www.revportpneumol.org
ORIGINAL
ARTICLE
Tuberculosis
in
children
from
diagnosis
to
decision
to
treat
S.
Ramos
a,∗,
R.
Gaio
b,
F.
Ferreira
c,
J.
Paulo
Leal
d,
S.
Martins
e,
J.
Vasco
Santos
f,g,
I.
Carvalho
h,i,
R.
Duarte
h,i,jaFacultyofMedicine,UniversityofPorto,AlamedaProf.HernâniMonteiro,Porto,Portugal
bDepartamentodeMatemática,FaculdadedeCiênciasdaUniversidadedoPorto&CentrodeMatemáticadaUniversidadedo
Porto,RuadoCampoAlegre,Porto,Portugal
cDepartamentodeMatemática,FaculdadedeCiênciasdaUniversidadedoPorto,RuadoCampoAlegre,Porto,Portugal dCRACS&INESC-PortoLA,FacultyofSciences,UniversityofPorto,RuadoCampoAlegre,Porto,Portugal
eUSFdoMar,ACeSGrandePortoIV-PóvoadeVarzim/ViladoConde,RuaJoséMoreiradeAmorim,PóvoadeVarzim,Portugal fDepartmentofCommunityMedicine,InformaticsandDecisioninHealth(MEDCIDS),FacultyofMedicine,UniversityofPorto,
AlamedaProf.HernâniMonteiro,Porto,Portugal
gCenterforHealthTechnologyandServicesResearch(CINTESIS),AlamedaProf.HernâniMonteiro,Porto,Portugal hCentroHospitalarVilaNovadeGaia/Espinho,RuaConceic¸ãoFernandes,VilaNovadeGaia,Portugal
iISPUP-EPIUnit,UniversidadedoPorto,RuadasTaipas,Porto,Portugal
jDepartamentodeCiênciasdaSaúdePúblicaeForenseseEducac¸ãoMédica,FaculdadedeMedicina,UniversidadedoPorto,
AlamedaProf.HernâniMonteiro,Porto,Portugal
Received28March2017;accepted25June2017 Availableonline25July2017
KEYWORDS Tuberculosis; Paediatric; Childhood; Mycobacterium tuberculosis; Treatment Abstract
Setting: Confirmation oftuberculosis(TB)inchildren isdifficult, so cliniciansuse different procedureswhendecidingtotreat.
Objective: Identifycriteriatoinitiate andmaintainTBtreatmentinchildrenyoungerthan5 years-old,withoutdiagnosisconfirmation.
Design:Aweb-basedsurveywasdistributedbyemailtothecorrespondingauthorsofjournal articlesonchildhoodTB.Theobservationswereclusteredintodisjointgroups,andanalyzed byWard’smethod.
Results:Wesentout260questionnairesandreceived64(24.6%)responses.Forty-six respon-dents(71.9%)saidthatmicrobiologicalconfirmationwasnotimportantforinitiationofanti-TB treatment, andthatthe epidemiologicalcontext andsigns/symptoms suggestive ofdisease weremostimportant.Sixty-onerespondents(95.3%)saidthatthedecisiontocontinuetherapy wasmainlydependentonclinicalimprovement.Aclusterofolderrespondents(medianage:52 years-old)whowereactiveatahospitalorprimaryhealthcarecentreplacedthemostvalue
∗Correspondingauthor.
E-mailaddress:[email protected](S.Ramos).
https://doi.org/10.1016/j.rppnen.2017.06.004
2173-5115/©2017SociedadePortuguesadePneumologia.PublishedbyElsevierEspa˜na,S.L.U.ThisisanopenaccessarticleundertheCC
onimmunologicaltestresultsandchestX-rays.Aclusterofyoungerrespondents(medianage: 38years-old)whowerelessexperiencedinmanagementofTBplacedmorevalueonInterferon GammaReleaseAssay(IGRA)resultsandchestcomputedtomography(CT)scans.Aclusterof respondentswithmoreexperienceintreatingTBandworkingatspecializedTBcentresplaced greatervalueontheclinicalresultsandspecificradiologicalalterations(‘‘tree-in-bud’’pattern andpleuraleffusion).
