantiretroviraltherapy.
bACkGROUND
7
Thescale-upofservicesforART,preventingmother-to-childtransmissionofHIV(PMTCT)and
HIVcounsellingandtestinghasledtoanincreaseinthenumbersofadultsandchildrenbeing
tested and diagnosed with HIV infection. Accurate data are needed on adults and children
diagnosedwithHIVinfectiontofacilitateestimationofthetreatmentandcareburden,toplanfor
effective prevention and care interventions and assess care interventions. WHO therefore
recommends that countries consider conducting reporting of newly diagnosed cases of HIV
infectioninadultsandchildren(Box1).Therequirementsfortheconfdentialityandsecurityof
HIVsurveillancedataarethesameasforAIDS-relatedreporting.Provider-initiatedreportingwill
be required to increase the completeness, timeliness and effciency of HIV case reporting.
Laboratory-initiated reporting alone will be insuffcient for reporting HIV, as other surveillance
informationfromthehealthcareproviderormedicalrecordswillberequired.
ForthepurposesofHIVcasedefnitionsforreportingandsurveillance,childrenaredefnedas
youngerthan15yearsofageandadultsas15yearsorolder
i
.
i ForthepurposesoftheUnitedNationsConventionontheRightsoftheChild,achildisahumanbeingyoungerthan18years,
unlessunderthelawapplicabletothechild,majorityisattainedearlier.TheUnitedNationsGeneralAssemblydefnesyouthas
people1524yearsold.AllUnitedNationsstatisticsonyoutharebasedonthisdefnition,andchildrenarethereforefrequently
assumedtobepeople14yearsoldandyounger.Aninfantisachildfrombirthuptoageoneyear.
SURVEILLANCE AND CASE REpORTING FOR HIV
WHO case definitiOn fOr HiV infectiOn
To facilitate the reporting of HIV infection, WHO recommends the following:
HIV cases diagnosed and not previously reported in each country should be reported according
to a standard national case defnition. A case of HIV infection is defned as an individual with HIV
infection irrespective of clinical stage (including severe or stage 4 clinical disease, also known
as AIDS) confrmed by laboratory criteria according to country defnitions and requirements.
Countries should develop and regularly review their testing algorithms for diagnostic and
surveillance purposes.
i
WHO provides a simplifed HIV case defnition designed for reporting
and surveillance (Box 1).
HIV infection is diagnosed based on laboratory criteria. Clinically diagnosing suspected or
probable HIV infection by diagnosing an AIDS-defning condition or HIV at any immunological
stage in an adult or child requires confrmation of HIV infection by the best age-appropriate test.
Further, as maternal HIV antibody transferred passively during pregnancy can persist for as long
as 18 months among children born to mothers living with HIV, positive HIV antibody test results
are diffcult to interpret in younger children, and alternative methods of diagnosis are
recommended.
Box 1. WHO case defnition for HIV infection
Adults and children 1 months or older
HIV infection is diagnosed based on:
positive HIV antibody testing (rapid or laboratory-based enzyme immunoassay). This is
confrmed by a second HIV antibody test (rapid or laboratory-based enzyme
immunoassay) relying on different antigens or of different operating characteristics;
and/or;
positive virological test for HIV or its components (HIV-RNA or HIV-DNA or ultrasensitive
HIV p24 antigen) confrmed by a second virological test obtained from a separate
determination.
Children younger than 1 months:
HIV infection is diagnosed based on:
positive virological test for HIV or its components (HIV-RNA or HIV-DNA or ultrasensitive
HIV p24 antigen) confrmed by a second virological test obtained from a separate
determination taken more than four weeks after birth
1
.
Positive HIV antibody testing is not recommended for defnitive or confrmatory
diagnosis of HIV infection in children until 18 months of age.
i Further technical information on algorithms for HIV testing by WHO can be found at http://www.who.int/diagnostics_laboratory/
evaluations/hiv/en/index.html.
WHO case definitiOn Of adVanced HiV

(infectiOn Or disease) (including aids) fOr repOrting:
Cases diagnosed with advanced HIV infection (including AIDS) not previously reported should be
reported according to a standard case defnition. Advanced HIV infection is diagnosed based on
clinical and/or immunological (CD4) criteria among people with confrmed HIV infection (Box 2).
Box 2. Criteria for diagnosis of advanced HIV (including AIDS
a
)
for reporting
Clinical criteria for diagnosis of advanced HIV in adults and children
with confrmed HIV infection:
presumptive or defnitive diagnosis of any stage 3 or stage 4 condition
b
.
and/or;
Immunological criteria for diagnosing advanced HIV in adults and
children fve years or older with confrmed HIV infection:
CD4 count less than 350 per mm
3
of blood in an HIV-infected adult or child.
and/or;
Immunological criteria for diagnosing advanced HIV in a child younger
than fve years of age with confrmed HIV infection:
%CD4+ <30 among those younger than 12 months;
%CD4+ <25 among those aged 1235 months;
%CD4+ <20 among those aged 3659 months.
a AIDS in adults and children is defned as; clinical diagnosis (presumptive or defnitive ) of any stage 4 condition (defned in Annex
1) with confrmed HIV infection: OR immunological diagnosis in adults and children with confrmed HIV infection and >5 years of
age; frst-ever documented CD4 count less than 200 per mm
3
or %CD4+ <15: OR among children with confrmed HIV infection
aged 1235 months frst ever documented %CD4 <20: OR among children with confrmed HIV infection and less than 12 months
of age frst ever documented %CD4 <25.
b Annex 1 provides criteria for presumptive or defnitive diagnosis of all conditions.
AIDS case reporting for surveillance is no longer required if HIV infection or advanced HIV
infection is reported.
10
ThereisnostandarddefnitionofprimaryHIVinfection.However,reportingprimaryHIVinfection,
where recognized and documented, is useful and should be encouraged. The United States
CentersforDiseaseControlandPrevention(CDC)areexpectedtodevelopacasedefnitionfor
reporting primary HIV infection. Primary HIV infection can be recognized in infants, children,
adolescents and adults; it can be asymptomatic or be associated with features of an acute
retroviral syndrome of variable severity [16-21]. Primary infection usually presents as an acute
febrileillness24weekspostexposure,oftenwithlymphadenopathy,pharyngitis,maculopapular
rash, orogenital ulcers and meningoencephalitis. Profound transient lymphopaenia (including
lowCD4)candevelop,andopportunisticinfectionsmayoccur,buttheseinfectionsshouldnot
be confused with clinical staging events developing in established HIV infection. Primary HIV
infectioncanbeidentifedbyrecentappearanceofHIVantibodyorbyidentifyingviralproducts
(HIV-RNAorHIV-DNAand/orultrasensitiveHIVp24antigen)withnegative(orweaklyreactive)
HIVantibody[16, 22, 23].
pRIMARy HIV INFECTION
11
Initially in 1990, a four-stage clinical staging system was developed for clinical purposes and
only for adults [24]. Subsequently in 2002, a three-stage system for children was proposed to
support rolling out ART [25]. This publication revises the 2003 WHO clinical staging of HIV-
relateddiseaseininfantsandchildren,whichisnowharmonizedwiththe1990classifcationof
diseaseforadultsandadolescents.Thisissimilartothefour-stageclinicalclassifcationofthe
UnitedStatesCDCrevisedin1994andoriginallyintendedforsurveillancepurposes[26].Both
the United States CDC and WHO clinical classifcations recognize primary HIV infection. It is
alsoproposedthattheappearanceofneworrecurrentclinicalstagingeventsorimmunodefciency
beusedtoassessindividualsoncetheyarereceivingART.
