Diagnosis of Lymph Node TB
Simon Bailey
Chest Physician
Manchester Royal Infirmary
Thur 6th Nov 2014
Overview
• Epidemiology – local data
• Patients present
• Case presentation – What would you do?
• Approach peripheral and mediastinal LN TB
• Newer molecular techniques
Eurosurveillance, Volume 18, Issue 12, 21
March 2013
UNITED
KINGDOM
2,360
49%
492
10%
130
3%
181
4%
320
7%
349
7%
150
3%
Eurosurveillance, Volume 18, Issue 12, 21
March 2013
89
2%
61
1%
647
14%
Proportion of TB case reports by site of disease, UK, 20042013
100
Proportion of cases (%)
90
80
70
60
50
40
30
20
10
0
2004
2005
2006
2007
2008
2009
Year
Pulmonary*
2010
Extra-pulmonary only
* With or without extra-pulmonary disease
Source: Enhance Tuberculosis Surveillance (ETS), Enhanced Surveillance of Mycobacterial Infections (ESMI)
Data as at: May 2014. Prepared by: TB Section, Centre for Infectious Disease Surveillance and Control, Public Health England
5
2011
Tuberculosis in the UK: 2014 report
2012
2013
Tuberculosis case reports by site of disease, UK, 2013
Cervical
Axillary
Inguinal
Intramammary
Mediastinal/
hilar
Site of disease*
Pulmonary
Extra-thoracic lymph nodes
Unknown extra-pulmonary
Intra-thoracic lymph nodes
Pleural
Other extra-pulmonary
Gastrointestinal
Bone – spine
Bone – other
±
Miliary
CNS – meningitis
Genitourinary
CNS – other
Cryptic
Laryngeal
Number of cases
Percentage**
4,096
1,874
931
916
673
689
432
353
220
52.1
23.9
11.9
11.7
8.6
8.8
5.5
4.5
0.5
211
172
145
129
39
19
2.8
2.7
2.2
1.8
1.6
0.2
*With or without disease at another site
**Percentage of cases with known site 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: Enhance Tuberculosis Surveillance (ETS), Enhanced Surveillance of Mycobacterial Infections (ESMI)
Data as at: May 2014. Prepared by: TB Section, Centre for Infectious Disease Surveillance and Control, Public Health England
6
Tuberculosis in the UK: 2014 report
2,763 35.6%
MRI Data
Christine Bell
Scrofula – King’s Evil
Clinical Presentation
•
•
•
•
•
Well. Only 44% symptoms Lee et al. Laryngoscope 102:Jan 1992
Painless
Cold abscess
Discharge
Different teams – ENT(32%), Surgeons(3.7%),
A+E(19%), Resp(33%), others(8%) - Haem
M. Gilhooly, M Woodhead. Efficacy of diagnostic techniques used for the investigation of lymph node Tuberculosis
• Bacterial load low. Formalin doesn’t help!
5 Stages – Jones and Campbell 1962
1. Enlarged, firm, mobile,
discrete nodes
2. Large rubbery nodes
fixed to surrounding
tissue
3. Central softeningabscess
4. Collar stud formation
5. Sinus tract formation
Jones PG, Campbell PE. Br J Surg.
1962;50:302-314
Lymph Node Stations
Diagnostic challenge
•
•
•
•
•
NTM
Bacterial
Fungal
Toxoplasmosis
Sarcoidosis
•
•
•
•
Cat scratch disease
Cystic Hygoma
Non specific hyperplasia
Malignancy
Hierarchy of diagnosis
1. Clinical diagnosis – Hx and Exam
2. Pathological
Cytological – FNA
Histological – Surgical
3. AFB’s
4. Molecular – PCR and others.
5. Microbiological - SENSTIVITIES
39yr Nepalease man – R groin LN
39yr Nepalease man – R groin LN
‘Large groin LN. 2.7X3.7cm
right paratracheal LN.
