Smear Negative PTB

Speaker: Previous Miri GH Medical Department Officer

 Definition
1. Clinical&RadiologicalfindingssuggestiveofTB
2. SmearAFB(atleast2):Negative
3. DecidedbyPhysiciantotreatasPTB.

4. Smearnegative,laterconfirmedbyculture,biopsyor
otherinvestigations.
50 years old man
CXR on 16/7/2012 and 22/8/2012
Given augmentin X 1 week
LOA for 2 month, LOW 2kg in 2 months.
SAFB x6 negative, mantoux 25mm
 Smear + : 5000-10 000 bacilli/ml of sputum2
Culture+: 10-100 bacilli/ml of sputum2
NAA technique: 1 bacilli.

1. Lin PL et al. J Imunol 2010; 185:15

2. Rouillon A. Transmission of tubercle bacilli:the effects of chemotherapy. Tubercle 1976;57:275
 Numberofbacteriaseenon
microscopyandinterpretation
 Burdenofthedisease
Thereare1.22 casesofsmearnegativeandextrapulmonary
TBforeverycaseofsmearpositiveTBindeveloping
countries1.

Morecommoninchildren,elderly,immunocompromised
(HIV,drugs,CKDetc).

Lowbacillaryburdenwithminimaldiseaseandno/less
cavitationescapeclinicaldetection.

1. Murray CJL, Styblo K, Rouillon A. Bull Int Union Tuberc Lung Dis 1990;65(1):6-24
LocalData
 TYPE OF NEW TB CASES DETECTED,
SARAWAK 2005
1329
1400

1200

1000

800

600
22
400
0
200

0
PTB EXTRA TB
Neg 463 220
Pos 865 0
 Transmissionofdisease
The relative transmission rate from patients with
smear-negative compared with smear-positive
PTB is around 22%.

Easier to treat. Better response, less relapse

rate.

Behr MA. Transmission of MTB from patients smear negative for AFB. Lancet
1999;353:444
 Clinicalpredictors
Historyaloneisnotabletodiagnosesmear
negativePTBconfidently.

LOA,fever,nightsweat,chestpain,
hemoptysisandbreathlessnessaremore
commoninPTBpatientscomparetothose
withoutPTB.
DifferentialdiagnosisofsmearnegPTB
1.OLD PTB
2. CAP
3.Old Scar-previous infection
4.Cancer
5. Bronchiectasis
5. ILD
6. Other infection-Meliodosis,
fungal infection. (esp if HIV +)
 SensitivityofAFBsmearmicroscopy
Smearmicroscopysensitivity:2280%incultureprovencases1.
Specificity>96%,PPV5080%
Falsepositive
NTM
Qualityofthesmearmicroscopyperformanceunderliesdifferencesin
sensitivity.

1. Kim TC. AFB in sputum smears of patients with PTB. Am Rev Respir Dis 1984;129:264
2. Rouillon A. Transmission of tubercle bacilli:the effects of chemotherapy. Tubercle 1976;57:275
 Reason for smear negative
Poor quality of specimen
Low bacilli load.
Inexperience laboratory technician-false
negative.
Immunocompromised state ie HIV
Extra-pulmonary TB
Not TB
Whatcanwedotoimprovemicroscopyyield?

Ensureatleast2/3goodqualitysputum(5
10mL)aresent.

Labenhancement:Ensureadequatetraining,
qualityassessmentandfacilities.

Useofothermicroscopytechniques:
Flourescence/LEDmicroscopy.
 Inducedsputumformicroscopy
90%sensitivity.
Gastriclavage=77%sensitivity
Bronchoscopy=77%sensitivity.

Inducedwith3%saline,usingultrasonic
nebulizertoadm56mL/minover15minutes.
Almostallpatientswillproducesputum.
Sensitivity
>5ml:92%
All specimens were process regardless of volume: 72.5%

Procedure
1. Decontamination: 2.0% NAOH+mucolytic agent NAC.
2. Incubation
3. Centrifugation/cytocentrifugation
4. Auramone-rhodmine fluorochrome staining
5. Entire smear examined.
 Mycobacterialculture
TheGoldstandardofdiagnosis
Sensitivityof3cultures>90%.
Falsepositive:contamination,NTM.
Solidvs liquidculturemedia.

AllpatientswhoaresuspectedofhavingTB
shouldhaveatleastoneTBculturedone.
 MycobacterialCulture
Local culture center

Culture resemble Negative

mycobacterium identified
Report

National culture center:

Sungai Buloh(MKAK):
Identification and sensitvity

Report Via MKAK Website

http//www.los.moh.gov.my/result/
 Tuberculinskintest:
Mantoux Test
PositiveTSTmaybedueto:
1. TBinfection:bothLatentorActive
2. PreviousBCGvaccination
Reaction>15mmofinduration,esp ifBCGwasgiven>15yearsago,arenot
likelycausedbyBCG.
BCGgivenatinfancyunlikecausingpositiveTSTesp inadult.
3. Atypicalmycobacteriumexposure.