C|inica| assessment prior to treatment
Clinical staging is used once HIV infection has been confrmed (serological and/or virological
evidence of HIV infection). An additional presumptive clinical diagnosis of severe HIV disease
(equivalent to severe immunodefciency) among infants younger than 18 months is suggested
foruseinsituationsinwhichdefnitivevirologicaldiagnosisofHIVinfectionisnotreadilyavailable
(Annex2).
The clinical events used to categorize HIV disease among infants, children, adolescents or
adultslivingwithHIVaredividedintothoseforwhichapresumptiveclinicaldiagnosismaybe
made (where syndromes or conditions can be diagnosed clinically or with basic ancillary
investigations) and those requiring a defnitive diagnosis (generally conditions described
accordingtocausationrequiringmorecomplexorsophisticatedlaboratoryconfrmation).Table
1 provides the clinical stage in simplifed terms describing the spectrum of HIV related
symptomatology, asymptomatic, mild symptoms, advanced symptoms and severe symptoms.
Tables3and4summarizetheclinicalstagingevents,andAnnex1providesfurtherdetailsofthe
specifceventsandthecriteriaforrecognizingthem.
Theclinicalstageisusefulforassessmentatbaseline(frstdiagnosisofHIVinfection)orentry
into long-term HIV care and in the follow-up of patients in care and treatment programmes. It
shouldbeusedtoguidedecisionsonwhentostartco-trimoxazoleprophylaxisandotherHIV-
relatedinterventions,includingwhentostartantiretroviraltherapy.Theclinicalstageshavebeen
showntoberelatedtosurvival,prognosisandprogressionofclinicaldiseasewithoutantiretroviral
therapyinadultsandchildren [27-38].
i
i ThroughtheconsultationprocesswithWHOMemberStates,HIVexpertshavesuggestedthat,ifthreeormoreconditionsfrom
anyoneclinicalstagearepresentatthesametime,theclinicalstagemaybeconsideredtobehigher.Forexample,concurrent
presence of three or more stage 2 clinical events would suggest clinical stage 3. However, adopting this approach requires
furtherstudy.
CLINICAL AND IMMUNOLOGICAL CLASSIFICATION
OF HIV AND RELATED DISEASE
12
Tab|e 1. WHO c|inica| staging of estab|ished HV infection
HV-associated symptoms WHO c|inica| stage
Asymptomatic 1
Mildsymptoms 2
Advancedsymptoms 3
Severesymptoms 4
C|inica| assessment of peop|e receiving antiretrovira| therapy
Treatment with potent and effective antiretroviral therapy regimens can reverse and improve
clinicalstatusinkeepingwithimmunerecoveryandsuppressionofviralload[37, 39-41].Newor
recurrentclinicalstagingeventsoncepeoplearereceivingantiretroviraltherapyformorethan24
weeksmaybeusedtoguidedecision-making,particularlywhentheCD4countisnotavailable.
It is assumed that the clinical staging events remain signifcant among people receiving
antiretroviral therapy as they are among children and adults before the start of antiretroviral
therapy.Inthefrst24weeksofstartinganantiretroviraltherapyregimen,clinicaleventsappear
largely due to immune reconstitution [42-46] (or the toxicity of antiretroviral therapy); after 24
weeks,clinicaleventsusuallyrefectimmunedeterioration.However,themonitoringofdisease
progression and response to therapy using clinical staging events urgently needs to be
validated.
mmuno|ogica| assessment
ThepathogenesisofHIVinfectionislargelyattributabletothedecreaseinthenumberofTcells
(aspecifctypeoflymphocyte)thatbeartheCD4receptor(CD4+).Theimmunestatusofachild
or adult living with HIV can be assessed by measuring the absolute number (per mm
3
) or
percentageofCD4+cells,andthisisregardedasthestandardwaytoassessandcharacterize
theseverityofHIV-relatedimmunodefciency.ProgressivedepletionofCD4
+
Tcellsisassociated
with progression of HIV disease and an increased likelihood of opportunistic infections and
otherclinicaleventsassociatedwithHIV,includingwastinganddeath[47-52].
13
mmune status in chi|dren
TheabsoluteCD4cellcountandthe%CD4+inhealthyinfantswhoarenotinfectedwithHIVare
considerablyhigherthanthoseobservedinuninfectedadultsandslowlydeclinetoadultvalues
bytheageofaboutsixyears.Agemustthereforebetakenintoaccountasavariableinconsidering
absoluteCD4countsor%CD4+[50, 53-59].Amongchildrenyoungerthanfveyearsofage,the
absolute CD4 count tends to vary within an individual child more than the %CD4+. Currently,
therefore,themeasurementofthe%CD4+isthoughttobemorevaluableinyoungerchildren
i
.
Absolute CD4 counts (and less so %CD4+) fuctuate within an individual and depend on
intercurrentillness,physiologicalchangesortestvariability.Measuringthetrendovertwoorthree
repeated measurements is therefore more informative than an individual value. Not all the
equipment in use in resource-constrained settings can accurately estimate the %CD4+. The
dedicatedcytometersaredesignedtoexclusivelyperformabsoluteCD4measurementswithout
theneedforahaematologyanalyserandthereforedonotprovide%CD4+
ii
.
Anyclassifcationofimmunestatushastoconsiderage.The1994immunologicalclassifcation
of the United States CDC has previously been used [60]. WHO has proposed a modifed
immunological classifcation based on more recent analysis of the prognosis. Analysis of
prognosisfrom17studiesofchildrenincluding3941childrenlivingwithHIVfromUnitedStates
andEuropeansettingsprovideestimationsofCD4andage-relatedriskofprogressiontoAIDS
ordeath[50].A%CD4+of35isassociatedwitha15%riskofprogressiontoAIDSinthenext12
monthsamongchildrenagedthreemonthsandan11%riskamongthosesixmonthsold.The
revisedWHOclassifcationattemptstobetterrefectthisincreasedriskintheseyoungerchildren.
Based on reanalysis of the data, the thresholds for severe immunodefciency in children have
been revised [30]. For children in the WHO classifcation, age-related severe HIV-related
immunodefciency is defned as values at or below age-related CD4 thresholds below which
childrenhaveagreaterthan5%chanceofdiseaseprogressiontosevereclinicalevents(AIDS)
ordeathinthenext12months.Furtherresearchisurgentlyrequiredtoassesstheprognostic
signifcance and to ascertain normal and disease-associated CD4 levels among African and
Asian children [61]. Note that, among children younger than one year, the immunological
categoriesdonotrefectthesamelevelofriskatanygivenage;thus,achildsixmonthsoldhas
a higher risk of progression for any given CD4 count than a child 11 months old. However, to
facilitate the scaling up of access to antiretroviral therapy, WHO proposes this simplifed
harmonizedimmunologicalclassifcationsystemforadultsandchildren.Theimmuneparameters
andthereforeclassifcationimprovewithsuccessfulantiretroviraltherapy(Table2)[30, 62-67].
