Pulmonary and Mediastinal TB Diagnostic Approaches

Dr Onn Min Kon TB Clinics St Mary’s Hospital + Hammersmith Hospital

History – ‘back to basics’ • • • • •

Symptoms Ethnicity/ age Recent arrival/ travel history Contact history BCG history

Table 1.2: Tuberculosis case reports by site of disease, UK, 2012 Site of disease*

Number of cases 4,563

Percentage** 52.1

Extra-thoracic lymph nodes

1,872

21.4

Intra-thoracic lymph nodes

946

10.8

Other extra-pulmonary

619

7.1

Pleural

651

7.4

Gastrointestinal

471

5.4

Bone – spine Cryptic ±

394

4.5

46

0.5

±

197

2.3

Bone – other

218

2.5

CNS – meningitis

187

2.1

Genitourinary

137

1.6

CNS – other

80

0.9

Laryngeal

16

0.2

Unknown extra-pulmonary

15

0.2

Pulmonary

Miliary

*With or without disease at another site **Percentage of cases with known sites of disease (8751) ±For Scotland cases, this includes both cryptic and miliary site CNS - Central Nervous System

Total percentage exceeds 100% due to infections at more than one site

Source: Enhanced Tuberculosis Surveillance (ETS), Enhanced Surveillance of Mycobacterial Infections (ESMI) Data as at July 2013 Prepared by: TB Section, Centre for Infectious Disease Surveillance and Control, Public Health England

Tuberculosis in the UK: 2013 report

ER studies

Breen IUALTD 2008 PTB 2003 - 2006 n=143 •Absent fever 37% •Absent sweats 39% •Absent weight loss 38% •All three symptoms were absent in 25% •factors associated drug-resistant TB ( aOR 3.58, P = 0.004) Non-HIV vs HIV (aOR 4.03. P=0.001)  female sex (aOR 3.15, P = 0.004)

Clinical Manifestations: Signs • • • • • • • • •

None Weight loss Usually few or none in chest Lymphadenopathy (esp ISC) Erythema nodosum (1ry) Uveitis (1ry) Phylectenular conjunctivitis (1ry) Lupus vulgaris Clubbing (chronic)

Clinical Diagnosis TB Pulmonary Chest X-Ray Presentations • Primary TB* – Mediastinal lymphadenopathy • Normally unilateral • Only 15% Bilateral Hilar Lymphadenopathy

– Pleural effusion – Lobar collapse/consolidation • Any segment • Anterior RUL/ medial RML commonest

– Miliary Pneumonic lesion with enlarged hilar nodes - consider primary TB

Clinical Diagnosis TB Pulmonary Chest X-Ray Presentations • Post-Primary TB – Classical: • • • •

– – – – –

Apices Apical and posterior segments Soft ‘fluffy’ /nodular upper zone Cavitation (10-30%)

Mid-zone disease (apex lower lobes) Bronchopneumonia Consolidation (Pleural effusion) Lymphadenopathy rare Beware the immunocompromised confounder

‘Normal’ CXR’s • SMH data – 13% ‘normal ‘ CXR’s with definite PTB Int J Tuberc Lung Dis. 2008 Apr;12(4):397-403. Normal chest radiography in pulmonary tuberculosis: implications for obtaining respiratory specimen cultures. Pepper T et al. • • • •

Urban TB clinic - Nashville October 1992 -July 2003 601 study patients 53 (9%) had normal CXRs: – 31/138 (22%) were human immunodeficiency virus (HIV) infected – 22/463 (5%) were non-HIV-infected/unknown

Clinical Manifestations PTB Role of CT • • • • • • •

‘Normal’ CXR Miliary Tree-in-bud Cavitation Lymphadenopathy Ruling out other diagnoses (Extrapulmonary sites)

Miliary TB • • • • • • •

2-6% primary TB 2-25% choroidal tubercles Fever 90% (classically morning) Hepatomegaly 1/3-1/2 Splenomegaly 15-30% Skin tests negative in 50% ?role of IGRA’s Anaemia 50%/ leukopenia 15%/lymphopenia 90%/leukaemoid reactions • 1-3 mm nodules (millet seed) – Micronodules yellow-white – Caseation in alveolar walls and interlobular septa

Miliary TB ii • HRCT – – – – – –

More sensitive (CXR only 59-69%) fine nodules Uniform distribution Interlobular septal thickening/ groundglass rare Rare diffuse alveolar filling Do not scar with calcification