>5years later >5years later

 TSTmantouxtest
Unabletodifferentiatebetweeninfectionvs
disease.(SameforIGRA:Quantiferon/Tspot
TBtest)
Forthediagnosisofactivedisease,TSTand
IGRAareNOTrecommended.
 TST
Falsenegative(2030%ofactiveTBcasesat
thetimeofinitialdiagnosis)
Elderly
Severehypoalbuminemia
Disseminatedtuberculosis
Immunocompromisedhost
Recentaccuteinfecion
Recentvaccinationwithlivevirus
ChronicillnessCKD
 In patient and outpatient setting.
1988
Mantoux Test: 0.1ml of PPD-RT25 (2TU).
Positive mantoux: 10mm.
85 cases of active TB cases: sputum direct smear, biopsy or culture.
30 cases of old TB: based on history, CXR, direct smear and culture.
17 of the 30 cases of old TB had positive mantoux.

Sensitivity: 73/112=65% PPV=73/85=85%

Specificity: 344/356=96% NPV=344/468=73%
 ESR
Toononspecific
Shouldnotbedependoninthediagnostic
algorithm.
 CXR
92%ofPTBcasesinlowTB/HIVprevalentcountrieshavetypicalappearanceson
CXR1

Only8%haveatypicalappearances:Lowerlobeinfiltrates,hilar lymphadenopathy,
miliary pattern,normal)

Sensitivity=7080%basedontypicalCXRChanges.
Specificity=6070%.

AsurveyinMalawi:MOmisdiagnosed1/3ofclinicalvignetteswhichdescribed
typicalradiographicsignsofTB2

Oldvs activeTB

1. Wilcke JT. Respir Med 1998;92:493

2. Harries AD. Bull World Health Organ 1998;76:651
 Management
1. Make sure
1. Take a good history and clinical examination.
Look for alternative diagnosis.

2. Sputum are really negative

Consider 3% NS neb for sputum induction, NG aspirate for AFB in
children, poor GCS patients.

3. Sputum is sent for TB culture and sensitivity.

If you dont send, it will NEVER come back.

4. CXR is reported by radiologist

Trace old CXR

5. Refer physician for decision on treatment.

 Clinical Decision Analysis
Symptoms/Si Imaging SputumAFB TBC/S Remark
gns (CXR)
+ + + + Treatment
+ + /pending Further Investigation or
treatment
+ FurtherInvestigation
+ + +/pending Treatment
+ + F/up SputumTBC/S
Laberror?(onlyscanty/one
SputumAFBpositive)
+ Furtherinvestigation
>>treatment

Consider clinical urgency of treatment.

 Improving the
diagnosis and
treatment of
smear-negative
pulmonary and
extrapulmonary Missed up to
54% of culture
tuberculosis pos case.
among adults and (DTM Nguyen; Tubercul

adolescents Research and

treatment;2012)

Recommendations Sensitivity=38.1
for HIV-prevalent and %.Specificity=
resource-constrained 74.5%
settings ( HF Swai BMC Research
ntes 2011;4:475)
 SPUTUM TB CXR
C/S
CXR consistent
+ with PTB

NO

Further
investigation
NAAT if
SPUTUM TB available
C/S
 TrialofAntibiotic
NottouseanyantiTB drugs,bothfirstlineor
secondline.
Quinolone:veryeffectiveSecondline AntiTB!!!
Augmentin:WHOclass5antiTB drug(uncertain
antiTB activity)
Amoxycillin,cefuroxime.Tetracycline.Doxycycline.

ONLYBEDONEAFTER3SMEARSARENEGATIVE
 TrialofAntibiotics
50%ofSmearNegCulturePoscasescan
responsetoantibiotic1.
Unrelatedfluctuationsindiseaseseverity
Successfultreatmentofasuperimposedbacterial
infection.
Unabletoexcludenonpneumonialung
diseases.

1. Wilkinson D. Diagnosing tuberculosis in resource poor setting:the value of a trail of

antibiotics. Trans Roy Soc Trop Med Hyg 1997;91:422
 TrialofTBdrugs
Notrecommended.
Poorspecificity:bacteriainfectionresponseto
rifampicin.
antiTBdrugstoxicity
DelayindiagnosisofnonTBdisease
ATTdrugresistance
 FurtherInvestigation
usealltoolsthatyouhavetoestablishthe
diagnosisifpossible.
1. CTThorax/HRCT
2. BAL,Transbronchial lungbiospy,openlung
biopsy.
3. FNAC,pleuralbiopsy.Etc
4. UseofNucleicacidamplificationtests.
5. Othertestsdeemedrelevant.
 HRCTLung
Candefinetheanatomicaldistributionbetter.