Immune parameters can be used to monitor the response to antiretroviral therapy, and it is
hopedthattheimmunologicalclassifcationwillfacilitatethis.
i Tocalculatethe%CD4+,usethefollowingformula:%CD4+=(absolutecountCD4(mm
3
)times100)/absolutetotallymphoctye
count(mm
3
).
ii WHOguidanceonCD4technologyisavailableat:http://www.who.int/diagnostics_laboratory/CD4_Technical_Advice_ENG.pdf.
14
mmune status in adu|ts
The normal absolute CD4 count in adolescents and adults ranges from 500 to 1500 cells per
mm
3
ofblood.Ingeneral,theCD4(%CD4+orabsolutecount)progressivelydecreasesasHIV
disease advances. As in children, individual counts may vary within an individual adult or
adolescentandassessingtheCD4countovertimeismoreuseful[68-73].TheCD4countusually
increases in response to effective combination antiretroviral therapy, although this may take
many months [74-78]. The proposed immunological classifcation outlines four bands of HIV-
related immunodefciency (Table 2): no signifcant immunodefciency, mild immunodefciency,
advanced immunodefciency and severe immunodefciency. The likelihood of disease
progression to AIDS or death without ART increases with increasing immunodefciency
(decreasingCD4)[79], opportunisticinfectionsandotherHIVrelatedconditionsareincreasingly
likely with CD4 counts below 200 per mm
3
[29, 80, 81]. Response to ART is affected by the
immunestageatwhichitisstarted,peoplecommencingARTwithadvancedimmunodefciency
(CD4>200350permm
3
)appeartohavebettervirologicaloutcomesthanthosewhocommence
withmoresevereimmunodefciency.AdultsstartingARTwithCD4<50permm
3
haveamuch
greaterriskofdeath[37, 40, 41, 76].AdultswhocommenceARTwithonlymildimmunodefciency
do not appear to obtain any additional benefts [41]. Revised antiretroviral therapy
recommendationsrefectthis.
i
PregnancydoesaffecttheCD4countalthoughthesignifcance
ofthesechangesisnotclearlyunderstood[58, 82],andforpracticalpurposestheimmunological
classifcationremainsthesame.
C|inica| decision-making
RegardlessofageorclinicalstageCD4testingisveryvaluableandshouldbeencouraged.Itis
usefultoguidethedecisiononinitiationofco-trimoxazoleandwhentostartfrst-lineARTorto
identifytreatmentfailureandtheneedtoswitchtoasecond-lineregimenofART.Measurement
ofCD4canalsobeusedtoassessandmonitorresponsetoART.
Whereclinicalandimmunologicalclassifcationsarebothavailable,immunestatus,refectedby
CD4(%CD4+orabsolutecount)isusuallymoreinformative.Thisisrefectedinthemostup-to-
dateWHOrecommendationsonARTforinfants,childrenandadults.
ii
Inyoungerchildren%CD4+
shouldbeused,andfromfveyearsofagetheabsolutecountispreferred.
Severe HIV-related disease always requires ART irrespective of whether defned by clinical
conditionorimmunestatus.AdvancedHIVdiseasebasedonimmunestatusrequiresconsidering
ART, especially when disease is advanced as defned clinically. Starting antiretroviral therapy
can usually be delayed if the immune status suggests that there is only mild or insignifcant
immunodefciency(%CD4+>30amongchildrenyoungerthan12months,>25amongchildren
1235 months or >20 in children over 36 months, or CD4 count >350 per mm
3
in adults and
olderchildren),andtheindividualisasymptomaticoronlyhasmildsymptoms.
i WHOrecommendationsforantiretroviraltherapyforadultsandchildrenandantiretroviraldrugsforpreventingmother-to-child
transmissionhavebeenrevisedin2006.DetailsareavailableontheWHOwebsiteat:
ii Availableathttp://www.who.int/hiv/pub/guidelines/arv/en/index.html.
15
Tab|e 2. WHO immuno|ogica| c|assifcation for estab|ished HV infection
HV-associated
immunodefciency
Age-re|ated CD4 va|ues
<11
months
(%CD4+)
1235
months
(%CD4+)
3659
months
(%CD4+)
>5 years
(abso|ute
number
per mm
3
or
%CD4+)
Noneornotsignifcant >35 >30 >25 >500
Mild 3035 2530 2025 350499
Advanced 2529 2024 1519 200349
Severe <25 <20 <15 <200or<15%
Tab|e 3. WHO c|inica| staging of HV/ADS for adu|ts and ado|escents
with confrmed HV infection
i
C|inica| stage 1
Asymptomatic
Persistentgeneralizedlymphadenopathy
C|inica| stage 2
Moderateunexplainedweightloss
(<10%ofpresumedormeasuredbodyweight)
I
Recurrentrespiratorytractinfectionssinusitis,tonsillitis,otitismediaandpharyngitis)
Herpeszoster
Angularcheilitis
Recurrentoralulceration
Papularpruriticeruptions
Seborrhoeicdermatitis
Fungalnailinfections
i Assessmentofbodyweightinpregnantwomanneedstoconsidertheexpectedweightgainofpregnancy.
16
Adu|ts and ado|escents
i
ii
C|inica| stage 3
Unexplained
i
severeweightloss(>10%ofpresumedormeasuredbodyweight)
Unexplainedchronicdiarrhoeaforlongerthanonemonth
Unexplainedpersistentfever(above37.6Cintermittentorconstant,
forlongerthanonemonth)
Persistentoralcandidiasis
Oralhairyleukoplakia
Pulmonarytuberculosis(current)
Severebacterialinfections(suchaspneumonia,empyema,pyomyositis,
boneorjointinfection,meningitisorbacteraemia)
Acutenecrotizingulcerativestomatitis,gingivitisorperiodontitis
Unexplainedanaemia(<8g/dl),neutropaenia(<0.510
9
perlitre)
orchronicthrombocytopaenia(<5010
9
perlitre)
C|inica| stage 4
ii
HIVwastingsyndrome
Pneumocystispneumonia
Recurrentseverebacterialpneumonia
Chronicherpessimplexinfection(orolabial,genitaloranorectal
ofmorethanonemonthsdurationorvisceralatanysite)
Oesophagealcandidiasis(orcandidiasisoftrachea,bronchiorlungs)
Extrapulmonarytuberculosis
Kaposissarcoma
Cytomegalovirusinfection(retinitisorinfectionofotherorgans)
Centralnervoussystemtoxoplasmosis
HIVencephalopathy
Extrapulmonarycryptococcosisincludingmeningitis
Disseminatednon-tuberculousmycobacterialinfection
Progressivemultifocalleukoencephalopathy
Chroniccryptosporidiosis(withdiarrhoed)
Chronicisosporiasis
Disseminatedmycosis(coccidiomycosisorhistoplasmosis)
Recurrentnon-typhoidalSalmonellabacteraemia
Lymphoma(cerebralorB-cellnon-Hodgkin)orothersolidHIV-associatedtumours
Invasivecervicalcarcinoma
Atypicaldisseminatedleishmaniasis
SymptomaticHIV-associatednephropathyorsymptomaticHIV-associatedcardiomyopathy
i Unexplainedreferstowheretheconditionisnotexplainedbyothercauses.
ii Someadditionalspecifcconditionscanalsobeincludedinregionalclassifcations(suchasreactivationofAmericantrypanoso-
miasis[meningoencephalitisand/ormyocarditis])intheWHORegionoftheAmericasanddisseminatedpenicilliosisinAsia).