Miliary TB iii • Diagnosis – – – – – –

Sputum only 50% positive culture TBB 63% positive histology/smear Lung/ liver/ spleen 80-90% Kidney 60% Bone Marrow 25-75% Use CSF to define length of treatment (CSF disease in up to 20%) – Tuberculin test poor sensitivity

• Trial of treatment

– Expect pyrexia to respond 7-10 days – Clinical improvement 4-6 weeks

‘Tree in bud’ • • • •

Multiple linear branching structures Lobar or segmental ?Marker of activity Good marker of TB in association with cavitation/ nodular opacification

Intrapulmonary LN • • • •

> 2cm Unilateral Paratracheal/hilar/subcarinal Hypodense central area – correlates to necrosis

• Rim enhancement • Calcify later

‘Get the bug’ • • • • • •

Sputum induction Bronchoscopy EBUS/EUS PCR techniques Drug resistance ‘fast track’ techniques Imaging / role of PET

Culture • • •

Chief Medical Officer’s Action Plan Stopping Tuberculosis in England 65 % of all pulmonary tuberculosis cases to be confirmed by culture European Centre for Disease Prevention and Control target PTB > 80 % culture confirmation UK 2013 report: – – – – –

•

59.4% (5,200/8,751) were culture confirmed Pulmonary cases 68.7% Extra-pulmonary cases 49.5% Only 60.5% of pulmonary TB cases (2,761/4,563) had sputum smear result 51.1% (1,411/2,761) were sputum smear +ve

Leahy et al - St Mary’s (ICHNT)/ RFH/ UHBT – – – –

Among 123 cases PTB 91% had sputum or lung fluid sent for smear and culture 56% smear positive 80% being culture-positive

Respiratory TB Samples • Sputum • Induced sputum • Bronchoscopy/BAL • Gastric lavage • Pleural aspirate/biopsy • Biopsy CT guided/thorascopic • Lymph node biopsy/aspirate • Transbronchial needle aspiration • Endobronchial Ultrasound Needle Aspiration • Endoscopic Ultrasound Needle Aspiration

Smear positivity and bacillary load

Smear negativity and bacillary load

Effect of number of samples + concentration Peterson et al, J Clin Micr 1999; 37(11): 3564-8 US study compared cumulative proportion of +ve smears upon microscopy for direct vs concentrated sputum (all patients were subsequently M. tuberculosis culture +ve); 3 or more specimens were received: Sample 1 1,2 1,2,3

Direct 57 76 81

(%)

Concentrated (%) 74 83 91

ECDC/ERS TASK FORCE REPORT ERJ 2012 • Based on feasibility and cost-effectiveness analyses, the WHO and the ISTC recommend the collection of at least two sputum samples for diagnosis • Collection of a third sample has been shown to increase the diagnostic yield by 2–3%, EU/ EEA countries may decide to maintain the previous recommendation of collecting three sputum samples on the same day (not necessarily on consecutive days) • at least one early morning sample from the patient

Sputum Practicalities • Minimum 3 samples • At least 1 sample first thing in morning • Induced sputum – – – – –

3% Hypertonic saline 20 minutes using ultrasonic nebuliser Infection control issues Better yield than gastric wash in children 3 consecutive better yield than bronchoscopy?

Nucleic Acid Amplification In respiratory samples: • High specificity 95-100% • Sensitivity 50-95% • Most positive in smear positive cases • Least positive in smear negative cases

NAA – NICE 2006/2011 Indications: 1) rapid confirmation of a diagnosis in a sputum smear-positive person would alter care OR 2) before conducting a large contact-tracing initiative 3) Rapid diagnostic tests for M. tuberculosis complex identification should be conducted on biopsy material only if: ● all the sample has been inappropriately placed in formalin, and ● AFB are visible on microscopy. Non-respiratory TB •

Even if rapid diagnostic tests are negative (eg pleural fluid, CSF and urine) - Clinical signs and other laboratory findings consistent with TB meningitis should be Rx

Chang 2012 • • • • • • •

PTB Sensitivity 90.4% PTB Specificity 98.4% Sensitivity Rif resistance 94.1% Specificity for Rif resistance 97.0% EPTB Sensitivity 80.4% EPTB Specificity 86.1% Paediatrics PTB less (74.3%) than adults (90.8%)