5mm R ML GGO’
Q. How do you proceed?
Q. What do you do next?
1. FNA to R groin? – cyto,micro,molecular and
start Tx if granulomatous
2. FNA to R groin? – cyto,micro,molecular and
start Tx only if PUS
3. Excisional biopsy R groin and await the
results?
4. FNA to R groin, Bronchoscopy (wash R
middle lobe) and EBUS (R paratracheal)
Q. What do you do next?
1. FNA to R groin? – cyto,micro,molecular and
start Tx if pus
2. FNA to R groin? – cyto,micro,molecular and
start Tx if granulomatous
3. Excisional biopsy R groin and await the results?
4. FNA to R groin, Bronchoscopy (wash R
middle lobe) and EBUS (R
paratracheal)
What we did
• 13/8 – FNA R groin in clinic. No PUS
What we did
• 13/8
• 13/8
• 18/8
• 18/8
– FNA R groin in clinic. No PUS
– Granulomatous lymphadenitis(email)
WE HAD A GOOD THINK!!
– FNA X2 – green needle. All for TB
- Bronch – lavage R middle lobe
- EBUS – R paratracheal node
- Voractiv
R Groin FNA X2
Q. To FNA or to Biopsy?
Peripheral nodes
1995-2004
100 patients
90%
L P Ormerod et al. Int J Tuber Lung Dis
2011:15(3):375-378
Open biopsy gold standard
TABLE IV.
Comparison of results from diagnostic procedures
Method used
FNAB
Open Biopsy
(29 patients) (30 patients)
Positive culture
18(62%)
28(93%)
Positive pathology
16(55%)
23(77%)
Positive AFB’s
10(34%)
11(37%)
Non diagnostic
5(17%)
Lee et al, Cervical tuberculosis.
Laryngoscope 102:Jan 1992
Or is it that Good?
Table3. Diagnostic tests in tuberculous lymphadenitis
Procedure
No. Positive Total % positive
Fine-needle aspirate
Cytology
11
35
31
AFB smear
7
21
33
TB culture
9
18
50
Excisional lymph node biopsy
Histology
76
78
97
AFB smear
45
77
58
TB culture
38
61
62
M. Y. Khan et al. Clinico-diagnostic experience with tuberculous
lymphadenitis in Saudi Arabia
ClinicalMicrobiologyandInfection,Volume6Number3,March2000
TABLE 3,Primary Diagnostic Tests in Tuberculous Lymphadenitis
Location (Year)
Culture (+)
AFB (+)
GI (+)
Culture + GI (+)
NAAT (+)
California (‘92)
Excisional Biopsy
28/30 (93%)
11/30 (37%)
23/30 (77%)
N/A
N/A
FNA
18/29 (62%)
10/29 (35%)
16/29 (55%)
N/A
N/A
Excisional Biopsy
12/39 (31%)
2/39 (5%)
32/39 (82%)
N/A
N/A
FNA
8/26 (31%)
2/26 (8%)
N/A
N/A
N/A
44/238 (18%)
58/238 (24%)
84/238 (35%)
N/A
N/A
Excisional Biopsy
4/22 (18%)
5/22(23%)
13/22 (59%)
17/22 (77%)
15/22 (68%)
FNA
2/22 (10%)
4/22 (18%)
7/22 (32%)
9/22 (41%)
12/22 (55%)
Excisional Biopsy
24/34 (71%)
15/39 (38%)
36/31 (88%)
N/A
N/A
FNA
UK (‘10)
FNA
48/77 (62%)
5/19 (26%)
47/76 (62%)
N/A
N/A
65/97 (67%)
22/97 (23%)
77/97 (79%)
88/97 (91%)
N/A
France(‘99)
California(‘99)
FNA
India (‘00)
California (‘05)
Clinical Infectious Diseases
2011;53(6):555–562
TABLE 3,Primary Diagnostic Tests in Tuberculous Lymphadenitis
Location (Year)
Culture (+)
AFB (+)
GI (+)
Culture + GI (+)
NAAT (+)
California (‘92)
Excisional Biopsy
28/30 (93%)
11/30 (37%)
23/30 (77%)
N/A
N/A
FNA
18/29 (62%)