17
Tab|e 4. WHO c|inica| staging of HV/ADS for chi|dren with confrmed HV
infection
C|inica| stage 1
Asymptomatic
Persistentgeneralizedlymphadenopathy
C|inica| stage 2
Unexplainedpersistenthepatosplenomegaly
Papularpruriticeruptions
Fungalnailinfection
Angularcheilitis
Linealgingivalerythema
Extensivewartvirusinfection
Extensivemolluscumcontagiosum
Recurrentoralulcerations
Unexplainedpersistentparotidenlargement
Herpeszoster
Recurrentorchronicupperrespiratorytractinfections
(otitismedia,otorrhoea,sinusitisortonsillitis)
C|inica| stage 3
Unexplained
i
moderatemalnutritionorwastingnotadequatelyrespondingtostandardtherapy
Unexplainedpersistentdiarrhoea(14daysormore)
Unexplainedpersistentfever(above37.5Cintermittentorconstant,
forlongerthanonemonth)
Persistentoralcandidiasis(afterfrst68weeksoflife)
Oralhairyleukoplakia
Acutenecrotizingulcerativegingivitisorperiodontitis
Lymphnodetuberculosis
Pulmonarytuberculosis
Severerecurrentbacterialpneumonia
Symptomaticlymphoidinterstitialpneumonitis
ChronicHIV-associatedlungdiseaseincludingbrochiectasis
Unexplainedanaemia(<8g/dl),neutropaenia(<0.510
9
perlitre)
andorchronicthrombocytopaenia(<5010
9
perlitre)
i
i Unexplainedreferstowheretheconditionisnotexplainedbyothercauses.
18
Chi|dren
C|inica| stage 4
i
Unexplainedseverewasting,stuntingorseveremalnutritionnotresponding
tostandardtherapy
Pneumocystispneumonia
Recurrentseverebacterialinfections(suchasempyema,pyomyositis,
boneorjointinfectionormeningitisbutexcludingpneumonia)
Chronicherpessimplexinfection(orolabialorcutaneousofmorethanonemonths
durationorvisceralatanysite)
Oesophagealcandidiasis(orcandidiasisoftrachea,bronchiorlungs)
Extrapulmonarytuberculosis
Kaposisarcoma
Cytomegalovirusinfection:retinitisorcytomegalovirusinfectionaffectinganotherorgan,
withonsetatageolderthanonemonth
Centralnervoussystemtoxoplasmosis(afteronemonthoflife)
Extrapulmonarycryptococcosis(includingmeningitis)
HIVencephalopathy
Disseminatedendemicmycosis(coccidiomycosisorhistoplasmosis)
Disseminatednon-tuberculousmycobacterialinfection
Chroniccryptosporidiosis(withdiarrhoed)
Chronicisosporiasis
CerebralorB-cellnon-Hodgkinlymphoma
Progressivemultifocalleukoencephalopathy
SymptomaticHIV-associatednephropathyorHIV-associatedcardiomyopathy
i
i Someadditionalspecifcconditionscanalsobeincludedinregionalclassifcations(suchasreactivationofAmericantrypano-
somiasis[meningoencephalitisand/ormyocarditis]intheWHORegionoftheAmericas,disseminatedpenicilliosisinAsiaand
HIV-associatedrectovaginalfstulainAfrica).
19
CRTERA FOR HV STAGNG EVENTS
Adu|ts (15 years or o|der)
C|inica| event C|inica| diagnosis Defnitive diagnosis
C|inica| stage 1
Asymptomatic. NoHIV-relatedsymptoms
reportedandnosignson
examination.
Notapplicable.
Persistentgeneralized
lymphadenopathy.
Painlessenlargedlymph
nodes>1cmintwoormore
non-contiguoussites
(excludinginguinal)inthe
absenceofknowncause
andpersistingforthree
monthsormore.
Histology.
C|inica| stage 2
Unexplainedmoderate
weightloss(<10%ofbody
weight).
Reportedunexplained
involuntaryweightlossin
pregnancyfailuretogain
weight.
Documentedweightloss
<10%ofbodyweight.
Recurrentupperrespiratory
tractinfections(current
eventplusoneormorein
lastsix-monthperiod).
Symptomcomplex,suchas
unilateralfacepainwith
nasaldischarge(sinusitis),
painfulinfamedeardrum
(otitismedia)or
tonsillopharyngitiswithout
featuresofviralinfection
(suchascoryzaorcough).
Laboratorystudieswhere
available,suchascultureof
suitablebodyfuid.
Herpeszoster. Painfulvesicularrashin
dermatomaldistributionofa
nervesupply,doesnot
crossthemidline.
Clinicaldiagnosis.
Angularcheilitis. Splitsorcracksattheangle
ofthemouthnotduetoiron
orvitamindefciency,usually
respondtoantifungal
treatment.
Clinicaldiagnosis.
ANNEx 1.
pRESUMpTIVE AND DEFINITIVE CRITERIA FOR RECOGNIzING HIV-RELATED
CLINICAL EVENTS IN ADULTS (15 yEARS OR OLDER) AND CHILDREN (yOUNGER
THAN 15 yEARS) WITH CONFIRMED HIV INFECTION
20
Recurrentoralulceration
(twoormoreepisodesin
lastsixmonths).
Aphthousulceration,
typicallypainfulwithahalo
ofinfammationandayellow-
greypseudomembrane.
Clinicaldiagnosis.
Papularpruriticeruption. Papularpruriticlesions,
oftenwithmarkedpost-
infammatorypigmentation.
Clinicaldiagnosis.
Seborrhoeicdermatitis. Itchyscalyskincondition,
particularlyaffectinghairy
areas(scalp,axillae,upper
trunkandgroin).
Clinicaldiagnosis.
Fungalnailinfection. Paronychia(painfulredand
swollennailbed)or
onycholysis(separationof
thenailfromthenailbed)of
thefngernails(white
discolorationespecially
involvingproximalpartof
nailplatewiththickening
andseparationofthenail
fromthenailbed).
Fungalcultureofthenailor
nailplatematerial.