Steingart KR, Sohn H, Schiller I, Kloda LA, Boehme CC, Pai M, Dendukuri N. Xpert® MTB/RIF assay for pulmonary tuberculosis and rifampicin resistance in adults. Cochrane Database of Systematic Reviews 2013, Issue 1. Art. No.: CD009593. •

Initial test replacing smear microscopy (15 studies, 7517 participants) – –

•

Add-on test following a negative smear (14 studies, 5719 participants) – –

• • • • •

pooled sensitivity of 67% pooled specificity of 98%

Smear +ve, culture +ve TB - pooled sensitivity was 98% (95%CrI 97% to 99%) Smear -ve, culture +ve TB - pooled sensitivity was 68% (95% CrI 59% to 75%) HIV +ve - pooled sensitivity 80% (95% CrI 67% to 88%) Non HIV – pooled sensitivity 89% (95% CrI 81% to 94%) Rifampicin resistance detection (11 studies, 2340 participants) – –

•

pooled sensitivity of 88% pooled specificity of 98%

pooled sensitivity of 94% (95% CrI 87% to 97%) pooled specificity of 98% (95% CrI 97% to 99%)

Distinguish between TB and nontuberculous mycobacteria (NTM) –

139 specimens with NTM, was positive in only 1 specimen

Steingart KR, Sohn H, Schiller I, Kloda LA, Boehme CC, Pai M, Dendukuri N. Xpert® MTB/RIF assay for pulmonary tuberculosis and rifampicin resistance in adults. Cochrane Database of Systematic Reviews 2013, Issue 1. Art. No.: CD009593

• False positive rates if hypothetical cohort of 1000 individuals suspected of having rifampicin resistance (proxy for MDR-TB) • Prevalence of rifampicin resistance: – High prevalence 30% - wrongly identify 14 cases – Low prevalence 2% - wrongly identify 20 cases (increase of 43%)

Bronchoscopy • In smear negative disease – BAL +ve AFB in 34% – BAL culture +ve in 95% – Exclusive diagnosis in 46%

• Endobronchial involvement • Miliary disease – consider transbronchial biopsy (73%) and brush (57%)

• • • •

Excluding other causes of obstruction Infection control issues Safe Post bronchoscopy sample

Bronchoscopy post negative Induced Sputum • Diagnostic yield of bronchoscopy in patients with -ve initial induced-sputum results both via smear and NAA testing • Methods: 30 consecutive cases of suspected PTB between 2001 and 2007 with diagnostic bronchoscopy after negative IS • BAL was culture positive for M-TB in 3/30 cases (10%)

• • • •

19/57 (33.3%) converted to smear positive post bronchoscopy 5/57 (8.8%) exclusively smear positive on PBS 43/57 (75.4%) cultured on PBS sample 4 (7%) exclusively PBS culture

Urine Based Diagnostic Tests Lipoarabinomannan (LAM) •Glycolipid outer membrane MTB (but also other mycobacteria) •Antigen excreted by urine •Commercially available assays •Performs well in HIV +ve - Best at lowest CD4 counts •Less promising non-HIV TB •ELISA (Clearview) or lateral flow assays (Allere) •Lateral Flow – sens 37% spec 97% in micro proven (very similar to ELISA) •CD4 < 100 – sens 19.6% vs CD4 > 100 sens 63% •TB-LAM Ag urine dip stick - Point of care - Cheap ($3.50 per test)

Niche – HIV and CD4 < 100 SE Dorman IUALTD 2012

Bronchoscopy vs Induced Sputum? • Current data – probably equivalent in high probability PTB • No good head to head studies • Bronchoscopy – if significant differential diagnosis – Directed to limited lesions – Combine FNA/TBBx/EBUS

• Pragmatics/ infection control

Suspected PTB 3 x sputum -ve

Localised disease ?alternative diagnoses No

Induced sputum -ve

Yes

Bronchoscopy

TBNA in TB •

Bilaçero lu et al. - Chest 2004;126:259-267 – non HIV Histo/cytological

63 (75%) cases histology - 48 patients [76%]; cytology - 9 patients [14%] bacteriologic studies

•

21 patients [33%] smear 8 patients/ culture 17 patients Harkin et al. - Am. J. Respir. Crit. Care Med. 1998;157,6, :1913-1918 – – – – – –

HIV cases 44 procedures in 41 patients Adequate sampling - 80% Diagnostic - 23 of 44 (52%) procedures TBNA exclusive diagnosis -13 of 41 (32%) patients 23 (52%) patients with mycobacterial disease - diagnosis in 20 of 23 (87%) Of positive TBNA Sm +ve 11, culture in 14, histology in 15