10/29 (35%)
16/29 (55%)
N/A
N/A
12/39 (31%)
2/39 (5%)
32/39 (82%)
N/A
N/A
N/A
FNA
California(‘99)
FNA
44/238 (18%)
58/238 (24%)10 –
84/238
(35%)
CULTURE+VE
67%
India (‘00)
GRANULOMA
35-79%
Excisional Biopsy
4/22 (18%)
5/22(23%)
13/22 (59%)
N/A
BIOPSY
N/A
18-93%
59-88%
17/22 (77%)
N/A
15/22 (68%)
FNA
9/22 (41%)
12/22 (55%)
France(‘99)
Excisional Biopsy
FNA
8/26 (31%)
2/26 (8%)
N/A
2/22 (10%)
4/22 (18%)
7/22 (32%)
Excisional Biopsy
24/34 (71%)
15/39 (38%)
36/31 (88%)
N/A
N/A
FNA
UK (‘10)
FNA
48/77 (62%)
5/19 (26%)
47/76 (62%)
N/A
N/A
65/97 (67%)
22/97 (23%)
77/97 (79%)
88/97 (91%)
N/A
California (‘05)
Clinical Infectious Diseases
2011;53(6):555–562
Algorithm – P Ormerod
• 100 patients – 49 FNA 38(77.5%) PUS
• PUS – Culture +ve 71%
PERIPHERAL LN - FNA
PUS
TB culture
and treat
No PUS
BIOPSY
L P Ormerod et al. Int J Tuber Lung Dis
2011:15(3):375-378
Lymph Node Stations
Mediastinoscopy
• 9/14 patients with TB
histology or culture +ve
(64%)THORAX: 1978 EW Cameron
• 14/18 patients with TB
histology orculture +ve
(78%)THORAX: 1985 J B Cookson et al
EBUS – Endobronchial Ultrasound
EBUS – Endobronchial Ultrasound
• Bronchoscope with small US
at end.
• Direct visualisation and real
time LN sampling
• Sedation
• Outpatient setting
• 1-1.5hr till discharge
• Lung cancer staging
• Used in benign mediastinal
lymphadenitis
ENDOBRONCHIAL ULTRASOUND
EBUS-TBFNA
• 20 patients. Diagnostic
accuracy 79%. Cytology
83%. Culture +ve 63%
J.Keane et al. AJRCCM 183;2011
• 156 patients. 4 centres
London 2 yr. Cytology
134(86%). Culture +ve
74(47%)
Navani et al. Thorax. Oct2011;66(10):889-893
Cmft lymph node data
p=0.037
90
80
70
60
50
%
Diagnostic
Pathology
Culture
40
30
20
10
0
EBUS
CERVICAL
22 patients
32 patients
FNA/biopsy
Mellisa Sherlock 4yr medical student
Hierarchy of diagnosis
1. Clinical diagnosis – Hx and Exam
2. Pathological
Cytological – FNA
Histological – Surgical
3. AFB’s
4. Molecular – PCR and others.
5. Microbiological - SENSTIVITIES
Molecular techniques - PCR
Molecular techniques - PCR
• Nucleic acid amplification tests for the diagnosis of
tuberculous lymphadenitis: a systematic review. The International journal of
tuberculosis and lung disease2007, 11(11):1166-1176
• 36 papers. Sen 2-100%. Specificity 28-100%. False-ve/+ve
• 73 patients –
Biopsy PCR
Sen 63.4% Spec 96.9%
FNA PCR
Sen 17.1% Spec 100%
‘Did not increase the yield of rapid diagnosis’ Linasmita et al. Clin Infect Dis 2012
Molecular techniques – PCR/FISH
•
•
•
•
41 patients – biopsies
22 Histo +VE 19 Histo –ve
PCR Sen 62.5% Spec 77.8%
Modified DNA FISH
Sen 71.1% Spec 84%
‘PCR and DNA FISH showed a
signif increase in no cases
detected and a higher
sen/spec compared to
traditional methods’
Mycobaterium tuberculosis complex detected by
modified fluorescent in situ hybridization in lymph
nodes of clinical samples. J Infect Dev Ctries 2012;6:58.