C|inica| stage 3
Unexplainedsevereweight
loss(morethan10%ofbody
weight).
Reportedunexplained
involuntaryweightloss
(>10%ofbodyweight)and
visiblethinningofface,waist
andextremitieswithobvious
wastingorbodymassindex
<18.5kg/m2;inpregnancy,
theweightlossmaybe
masked.
Documentedlossofmore
than10%ofbodyweight.
21
Unexplainedchronic
diarrhoeaforlongerthan
onemonth.
Chronicdiarrhoea(looseor
waterystoolsthreeormore
timesdaily)reportedfor
longerthanonemonth.
Threeormorestools
observedanddocumented
asunformed,andtwoor
morestooltestsrevealno
pathogens.
Unexplainedpersistentfever
(intermittentorconstantand
lastingforlongerthanone
month).
Feverornightsweatsfor
morethanonemonth,either
intermittentorconstantwith
reportedlackofresponseto
antibioticsorantimalarial
agents,withoutother
obviousfociofdisease
reportedorfoundon
examination;malariamustbe
excludedinmalariousareas.
Documentedfever>37.5C
withnegativebloodculture,
negativeZiehl-Nielsenstain,
negativemalariaslide,
normalorunchangedchest
X-rayandnootherobvious
focusofinfection.
Persistantoralcandidiasis. Persistentorrecurring
creamywhitecurd-like
plaquesthatcanbescraped
off(pseudomembranous)or
redpatchesontongue,
palateorliningofmouth,
usuallypainfulortender
(erythematousform).
Clinicaldiagnosis.
Oralhairyleukoplakia. Finewhitesmalllinearor
corrugatedlesionsonlateral
bordersofthetonguethat
donotscrapeoff.
Clinicaldiagnosis.
22
Pulmonarytuberculosis
(current).
Chronicsymptoms:(lasting
atleast23weeks)cough,
haemoptysis,shortnessof
breath,chestpain,weight
loss,fever,nightsweats;
PLUSEITHER
positivesputumsmear;
OR
negativesputumsmear;
AND
compatiblechestradiograph
(includingbutnotrestricted
toupperlobeinfltrates,
caritation,pulmonary
fbrosistshrinkage.
Noevidenceof
extrapulmonarydiseas.
IsolationofM. Tuberculosis
onsputumcultureor
histologyoflungbiopsy
(withcompatiblesymptoms).
Severebacterialinfection
(suchaspneumonia,
meningitis,empyema,
pyomyositis,boneorjoint
infection,bacteraemiaand
severepelvicinfammatory
disease).
Feveraccompaniedby
specifcsymptomsorsigns
thatlocalizeinfectionand
responsetoappropriate
antibiotic.
Isolationofbacteriafrom
appropriateclinical
specimens(usuallysterile
sites).
Acutenecrotizingulcerative
gingivitisornecrotizing
ulcerativeperiodontitis.
Severepain,ulcerated
gingivalpapillae,loosening
ofteeth,spontaneous
bleeding,badodourand
rapidlossofboneand/or
softtissue.
Clinicaldiagnosis.
23
Unexplainedanaemia
(<8g/dl),neutropaenia
(<0.510
9
perlitre)or
chronic(morethanone
month)thrombocytopaenia
(<5010
9
perlitre).
Notpresumptiveclinical
diagnosis.
Diagnosedonlaboratory
testingandnotexplainedby
othernon-HIVconditions;
notrespondingtostandard
therapywithhaematinics,
antimalarialagentsor
anthelminticagentsas
outlinedinrelevantnational
treatmentguidelines,WHO
IntegratedManagementof
ChildhoodIllnessguidelines
orotherrelevantguidelines.
C|inica| stage 4
HIVwastingsyndrome. Unexplainedinvoluntary
weightloss(>10%baseline
bodyweight),withobvious
wastingorbodymassindex
<18.5;
PLUSEITHER
unexplainedchronic
diarrhoea(looseorwatery
stoolsthreeormoretimes
daily)reportedforlonger
thanonemonth;
OR
reportsoffeverornight
sweatsformorethanone
monthwithoutothercause
andlackofresponseto
antibioticsorantimalarial
agents;malariamustbe
Documentedweightloss
(>10%ofbodyweight);
PLUSEITHER
twoormoreunformedstools
negativeforpathogens;
OR
documentedtemperatureof
>37.5Cwithnoothercause
ofdisease,negativeblood
culture,negativemalaria
slideandnormalor
unchangedchestX-ray.
24
Pneumocystispneumonia. Dyspnoeaonexertionor
nonproductivecoughof
recentonset(withinthepast
threemonths),tachypnoea
andfever;
AND
ChestX-rayevidenceof
diffusebilateralinterstitial
infltrates;
AND
Noevidenceofbacterial
pneumonia;bilateral
crepitationsonauscultation
withorwithoutreducedair
entry.
Cytologyor
immunofuorescent
microscopyofinduced
sputumorbronchoalveolar
lavageorhistologyoflung
tissue.
Recurrentbacterial
pneumonia;
(thisepisodeplusoneor
moreepisodesinlastsix
months).
Currentepisodeplusoneor
morepreviousepisodesin
thepastsixmonths;acute
onset(<2weeks)ofsevere
symptoms(suchasfever,
cough,dyspnoea,andchest
pain)PLUSnew
consolidationonclinical
examinationorchestX-ray;
responsetoantibiotics.
Positivecultureorantigen
testofacompatible
organism.
Chronicherpessimplex
virusinfection(orolabial,
genitaloranorectal)ofmore
thanonemonthorvisceral
infectionofanyduration.
Painful,progressive
anogenitalororolabial
ulceration;lesionscaused
byrecurrenceofherpes
simplexvirusinfectionand
reportedformorethanone
month.Historyofprevious
episodes.Visceralherpes
simplexvirusrequires
defnitivediagnosis.
PositivecultureorDNA(by
polymerasechainreaction)
ofherpessimplexvirusor
compatiblecytologyor
histology.
25
Oesophagealcandidiasis. Recentonsetofretrosternal
painordiffcultyon
swallowing(foodandfuids)
togetherwithoralcandidasis.
Macroscopicappearanceat
endoscopyor
bronchoscopy,orby
microscopyorhistology.
Extrapulmonarytuberculosis. Systemicillness(suchas
fever,nightsweats,
weaknessandweightloss).
Otherevidencefor
extrapulmonaryor
disseminatedtuberculosis
variesbysite:
Pleural,pericardia,peritoneal
involvement,meningitis,
mediastinalorabdominal
lymphadenopathyorostetis.
Discreteperipherallymph
nodeMycobacterium
tuberculosisinfection
(especiallycervical)is
consideredalesssevere
formofextrapulmonary
tuberculosis.
M. tuberculosisisolationor
compatiblehistologyfrom
appropriatesiteor
radiologicalevidenceof
miliarytuberculosis;
(diffuseuniformlydistributed
smallmiliaryshadowsor
micronodulesonchest
X-ray).