Conclusion:TBmanagementvariedaccordingtotheage,worklocationandexperienceofthe clinicians.Itisnecessarytoestablishstandardizedguidelinesusedforthediagnosisanddecision totreatTBinchildren.
©2017SociedadePortuguesadePneumologia.PublishedbyElsevierEspa˜na,S.L.U.Thisisan openaccessarticleundertheCCBY-NC-NDlicense( http://creativecommons.org/licenses/by-nc-nd/4.0/).
Introduction
Childhood tuberculosis (TB) is a serious public health problem,1---3andaconsequenceofpoorcontrolofTBinthe
adultpopulation.3Earlydiagnosisandinitiationoftherapyis
crucialforeffectiveTBcontrol.Delayeddiagnosisincreases theriskofdeathandTBtransmissioninthecommunity.4,5
In 2014, the World Health Organization (WHO) repor-tedtherewereapproximately340,000incidentcasesofTB amongallcountriesintheEuropeanRegion.Childrenunder 15years-oldaccounted for 3.9%of allcases,andchildren under5years-oldaccountedfor1.6%ofallcases.1
Confirmationof a TB diagnosis by identification of the infectiousagentcan bedifficultin children.6 In2009,the
rateofdiagnosticconfirmationamongpaediatriccaseswas only 19.2%.7 Sampling is particularly difficult in children
under 10 years-old, and even if samples are obtained, the paucibacillary nature of the lesions may produce false-negative results.5,6,8---10 Thus, gastric lavage is
fre-quently used for the diagnosis of TB in children under 6 years-old.6,10---12 Currently, clinicians consider clinical
presentation,historyofrecentcontactwithinfected indi-viduals,immunologicalevidence of infection, radiological signscompatiblewithTB,andlackofclinicalimprovement followingantibacterialtreatment asindicators of TB,and forinitiationofTBtreatment.5,6,13,14 However,the
variabi-lityand lowspecificityofclinical andradiologicalfindings inchildrenindicatethatadiagnosisbasedonthesecriteria shouldbeviewedwithahighdegreeofsuspicion.5,15
This study aimsto identify the criteriain Europe that mostfrequentlyleadtotheinitiationandmaintenanceof empiric antibiotic treatment in children younger than 5 years-oldwithsuspectedTB,butwithoutdiagnostic confir-mation. It is also examined the relationship of different characteristicsofclinicianswithvaryingattitudestowards thediagnosisandtreatmentofchildhoodTB.
Methods
This study was based on the implementation of a web-basedsurvey,throughGoogleDrive,directedatdoctorsand researchersinEuropewhohadexperiencetreatingchildren withTB. This survey consisted of 28 multiple-choice and
simple-answerquestions,divided into3sections:(i) iden-tification(age,gender,country,jobtitle,localityofwork, specialization,andyearsinthejob);(ii)experience(years in TB and childhood TB, time spent in those areas, and number of patients withTB diagnoses);and (iii) diagnos-ticcriteria.Severalquestionsinthislastsectionrelatedto clinicalexperiencewithchildrenunder5years-oldwhohad TB, but without confirmation ofdiagnosis, toidentify the mostimportantcriteriausedtostarttreatmentandto dif-ferentiatethemostimportantsymptomsandresultsamong radiological,immunological,andconfirmationtestsinthese children.Themaincriteriausedtomaintaintreatment, wit-houtTBconfirmation,werealsoidentified.Alltheresponses wereanonymous.
The names and addresses of the surveyed researchers werecollectedusingsoftwarespecificallydevelopedforthis purpose (described below). This software combines data from several sources, because we were unable to find a singlesourcewithdataonresearchpapersandtheir corres-pondingauthors.Thedatasourceswere:PubMed,theDigital ObjectIdentifier(DOI)System,andthewebsitesofjournals thatpublishedthepapers.