Molecular tests TB - cmft
Kit
Direct samples
Cultures
Organism detected
Resistance detected
Results within
Hain DRplus (v2)
Pulmonary: Smear + or
-
Yes
M.tb complex
RIF/INH
7 hours
Hain DRsl
Pulmonary: Smear +
Yes
M.tb complex
Fluoroquinolones,
Aminoglycoside
s, Cyclic
peptides
7 hours
No
Yes
13 most common
Mycobacteria
sp.
None
6 hours
Cepheid GeneXpert
TB/RIF
Pulmonary: Smear + or
-
Not validated
M.tb complex
RIF
2 hours
Hain Fluorotype MTB
Pulmonary and nonpulmonary
(excl. blood)
Not validated
M.tb complex
None
3 hours
(sl = second line)
Hain CM
(CM = common mycobac.)
Line probe assays
Cepheid GeneXpert system
Hain Fluorotype system
PCR-Cepheid/Xpert®MTB/RIF
• 2002. Pulmonary TB
• Result within 2 hrs
•Limit detection 131 CFU/ml (AFB +ve – 10,000 CFU/ml)
Steingart KR et al.(2014) "Xpert® MTB/RIF
assay for pulmonary tuberculosis.
COCHRANE DATABASE SYST REV 2014
Rapid molecular detection of tuberculosis
and rifampacin resistance NEngJMed
2010;363:1005-1015
PCR-Cepheid/Xpert®MTB/RIF
Sputum
SENSITIVITY 88%
SPECIFICITY 99%
‘provides accurate results and allows rapid
initiation of MDR-TB Tx pending culture + DST
• 2002. Pulmonary TB
• Result within 2 hrs
•Limit detection 131 CFU/ml (AFB +ve – 10,000 CFU/ml)
Steingart KR et al.(2014) "Xpert® MTB/RIF
assay for pulmonary tuberculosis.
COCHRANE DATABASE SYST REV 2014
Rapid molecular detection of tuberculosis
and rifampacin resistance NEngJMed
2010;363:1005-1015
Cepheid/Xpert®MTB/RIF – Extrapulm
TB
Eur Resp J 2014:Aug,44(2):435-46
• 18 studies 4461 samples
• Accuracy of Xpert compared
with culture
• Lymph node tissue or
aspirates
• SEN 83.1% (95%CI 71-90.7%) V
Cult. 81.2% (95%CI 72.4-87.7%)
Xpert MTB/RIF assay for the
diagnosis of extra pulm TB:
a systematic review and
meta analysis
Cepheid/Xpert®MTB/RIF – Extrapulm
TB
Eur Resp J 2014:Aug,44(2):435-46
• 18 studies 4461 samples
• Accuracy of Xpert compared
with culture and a
composite reference
standard (CRS)
• Lymph node tissue or
aspirates
• SEN 83.1% (95%CI 71-90.7%) V
Cult. 81.2% (95%CI 72.4-87.7%) V
CRS
Xpert MTB/RIF assay for the
diagnosis of extra pulm TB:
a systematic review and
meta analysis
WHO – recommends Xpert over conventional
tests for the diagnosis of TB in lymph nodes
and other tissues
Cepheid/Xpert®MTB/RIF - EBUS
Summary
•
•
•
•
Lymph node TB is very common – cervical
Culture/sensitivity gold standard
Biopsy is better than FNA – caveats
Mediastinum/hilar LN now easily accessible –
reasonable results
• Molecular techniques – interesting/likely to
become increasingly helpful
ANY QUESTIONS?