Kaposisarcoma. Typicalgrossappearancein
skinororopharynxof
persistent,initiallyfat,
patcheswithapinkor
violaceouscolour,skin
lesionsthatusuallydevelop
intoplaquesornodules.
endoscopyor
bronchoscopy,orby
histology.
26
Cytomegalovirusdisease
(otherthanliver,spleenor
lymphnode).
Retinitisonly:maybe
diagnosedbyexperienced
clinicians.Typicaleye
lesionsonfundoscopic
examination:discrete
patchesofretinalwhitening
withdistinctborders,
spreadingcentrifugally,
oftenfollowingblood
vessels,associatedwith
retinalvasculitis,
haemorrhageandnecrosis.
Compatiblehistologyor
cytomegalovirus
demonstratedin
cerebrospinalfuidby
cultureorDNA(by
polymerasechainreaction).
Centralnervoussystem
toxoplasmosis.
Recentonsetofafocal
nervoussystemabnormality
consistentwithintracranial
diseaseorreducedlevelof
consciousnessAND
responsewithin10daysto
specifctherapy.
Positiveserumtoxoplasma
antibodyAND(ifavailable)
singleormultipleintracranial
masslesionon
neuroimaging(computed
tomographyormagnetic
resonanceimaging).
HIVencephalopathy. Disablingcognitiveand/or
motordysfunctioninterfering
withactivitiesofdailyliving,
progressingoverweeksor
monthsintheabsenceofa
concurrentillnessor
conditionotherthanHIV
infectionthatmightexplain
thefndings.
Diagnosisofexclusion:and
(ifavailable)neuroimaging
(computedtomographyor
magneticresonance
imaging).
Extrapulmonary
cryptococcosis(including
meningitis).
Meningitis:usuallysubacute,
feverwithincreasingsevere
headache,meningism,
confusion,behavioural
changesthatrespondto
cryptococcaltherapy.
IsolationofCryptococcus
neoformansfrom
extrapulmonarysiteor
positivecryptococcal
antigenteston
cerebrospinalfuidorblood.
27
Disseminatednon-
tuberculousmycobacteria
infection.
Nopresumptiveclinical
diagnosis.
Diagnosedbyfnding
atypicalmycobacterial
speciesfromstool,blood,
bodyfuidorotherbody
tissue,excludingthelungs.
Progressivemultifocal
leukoencephalopathy.
diagnosis.
Progressivenervoussystem
disorder(cognitive
dysfunction,gait/speech
disorder,visualloss,limb
weaknessandcranialnerve
palsies)togetherwith
hypodensewhitematter
lesionsonneuro-imagingor
positivepolyomavirusJC
polymerasechainreaction
oncerebrospinalfuid.
Chroniccryptosporidiosis
(withdiarrhoealastingmore
thanonemonth).
diagnosis.
Cystsidentifedonmodifed
Ziehl-Nielsenstain
microscopicexaminationof
unformedstool.
Chronicisosporiasis. Nopresumptiveclinical
diagnosis.
IdentifcationofIsospora.
Disseminatedmycosis
(coccidiomycosisor
histoplasmosis).
diagnosis.
Histology,antigendetection
orculturefromclinical
specimenorbloodculture.
Recurrentnon-typhoid
Salmonellabacteraemia.
diagnosis.
Bloodculture.
Lymphoma(cerebralorB-
cellnon-Hodgkin).
diagnosis.
Histologyofrelevant
specimenor,forcentral
nervoussystemtumours,
neuroimagingtechniques.
Invasivecervicalcarcinoma. Nopresumptiveclinical
diagnosis.
Histologyorcytology.
28
Atypicaldisseminated
leishmaniasis.
diagnosis.
Diagnosedbyhistology
(amastigotesvisualized)or
culturefromanyappropriate
clinicalspecimen.
Symptometic
HIV-associatednephropathy.
diagnosis.
Renalbiopsy.
Symptometic
HIV-associated
cardiomyopathy.
diagnosis.
Cardiomegalyandevidence
ofpoorleftventricular
functionconfrmedby
echocardiography.
29
CRTERA FOR WHO CLNCAL STAGNG EVENTS
Chi|dren (younger than 15 years)
C|inica| stage 1
Asymptomatic. NoHIV-relatedsymptoms
reportedandnoclinical
signsonexamination.
Notapplicable.
Persistentgeneralized
lymphadenopathy.
Persistentenlargedlymph
nodes>1cmattwoormore
non-contiguoussites
(excludinginguinal)without
knowncause.
Clinicaldiagnosis.
C|inica| stage 2
Unexplainedpersistent
hepatosplenomegaly.
Enlargedliverandspleen
withoutobviouscause.
Clinicaldiagnosis.
Papularpruriticeruptions. Papularpruriticvesicular
lesions.
Clinicaldiagnosis.
Fungalnailinfections. Fungalparonychia(painful,
redandswollennailbed)or
onycholysis(painless
separationofthenailfrom
thenailbed).Proximalwhite
subungualonchomycosisis
uncommonwithout
immunodefciency.
Clinicaldiagnosis.
Angularcheilitis. Splitsorcracksattheangle
ofthemouthnotattributable
toironorvitamindefciency,
andusuallyrespondingto
antifungaltreatment.
Clinicaldiagnosis.
Linealgingivalerythema. Erythematousbandthat
followsthecontourofthe
freegingivalline;maybe
associatedwith
spontaneousbleeding.
Clinicaldiagnosis.
30
Extensivewartvirus
infection.
Characteristicwartyskin
lesions;smallfeshygrainy
bumps,oftenrough,faton
soleoffeet(plantarwarts);
facial,morethan5%ofbody
areaordisfguring.
Clinicaldiagnosis.
Extensivemolluscum
contagiosuminfection.
Characteristicskinlesions:
smallfesh-coloured,pearly
orpink,dome-shapedor
umbilicatedgrowthsmaybe
infamedorred;facial,more
than5%ofbodyareaor
disfguring.Giantmolluscum
mayindicatemoreadvanced
immunodefciency.
Clinicaldiagnosis.
Recurrentoralulceration. Currenteventplusatleast
onepreviousepisodein
pastsixmonths.Aphthous
ulceration,typicallywitha
haloofinfammationand
yellow-grey
pseudomembrane.
Clinicaldiagnosis.
parotidenlargement.
Asymptomaticbilateral
swellingthatmay
spontaneouslyresolveand
recur,inabsenceofother
knowncause,usually
painless.
Clinicaldiagnosis.
Herpeszoster. Painfulrashwithfuid-flled
blisters,dermatomal
distribution,canbe
haemorrhagicon
erythematousbackground,
andcanbecomelargeand
confuent.Doesnotcross
themidline.
Clinicaldiagnosis.
31
Recurrentorchronicupper
respiratorytractinfection.
Currenteventwithatleast
oneepisodeinthepastsix
months.Symptomcomplex;
feverwithunilateralface
painandnasaldischarge
(sinusitis)orpainfulswollen
eardrum(otitismedia),sore
throatwithproductivecough
(bronchitis),sorethroat
(pharyngitis)andbarking
croup-likecough
(laryngotrachealbronchitis).