The collection process was driven by a web inter-face,wheretheuserspecified thekeywords(‘‘paediatric, tuberculosis’’) and time interval (1 January 2005 to 20 December 2015). These data were submittedto a server, andprocessedinthreestages.First,thePubMeddatabase wasqueriedusingtheEntrezProgrammingUtilities,16which
returneddataonpaperswiththeselectedcriteria(n=1573), andthetitleandDOIofeachpaper.PubMeddoesnotrecord thecorrespondingauthors,sothisinformationwasretrieved fromthejournalweb sites.Second, theDOIname resolu-tionservice17wasusedtoobtaineachpaper’sURLfromits
DOI.Third,usingthisURL,thepaper’swebpagewas retrie-vedfromthejournal’swebsite,andthenameandemailof thecorrespondingauthorwasextracted(n=260),whenthis informationwasavailable.
Descriptivestatistics(absoluteandrelativefrequencies) are given for categorical variables, and medians, with minima andmaxima, aregiven forquantitative variables. Thechi-squaredtest(orFisher’stest,asadequate) evalua-ted the independence between two categorical variables while the Mann---Whitney (resp. the Kruskall---Wallis) test accessed the existence of significant differences between
the distributions of two (resp. or a higher number of) independentquantitativevariables.
All collected observations were clustered into disjoint groupsaccordingtoresponsesinthe‘‘diagnosticcriteria’’ section of the survey. As the variables were categorical, several agglomerative hierarchical clustering techniques, with a dissimilarity matrix given by the Gower distance, wereused.The finalclusteringwasfromthemethodwith thehighestagglomerativecoefficient(Ward’smethod).The divisionconsistedof4clusters,oneofwhichwaseliminated becauseitonlyhad2participants(outliers).
ThestatisticalanalyseswereperformedusingRLanguage andSoftwareEnvironmentforStatisticalComputation (ver-sion3.3.0).18Thesignificancelevelwassetat0.05.
Thedefinitionof‘‘confirmationofdiagnosis’’isapositive smearandnucleicacid-amplificationtestorpositiveculture forMycobacteriumtuberculosis.
ThestudywasapprovedbytheEthicsCommitteeofthe EPIUnit --- Institute of Public Health, University of Porto, Porto,Portugal.
Results
The overall response rate was 24.6% (64/260). The res-pondentshad amedian age of 46.5years(range:28---70), 54.7%(n=35)werefemale,andmostwerefromEuropean countriesotherthanPortugal(78.1%;n=50).The greatest numberofrespondentswerefromItaly(15.6%;n=10), Tur-key (10.9%; n=7), and the United Kingdom (9.4%; n=6). Thirty-nine respondents (60.9%) were medical doctors, 2 (3.1%)wereresearchers,and23(35.9%)werebothdoctors andresearchers.Amongthedoctors,26(40.6%)were pae-diatricians,19(29.7%)werepneumologists,and11(17.2%) were infectious disease specialists.In addition, 13 of the doctors (20.3%) worked in specialized TB centres and 51 (79.7%)workedinahospitalor aprimarycaresetting.TB accountedfor morethanhalf ofthemonthlyworkloadfor 15.6%(n=10)of thedoctors,andinfantTB accountedfor morethanone-quarterof themonthlyworkloadfor25.0% (n=16)ofthedoctors.In2014,therespondentsdiagnosed amedianof3(range:0---100)childrenyoungerthan5 years-oldwithTB,andamedianof2(range:0---50)hadconfirmed diagnosesofTB.