Endoscopic Ultrasound (EUS) Needle Aspiration • Negligible risk of infection or bleeding • Good for inf pulm ligament, subcarinal, and APW nodes • Difficult to sample anterolateral to the trachea (2R, 2L, 4R and 4L)

Granulomatous mediastinal adenopathy: can endoscopic ultrasound-guided fineneedle aspiration differentiate between tuberculosis and sarcoidosis? Fritscher-Ravens A, Ghanbari A, Topalidis T, Pelling M, Kon OM, Patel K, Arlt A, Bhowmik A. Endoscopy. 2011 Nov;43(11):955-61

• • • •

72 consecutive patients with mediastinal lymphadenopathy > 12 months' follow-up including further investigations Adequate samples 71/72 patients (36 male; mean age 50.2 years) Final diagnosis – – – – –

• •

30 cases of sarcoidosis 28 of tuberculosis 4 malignancies 1 abscess 9 benign lymphadenopathies

The size of lymph nodes on EUS varied from 0.5 cm to 4.2 cm Results – Clinical TB Sens 86%, spec 100%, and PPV 100% and NPV 100% – Sarcoidosis were Sens 100%, spec 93%, and PPV 91% and NPV 100% – Culture TB : Sens 71%, spec 100%, and PPV 100% and NPV 84%

•

EUS FNA led to a definite diagnosis in 64/72 cases (89 %)

Thorax 2011

Methods

• Multicentre Study

– SMH, UCL, GST, Papworth

• Patients' with Intrathoracic lymph node TB who underwent EBUS identified • Exclusion criteria – BAL or Sputum Smear positive – Other peripheral nodes to sample – Must have completed and responded to TB treatment

Results • 156 cases over 4 sites • Diagnostic procedure in 146 cases (94%) • Pathology consistent with TB in 134 (86%) • Microbiology consistent with TB in 82 (53%) – Smear 27 patients (17%) – Culture 74 (47%) – 8 patients (5%) were Isoniazid resistant

• Mediastinoscopy – Positive histological/microbiological daignosis in 71% – Culture positive rate of 48% – 1-2% morbidity and General Anaesthetic

How does EBUS compare? • Endoscopic ultrasound guided fine needle aspiration (EUS-FNA) – Diagnostic yield 86-93%, Culture rate 21-71%? – Doesn’t allow access to Rt. Paratracheal Nodes which were sampled in 47% of our patients • Mediastinoscopy – Culture positive rate of 48-70% – 1-2% morbidity and General Anaesthetic – posterior sub-carinal and hilar nodes are inaccessible • Bronchoscopy and Blind FNA? – 26% Culture rate (17/63)

Pleural TB •

Rupture of sub-pleural caseous focus into pleural space

•

Aspirate – – – – –

Straw coloured High protein (ratio > 0.5) Low glucose pH 7.2-7.4 Lymphocytic >50%

– Raised ADA (>40IU sensitivity 96-100% specificity 89-97%) – Pleural interferon gamma > 138pg/ml sensitivity 90% and specificity 97% – Smear < 5% – Culture only positive in 23-67% – ?role of PCR

Gene Xpert and Pleural TB Christopher et al ERJ 2013 Jul 30

Other Nucleic acid amplification Tests in TB pleuritis • Lin CM et al Plos One 2012; 7(9): 44842 – – – –

Retrospective analysis 150 suspected TB pleural effusions 55 confirmed TB pleural effusion 20/55 positive AMTD (36.4% sensitivity) Sensitivity of pleural fluid + sputum culture + AMTD+ pleural biopsy = 82.4%

• Rosso et al BMC Res Notes 2011;4:29 – 150 suspected pleural effusions – 98 confirmed TB effusion – 42.8% sensitivity, 98% specificity MTB PCR

• Pai et al BMC Inf Dis 2004; 4:6 – Meta analysis of NAATs - 62% sensitivity

Pleural TB 2 • Pleural Biopsy – Histology Granuloma - yield increases to 60% (?87% with 6 passes in experienced hands) – Culture (can increase microbiology yield to 80-90%) – Archival tissue can use NAA techniques (low sens/hi spec)

• Parenchymal involvement significant (18.9-78%) – Consider CT and BAL/induced sputum (50%)

• VATS – High sensitivity and specificity ?role medical thoracoscopy

PET Standardised uptake value (SUV) corrected for body weight >3-4 definite