Persistentorrecurrentear
discharge.
Clinicaldiagnosis.
C|inica| stage 3
Unexplainedmoderate
malnutritionorwasting.
Weightloss:lowweight-for-
age,upto2standard
deviationsfromthemean,
notexplainedbypooror
inadequatefeedingandor
otherinfections,andnot
adequatelyrespondingto
standardmanagement.
Documentedlossofbody
weightof2standard
deviationsfromthemean,
failuretogainweighton
standardmanagementand
noothercauseidentifed
duringinvestigation.
diarrhoea.
(14daysormore)diarrhoea
(looseorwaterystool,three
ormoretimesdaily),not
respondingtostandard
treatment.
Stoolsobservedand
documentedasunformed.
Cultureandmicroscopy
revealnopathogens.
32
Unexplainedpersistentfever;
(>37.5Cintermittentor
constantforlongerthanone
month).
Reportsoffeverornight
sweatsforlongerthanone
month,eitherintermittentor
constant,withreportedlack
ofresponsetoantibioticsor
antimalarialagents.Noother
obviousfociofdisease
reportedorfoundon
examination.Malariamustbe
Documentedfeverof
>37.5Cwithnegativeblood
culture,negativemalaria
slideandnormalor
unchangedchestX-rayand
nootherobviousfociof
disease.
Oralcandidiasis;
(afterthefrst68weeks
oflife).
Persistentorrecurring
creamywhitetoyellowsoft
smallplaqueswhichcanbe
scrapedoff
(pseudomembranous),or
redpatchesontongue,
palateorliningofmouth,
usuallypainfulortender
(erythematousform).
Microscopyorculture.
Oralhairyleukoplakia. Finesmalllinearpatcheson
lateralbordersoftongue,
generallybilaterally,thatdo
notscrapeoff.
Clinicaldiagnosis.
Acutenecrotizingulcerative
gingivitisorstomatitis,or
acutenecrotizingulcerative
periodontitis.
Severepain,ulcerated
gingivalpapillae,loosening
ofteeth,spontaneous
bleeding,badodour,and
rapidlossofboneand/or
softtissue.
Clinicaldiagnosis.
Lymphnodetuberculosis. Non-acute,painlesscold
enlargementofperipheral
lymphnodes,localizedto
oneregion.Responseto
standardantituberculosis
treatmentinonemonth.
Histologyorfneneedle
aspiratepositiveforZiehl-
Nielsenstainorculture.
33
Pulmonarytuberculosis. Nonspecifcsymptoms,
suchaschroniccough,
fever,nightsweats,anorexia
andweightloss.Intheolder
childalsoproductivecough
andhaemoptysis.Historyof
contactwithadultswith
smear-positivepulmonary
tuberculosis.Noresponseto
standardbroad-spectrum
antibiotictreatment.
Oneormoresputumsmear
positiveforacid-fastbacilli
and/orradiographic
abnormalitiesconsistent
withactivetuberculosisand/
orculture-positivefor
Mycobacterium.
Severerecurrentbacterial
pneumonia.
Coughwithfastbreathing,
chestindrawing,nasalfaring,
wheezing,andgrunting.
Cracklesorconsolidationon
auscultation.Respondsto
courseofantibiotics.Current
episodeplusoneormorein
previoussixmonths.
Isolationofbacteriafrom
appropriateclinical
specimens(induced
sputum,bronchoalveolar
lavageandlungaspirate).
Symptomaticlymphocytic
interstitialpneumonia.
diagnosis.
ChestX-ray:bilateral
reticulonodularinterstitial
pulmonaryinfltratespresent
formorethantwomonths
withnoresponsetoantibiotic
treatmentandnoother
pathogenfound.Oxygen
saturationpersistently<90%.
Corpulmonaleandincreased
exercise-inducedfatigue.
Characteristichistology.
ChronicHIV-associatedlung
disease(including
bronchiectasis).
Historyofcoughproductive
ofcopiousamountsof
purulentsputum
(bronchiectasisonly),withor
withoutclubbing,halitosis,
andcrepitationsand/or
wheezesonauscultation.
ChestX-raymayshow
honeycombappearance
(smallcysts)and/orpersistent
areasofopacifcationand/or
widespreadlungdestruction,
withfbrosisandlossof
volume.
34
Unexplainedanaemia(<8g/
dl),neutropaenia
(<0.510
9
perlitre)andor
chronicthrombocytopaenia
(<5010
9
perlitre).
diagnosis.
Laboratorytesting,not
explainedbyothernon-HIV
conditions,notresponding
tostandardtherapywith
haematinics,antimalarial
agentsoranthelmintic
agentsasoutlinedinWHO
IntegratedManagementof
ChildhoodIllnessguidelines.
C|inica| stage 4
Unexplainedseverewasting,
stuntingorsevere
malnutritionnotadequately
respondingtostandard
therapy.
Persistentweightloss
stuntingwastingor
malnutritionnotexplained
bypoororinadequate
feeding,otherinfectionsand
notadequatelyresponding
intwoweekstostandard
therapy.Visiblesevere
wastingofmuscles,withor
withoutoedemaofbothfeet,
and/orweight-for-heightof
3standarddeviationsfrom
themean,asdefnedby
WHOIntegrated
ManagementofChildhood
Illnessguidelines.
Documentedweightfor
heightorweightforageof
morethan3standard
deviationsfromthemean
withorwithoutoedema.
35
Pneumocystispneumonia. Drycough,progressive
diffcultyinbreathing,
cyanosis,tachypnoeaand
fever;chestindrawingor
stridor.(Severeorvery
severepneumoniaasin
WHOIntegrated
ManagementofChildhood
Illnessguidelines.)Rapid
onsetespeciallyininfants
youngerthansixmonthsof
age.Responsetohigh-dose
co-trimoxazolewithor
withoutprednisolone.Chest
X-rayshowstypicalbilateral
perihilardiffuseinfltrates.
Cytologyor
immunofuorescent
microscopyofinduced
sputumorbronchoalveolar
lavageorhistologyoflung
tissue.
Recurrentseverebacterial
infection,suchasempyema,
pyomyositis,boneorjoint
infectionormeningitisbut
excludingpneumonia.
Feveraccompaniedby
specifcsymptomsorsigns
thatlocalizeinfection.
Respondstoantibiotics.
Currentepisodeplusoneor
moreinprevioussixmonths.
Cultureofappropriate
clinicalspecimen.
Chronicherpessimplex
infection;(orolabialor
cutaneousofmorethanone
monthsdurationorvisceral
atanysite).
Severeandprogressive
painfulorolabial,genital,or
anorectallesionscausedby
herpessimplexvirus
infectionpresentformore
thanonemonth.
Cultureand/orhistology.
Oesophagealcandidiasis;
(orcandidiasisoftrachea,
bronchiorlungs).
Diffcultyinswallowing,or
painonswallowing(food
andfuids).Inyoung
children,suspect
particularlyiforalCandida
observedandfoodrefusal
occursand/ordiffcultyor
cryingwhenfeeding.
endoscopy,microscopyof
specimenfromtissueor
macroscopicappearanceat
bronchoscopyorhistology.