Forty-six respondents(71.9%)reportedthat microbiolo-gicalconfirmationwasnotimportantfortheirdecisionsto initiateanti-TBtreatment.Respondentsparticularlyvalued theepidemiologicalcontext(89.1%;n=57),signsand symp-toms suggestive of disease (85.9%; n=55), radiological findings (76.6%; n=49), patient age (48.4%; n=31), and resultsofthetuberculinskintest(TST)/interferongamma release assay (IGRA) (45.3%; n=29). The most frequently requested exams following suspicionof TB were chest X-ray(95.3%; n=61),which wasconsidered more important (78.3%; n=47) than a chest CT scan (21.7%; n=13). The respondentsalsoplacedgreatimportanceontheTST/IGRA results (75%; n=48), and the TST was considered more important (56.3%; n=27) than the IGRA (43.8%; n=21). Regarding sample collection, gastric lavage wasthe most commonly requested method (51.6%; n=33), followed by collectionof sputum(32.8%;n=21)(Table1).The respon-dents reportedthe most valueddeterminants for starting
Table 1 Exams most requested by survey respondents (n=64)duringtheirclinicalinvestigationofchildrenunder 5 years-old with suspected TB, but without diagnostic confirmation.
Exam Always Sometimes Never
TST/IGRA 48(75.0%) 11(17.2%) 5(7.8%) ThoraxX-ray 61(95.3%) 1 (1.6%) 2 (3.1%) ChestCT 9(14.1%) 44 (68.7%) 11 (17.2%) Sputumsample 21(32.8%) 33 (51.7%) 10 (15.5%) Gastriclavage 33(51.6%) 30 (46.8%) 1 (1.6%) Bronchoalveolarlavage 2(3.1%) 50 (78.1%) 12 (18.8%)
treatmentwithoutdiagnosticconfirmationwereweightloss (76.6%;n=49),persistentcough(75.0%;n=48)and prolon-gedfever(68.8%;n=44),especiallyiftheylastedmorethan 2weeks(65.6%; n=42),historyof exposuretoTB (87.5%; n=56), highTB prevalence inthe countryor areaof resi-dence(82.8%;n=53),andradiologicaltest results(93.8%; n=60),mainlycavitations(78.1%;n=47)andadenopathies (68.8%;n=44)(Table2).
Atotalof95.3%oftherespondentsreportedthat mainte-nanceoftherapy,despitenoconfirmationofdiagnosis,was mainlydependent onclinicalimprovement(85.3%;n=52), radiologicalimprovement(68.9%;n=42),andthepresence animmunosuppressedstate(59.0%;n=36).
Cluster 1 consisted of older respondents (median age: 52years-old) who worked in a hospitalor primary health carecentre(92.3%;n=24).Theserespondentsplacedmost valueontheimmunologicaltestresults(88.5%;n=23), espe-ciallytheTST(76.9%;n=20)ratherthantheIGRA,andthe chestX-ray(95.8%;n=23)ratherthantheCTscan.Cluster3 consistedofyoungerrespondents(medianage:38years-old) whohadlessexperienceinthediagnosisofTB inchildren (medianchildrendiagnosedwithTBin2014:0;median chil-drenwithconfirmeddiagnosisin2014:1).Theserespondents placedmostvalueontheclinicalfindings(100%;n=17),the IGRAtest(100%;n=17)ratherthantheTST,andthechest CTscan(33.3%; n=5)ratherthanthechest X-ray.Cluster 2consistedofrespondentswhohadmoreexperienceinthe diagnosisofTBinchildren(medianchildrendiagnosedwith TBin2014:8;medianchildrenwithconfirmedTBdiagnosisin 2014:3)andworkedinspecializedTBcentres(36.8%;n=7). Theserespondentsvaluedtheclinicalfindings(89.5---100%;
n=17---19)andspecificradiologicalalterations,suchasthe ‘‘tree-in-bud’’pattern(68.4%;n=13)andpleural effusion (79.0%;n=15).
Discussion
Atotalof71.9%oftherespondentsreportedthat microbio-logicalconfirmationwasnotimportantfortheirdecisionsto startantibiotictreatmentforTBinachildyoungerthan5 years-old.ThenewguidelinesformanagementofTBin chil-drenalsostatethatadiagnosisofTBcanbemadewithout confirmationby culture, although they recommend cultu-resforallchildrenwithsuspectedpulmonaryTB.19 Starke
etal.20recommendedthatsamplesshouldonlybecollected
infec-Table2 Importancethatsurveyrespondents(n=64)assignedtodifferentvariablesforinitiationofanti-bacillarytreatment inchildrenunder5years-oldwithsuspectedTB,butwithoutdiagnosticconfirmation.