Betterindefiningmass,cavity,consolidation,patternof
diffusenodules(random,lymphatic,centrilobular),collapse,
interstitialinvolvement.

HM Lee, Respiration 2010;79:454

67 years old lady with cough for 4
months. Weight loss of 6Kg.
Chronic smoker
Clinically crepitation noted at right upper
zone.
Right upper lobe mass with Lymphangitis
carcinomatosa
Bronchoscopy with Transbronchial lung biopsy:
Adenocarcinoma
 NAATinSmearNeg PTB
Metaaanalysis ofcommerciallybasedNAATforrespiratorysample.
InsmearPos PTB:Sensitivity=96%,specificity=85%.
InsmearNeg PTB:sensitivity=66%(5080),specificity=98%,
PPV=>95%.
Falsepostive ratecanbeveryhighifcarefulattentiontolab
qualitynotobserved.(CanadianTBStandard6th ed)

S. Greco et al. Thorax 2006;61:783

 NAATforthedetectionofSNTB
Xpert MTB/RIFassay:
Sensitivity72.5%forSmearNegculturepositiveisolates.
SecondXpert:increasesensivity by12.6%
ThirdXpert:increasesensitivityby5.1%.
Specificity=99.2%

Boehme CC. NEJM2010;363:1005

 SNTB:GenoType MTBDRplus
Crosssectionalstudy,SouthAfrica,Goldminers,29%HIV,highprevalence
ofsilicosis(Thibela TBcohort)

Smear Sensitivity
status
Negative 13.7%
Scanty 46.2%
1+ 69.1%
2+ 86.3% S.E Dorman.JCM, 2012
3+ 89.8%
 USCDC2009recommendationon
commercialNAAT
Smear NAAT Culture Recommendation
+ + pending TreatasTB.Traceculture.
+ pending 1. UseClinicaljudgment todecideonTBTreatment.
2. Consideradditionaltest.
3. CanconsidertosendsecondNAAT(apersoncanbe
presumedtohaveTBifbothNAATpositive,pending
culture)
pending 1. Useclinicaljudgment todecideonTBtreatment
(NAATunabletoexcludeTB)
2. Consideradditionaltests.
+ Pending 1. Send amplificationinhibitortestandrepeatNAAT.
2. IfInhibitornegClinicaljudgment/additionaltest.
3. ifinhibitorsneg +secondNAAT:presumedNTM
4. Ifinhibitorpositive(37%):NAATisnotausefultest.
 Case Study
65yearsold
gentlemen.
Coughfor5months,
LOW5Kg.
Well
Leftsupraclavicular
LN,Hard
 Summary
Develop your clinical acuity.

Read, ask.

Use all tests available to diagnose TB

Nucleicacidamplificationtestandbronchoscopyimprovethediagnosticaccuracyof
smearnegativetuberculosis.
Int J Tuberc Lung Dis. 2012
DESIGN: Dec;16(12):1674-9
BronchoscopywasperformedamongsmearnegativePTBsuspectstocollect
respiratoryspecimenstoassesstheefficacyandaccuracyoftheAmplified
MycobacteriumTuberculosisDirect(AMTD)testinthediagnosisofPTB.
RESULTS:
In105PTBsuspects,80werefinallyexcluded,ofwhomtwowerefalseAMTD
positive.PTB(n=25)wasdiagnosedin10patientsculturepositivefor
MycobacteriumTuberculosis(7/105bronchialwash/bronchoalveolarlavage
[BW/BAL]specimens,6/315expectoratedsputumspecimens[2positivein2
patients;1positivein2patients],andonewithboth),andin15patientswith
improvementafterantituberculosistreatment.Amongthe25PTBpatients,20
wereAMTDpositive,ofwhomfourwereculturepositive.ThreeAMTDnegative
patientswereculturepositive.ThesensitivityandspecificityofAMTDwere
respectively80.0%and97.5%.Thediagnosticyieldwashigherinrespiratory
specimensobtainedatbronchoscopyandmeasuredbyAMTDthaninconventional
sputumorBW/BALculture.
CONCLUSION:
NAAtestingonspecimenscollectedusingbronchoscopyprovidesahighlyefficient
andreliableapproachinthediagnosisofPTBinsmearnegativePTBsuspects.