36
Extrapulmonarytuberculosis. Systemicillnessusuallywith
prolongedfever,night
sweatsandweightloss.
Clinicalfeaturesoforgans
involved,suchassterile
pyuria,pericarditis,ascites,
pleuraleffusion,meningitis,
arthritis,orchitis,pericardial
orabdominal.
Positivemicroscopy
showingacid-fastbacillior
cultureofMycobacterium
tuberculosisfrombloodor
otherrelevantspecimen
exceptsputumor
bronchoalveolarlavage.
Biopsyandhistology.
Kaposisarcoma. Typicalappearanceinskin
ororopharynxofpersistent,
initiallyfat,patcheswitha
pinkorblood-bruisecolour,
skinlesionsthatusually
developintonodules.
Macroscopieappearenceor
byhistology.
Cytomegalovirusretinitisor
cytomegalovirusinfection
affectinganotherorgan,with
onsetatageolderthanone
month.
Retinitisonly.
Cytomegalovirusretinitismay
bediagnosedbyexperienced
clinicians:typicaleyelesions
onserialfundoscopic
examination;discretepatches
ofretinalwhiteningwith
distinctborders,spreading
centrifugally,oftenfollowing
bloodvessels,associated
withretinalvasculitis,
haemorrhageandnecrosis.
Defnitivediagnosisrequired
forothersites.Histologyor
cytomegalovirus
demonstratedin
cerebrospinalfuidby
polymerasechainreaction.
Centralnervoussystem
toxoplasmosisonsetafter
ageonemonth.
Fever,headache,focal
nervoussystemsignsand
convulsions.Usually
respondswithin10daysto
specifctherapy.
Computedtomographyscan
(orotherneuroimaging)
showingsingleormultiple
lesionswithmasseffector
enhancingwithcontrast.
37
Extrapulmonary
cryptococcosis(including
meningitis).
Meningitis:usually
subacute,feverwith
increasingsevereheadache,
meningism,confusionand
behaviouralchangesthat
respondtocryptococcal
therapy.
Cerebrospinalfuid
microscopy(Indiainkor
Gramstain),serumor
cerebrospinalfuid
cryptococcalantigentestor
culture.
HIVencephalopathy. Atleastoneofthefollowing,
progressingoveratleast
twomonthsintheabsence
ofanotherillness:
failuretoattain,orlossof,
developmentalmilestones
orlossofintellectualability;
OR
progressiveimpairedbrain
growthdemonstratedby
stagnationofhead
circumference;
OR
acquiredsymmetricalmotor
defcitaccompaniedbytwo
ormoreofthefollowing:
paresis,pathological
refexes,ataxiaandgait
disturbances.
Neuroimaging
demonstratingatrophyand
basalgangliacalcifcation
andexcludingothercauses.
Disseminatedmycosis
(coccidiomycosisor
histoplasmosis).
diagnosis.
Histology:usually
granulomaformation.
Isolation:antigendetection
fromaffectedtissue;culture
ormicroscopyfromclinical
specimenorbloodculture.
38
Disseminated
mycobacteriosis,otherthan
tuberculosis.
diagnosis.
Nonspecifcclinical
symptomsincluding
progressiveweightloss,
fever,anaemia,night
sweats,fatigueordiarrhoea;
pluscultureofatypical
mycobacterialspeciesfrom
stool,blood,bodyfuidor
otherbodytissue,excluding
thelung.
Chroniccryptosporidiosis;
(withdiarrhoea).
diagnosis.
Cystsidentifedonmodifed
Ziehl-Nielsenmicroscopic
examinationofunformed
stool.
ChronicIsosporiasis. Nopresumptiveclinical
diagnosis.
IdentifcationofIsospora.
CerebralorB-cellnon-
Hodgkinlymphoma.
diagnosis.
Diagnosedbycentral
nervoussystem
neuroimaging;histologyof
relevantspecimen.
Progressivemultifocal
leukoencephalopathy.
diagnosis.
Progressivenervoussystem
disorder(cognitive
dysfunction,gaitorspeech
disorder,visualloss,limb
weaknessandcranialnerve
palsies)togetherwith
hypodensewhitematter
lesionsonneuroimagingor
positivepolyomavirusJC
(JCV)polymerasechain
reactiononcerebrospinal
fuid.
SymptomaticHIV-
associatednephropathy.
diagnosis.
Renalbiopsy.
SymptomaticHIV-
associatedcardiomyopathy.
diagnosis.
Cardiomegalyandevidence
ofpoorleftventricular
functionconfrmedby
echocardiography.
3
Clinical criteria for presumptive diagnosis of severe HIV disease
among infants and children aged under 1 months in situations where
virological testing is not available
A presumptive diagnosis of severe HIV disease should be made if:
the infant is confrmed as HIV antibody-positive;
and
diagnosis of any AIDS-indicator condition(s)
a
can be made;
or
the infant is symptomatic with two or more of the following;
oral thrush
b
;
severe pneumonia
b
;
severe sepsis
b
.
Other factors that support the diagnosis of severe HIV disease in an
HIV-seropositive infant include:
recent HIV-related maternal death or advanced HIV disease in the mother;
CD4 <20%.
c
Confrmation of the diagnosis of HIV infection should be sought as soon as possible.
a AIDS indicator conditions include some but not all HIV clinical stage 4 conditions seen in children such as Pneumocystis pneu-
monia, oesophageal candidiasis, cryptococcal meningitis, cerebral toxoplasmosis, unexplained wasting or malnutrition.
b Defned in accordance with WHO Integrated Management of Childhood Illness guidelines:
Oral thrush: Creamy white soft small plaques on red or normally coloured mucosa which can often be scraped off (pseudomem-
branous), or red patches on tongue, palate or lining of mouth, usually painful or tender.
Severe pneumonia: Cough or diffcult breathing in a child with chest indrawing, stridor or any of the general danger signs
outlined in the WHO Integrated Management of Childhood Illness guidelines: that is lethargic or unconscious, not able to
drink or breastfeed, vomiting and presence or history of convulsions during current illness,.
Severe sepsis: Fever or low body temperature in a young infant with any severe sign, such as rapid breathing, chest indrawing,
bulging fontanelle, lethargy, reduced movement, not feeding or sucking breast-milk, convulsions, stiff neck.
c It is unclear how often the CD4 count is lowered in these conditions in HIV-uninfected children.
annex 2. presumptiVe diagnOsis Of seVere HiV disease in infants
40
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47
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ISBN 978 92 4 159562 9
For more information, contact:
World Health Organization
Department of HIV/AIDS
20, avenue Appia
1211 Geneva 27
Switzerland
E-mail: hiv-aids@who.int
www.who.int/hiv
Photograph: Gideon Mendel/The International HIV/AIDS Alliance/Corbis

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WHO CASE DEFINITIONS

OF HIV FOR SURVEILLANCE

WHO case definitiOn Of adVanced HiV

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