Variable Alwaysimportant Sometimesimportant Neverimportant
Asthenia 18(28.1%) 41(64.1%) 5(7.8%) Anorexia 20(31.3%) 38 (59.3%) 6 (9.4%) Nightsweating 24(37.5%) 35 (54.7%) 5 (7.8%) Persistentcough 48(75.0%) 13(20.3%) 3(4.7%) Prolongedfever 44(68.8%) 19 (29.6%) 1 (1.6%) Weightloss 49(76.6%) 13 (20.3%) 2 (3.1%)
Familysocialcontext 44(68.8%) 18 (28.1%) 2 (3.1%)
Countryorigin/areaof residencewithhigh prevalenceofTB 53(82.8%) 8 (12.5%) 3 (4.7%) Riskofexposure 56(87.5%) 5 (7.8%) 3 (4.7%) Pulmonarycavitation 50(78.1%) 9 (14.1%) 5 (7.8%) ‘‘Tree-in-bud’’appearance 24(37.5%) 36 (56.2%) 4 (6.3%) Consolidation 27(42.2%) 36 (56.2%) 1 (1.6%) Atelectasis 20(31.3%) 40 (62.5%) 4 (6.2%) Adenopathy 44(68.8%) 19 (29.6%) 1 (1.6%) Pleuraleffusion 32(50.0%) 31 (48.4%) 1 (1.6%) Enlargementofmediastinum 29(45.3%) 33 (51.6%) 2 (3.1%)
tionisdrug-resistant,thereis extra-pulmonaryTB, orthe diagnosisisuncertain.
When diagnosing TB without confirmation by culture, ourrespondentsplacedmostvalue ontheepidemiological context,signsand symptomssuggestiveof disease, radio-logical findings, and results of the TST and IGRA. These resultsaresimilartothoseofMaraisetal.21,22andGraham
etal.13, whoreportedthat diagnosticconfirmation is
dif-ficultin the earlystages of TB, and thatconsideration of recentcontacts,immunologicaldata,andradiologicalsigns allowaccuratediagnosisinmostcases.Similarly,Sant’Anna etal.23,24 reportedthat cultureconfirmation isnot
neces-saryforthediagnosisofTBinchildrenwhohadhadcontact withadultswhohadinfectiousTB,TSTpositivity,orclinical and/orradiologicalfindingssuggestiveofTB.6
Itis,therefore,necessarytodevelop guidelinesforthe diagnosisand treatmentof TB inchildren, inthe absence ofdiagnosticconfirmation,basedonthecriteriamentioned above.Althoughseveralauthorshaveproposedguidelines, theyarenotyetstandardized,makingcomparisonsdifficult, andtheyalsohavenotyetbeenvalidated.25 A‘‘score
sys-tem’’forpaediatricpulmonaryTBinBrazilhadasensitivity of89---98%andaspecificityof86---98%,withoutinclusionof bacteriologicalconfirmation.23,24
MaintainingTB therapywithoutconfirmationof diagno-sismainlyreliesuponclinicalandradiologicalimprovement, becauseresponsetoanti-bacillarytreatmentsupportsa pro-bable diagnosis of TB. However, Marais etal.26 identified
childrenwith persistentradiological signs andparoxysmal exacerbationof symptoms or signs afterstarting therapy, and concluded that these were not indications for chan-ging therapy. This is because radiological improvement may occur several months after resolution of symp-toms. Furthermore, after initiation of therapy,there can be immunological reconstitution phenomena with increa-sed inflammatory responses, in addition to the release
of toxins, and this may explain the exacerbation of symptoms/signs.26
Also,TB witha negativesputum culture is very likely tobepaucibacillary,withaverylowriskofacquiringdrug resistance, and this also favours continuation of therapy despitenoconfirmationof diagnosis.Compliancewiththe completetreatmentregimeniseffectiveinthesecases,due tothelowerprobabilityofadverseeffectsinchildrenthan adults.26
Weidentifiedthreeclustersofrespondentsaccordingto age,experience,andclinicalpractice.Ontheonehand,our resultsshowedthatthosewithlessclinicalexperiencewith TBvaluedthesamefactorsasthosewithmoreexperience (clinicalandradiologicalabnormalities).Ontheotherhand, respondents who were older and worked in primary care settings or hospitals placed greater importanceon immu-nologicaltestresults,especiallytheTST.Thesetestshave limitedability todistinguishlatent TBfromactiveTB3,9,27
andthesensitivityofTSTisverylowin children.3,28
Clini-ciansworkinginspecializedTBcentresgavelessimportance to immunologicaltest results, and greater importance to clinicalpresentationandradiologicalimages.Chenetal.29
showedthatphysicianswhohadlessexperiencewithTBhad anincreaseddurationofdiagnosis,andKamranKhanetal.30
showedthat16.5%ofpatientstreatedbyinexperiencedTB professionalsdiedinthefirstyearafterdiagnosis,compared withonly6.2%ofpatientstreatedbyexperienced TB pro-fessionals.Theseauthorsalsoidentifiedtheimportanceof differencesregardingdirectexperiencewithTB,notsimply intheareaofspecialization.30
A limitation of this study was the low response rate (24.6%). Weidentified names andcontacts usingsoftware that searched published papers on TB in children during the last 10 years.It wasnot possible todetermine if all questionnaires were received,if the email of the corres-ponding authors were stillactive, or ifthe corresponding
authorswere stillprofessionally active.The only datawe have from the correspondent is that he/she published a paper on TB in children and an email address. The cha-racteristics ofarespondentandyearsof experiencewere onlyavailableifthequestionnairewasanswered.However, ourmethodologyallowedidentificationof64clinicianswho made decisionsabout the management ofTB inchildren, andtheserespondentshaddifferentexperiencesandused differentstrategies.Anotherpossibleweaknessofourstudy isthat theanswerscouldnotbevalidated, andbad prac-ticescould havebeen omitted.However,we believe that because the questionnaire was anonymous (we could not linkthenameandemail tothequestionnaire,andall res-pondents were informedof this), respondents were more likelytoprovidehonestanswers.Thestrengthofthisstudyis thatitallowedclusteringofanswersaccordingtoprofession, age, experience, and work location. Our results indicate thereisaclearneedtoestablishawiderbasefordesigning guidelinesusedtodiagnoseandtreatTBinchildren.
Conclusions
The proceduresusedtodiagnose andtreat TB inchildren varyaccordingtoclinicians’experience,worklocation,and age.Thereisaneedforclinicianstousebetterguidelines andtoimprovethediagnosisandtreatmentofTBinyoung children.
Ethical
disclosures
Protection of human and animal subjects.The authors declarethatnoexperimentswereperformedonhumansor animalsforthisstudy.
Confidentialityofdata.Theauthorsdeclarethatnopatient dataappearinthisarticle.
Right to privacy and informed consent.The authors declarethatnopatientdataappearinthisarticle.
Authorship
Sofia Ramos: conceived the study and collaborated in all steps. RitaGaio: performed statistical analysis and revie-wedthe manuscript.Fábio Ferreira:performed statistical analysis.JoséPauloLeal:developedthemethodology.Sara Martins:collaboratedinallsteps.JoãoVascoSantos: contri-butedtostudydesignandreviewedthemanuscript.Isabel Carvalho:reviewed themanuscript.RaquelDuarte: super-visedallaspectsofthiswork.
Conflicts
of
interest
Theauthorshavenoconflictsofinteresttodeclare.
Acknowledgments
Rita Gaio and Fábio Ferreira were partially supported by CMUP(UID/MAT/00144/2013),whichisfundedbyFCT (Por-tugal) withnational (MEC)and European structural funds (FEDER),underthepartnershipagreementPT2020.
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