Tuberculosis Dr Anindo K. Banerjee Consultant Respiratory Physician Southampton General Hospital History repeating itself “The weariness, the fever and the fret Here, where men sit.
Download ReportTranscript Tuberculosis Dr Anindo K. Banerjee Consultant Respiratory Physician Southampton General Hospital History repeating itself “The weariness, the fever and the fret Here, where men sit.
Slide 1
Tuberculosis
Dr Anindo K. Banerjee
Consultant Respiratory Physician
Southampton General Hospital
Slide 2
History repeating itself
“The weariness, the fever and the fret
Here, where men sit and hear each other groan;
Where palsy shakes a few, sad, last grey hairs,
Where youth grows spectre-thin, and dies.”
Ode to a nightingale
Slide 3
TB incidence
Slide 4
TB regional
incidence
Slide 5
Southampton incidence
140
TB Notification rate
120
100
80
60
40
20
0
'6
4
'6
8
'7
2
'7
6
'8
0
'8
4
'8
8
'9
2
'9
6
'0
0
'0
4
'0
8
Slide 6
TB incidence by ethnic group 2011
1,800
300
1,600
Rate (per 100,000)
244
250
1,200
200
152
1,000
150
130
800
600
52
43
100
UK-born
Non-UK-born
Place of birth/Ethnic group
0
Mixed/other
Chinese
Bangladeshi
Pakistani
Indian
8
Black
8
White
Bangladeshi
64
50
6
Mixed/other
23
Pakistani
Indian
0
35
3
Black
200
31
Chinese
400
White
Number of cases
1,400
Rate (per 100,000)
256
Number of cases
Slide 7
800
40
700
35
600
30
500
25
400
20
300
15
200
10
100
5
0
0
Age group (years)
Male cases
Female cases
Rate in males
Rate in females
Rate (per 100,000)
Number of cases
TB incidence by age 2011
Slide 8
1,100
1,000
900
800
700
600
500
400
300
200
100
0
130
120
110
100
90
80
70
60
50
40
30
20
10
0
Age group (years)
Non-UK-born cases
Non-UK-born rate
Rate (per 100,000)
Number of cases
Non-UK born incidence by age 2011
Slide 9
200
10
180
9
160
8
140
7
120
6
100
5
80
4
60
3
40
2
20
1
0
0
Age group (years)
UK-born cases
UK-born rate
Rate (per 100,000)
Number of cases
UK born incidence by age 2011
Slide 10
Slide 11
TB site of disease 2011
Site of disease*
Pulmonary
Extra-thoracic lymph nodes
Intra-thoracic lymph nodes
Other extra-pulmonary
Pleural
Gastrointestinal
Bone – spine
Cryptic/miliary
Bone – other
CNS – meningitis
Genitourinary
CNS – other
Laryngeal
Unknown extra-pulmonary
Number of cases
4603
1906
919
633
668
436
378
268
205
191
145
87
14
15
*With or without disease at another site
**Percentage of cases with known sites of disease (8916)
CNS - Central Nervous System
Total percentage exceeds 100% due to infections at more than one site
Percentage**
51.6
21.4
10.3
7.1
7.5
4.9
4.2
3.0
2.3
2.1
1.6
1.0
0.2
0.2
Slide 12
TB pathogenesis
Slide 13
Natural
history
Live inside cells including
Type II pneumocytes
Lifelong risk 5-10%
Greatest in first 2 years
Slide 14
Natural history of active TB infection
Slide 15
Non-UK born incidence TB
by time after entry to UK
700
600
Number of cases
500
400
300
200
100
0
0
5
10
15
20
25
Years since entry to diagnosis
30
35
40
45
50+
Slide 16
Incidence of TB in exposed patients
Slide 17
At risk patients (latent TB)
•
•
•
•
•
•
•
•
•
HIV positive
IVDU
Solid organ transplant
Haematological malignancy
Jujunoileal bypass
Chronic renal failure or haemodialysis
Gastrectomy
Anti-TNF therapy
Silicosis
Slide 18
Symptomatology of TB
Slide 19
What do you do next?
Slide 20
Clinical specimens for TB
Microscopy
Culture
Sputum natural
High (50-80%)
High (>80%)
Sputum induced
Moderate
Moderate
Bronchial wash
Moderate
Moderate (25-90%)
Nasopharyngeal asp
Moderate
Moderate
Pleural fluid
Low (<5-10%)
Low (<25-50%)
CSF
Low (<5-10%)
Moderate (30-90%)
Peritoneal fluid
Low (<5%)
Low (20%)
Pericardial fluid
Low
Low
Synovial fluid
Low
Moderate (<80%)
Blood
Not applicable
Low
Bone marrow
Not applicable
Moderate-high
Slide 21
CSF in meningeal TB
Clear
80-90%
Pressure>25
50%
White cells
5-1000 x103ml-1
Neutrophils
10-70%
Lymphocytes
30-90%
Protein
0.45-3
Lactate
5-10
CSF / blood glucose
<95%
Slide 22
To help diagnosis: meningeal TB
•
•
•
•
10ml CSF for analysis (at least 6ml)
Long look at smear (45mins)
Image chest and abdomen: other signs TB
PCR: good sensitivity if smear positive, not evaluated
in smear negative disease
• Not useful
– CSF Adenosine deaminase
– Tuberculin skin test
– Interferon assay
Slide 23
Biopsy for TB
Microscopy
Culture
Peripheral lymph node
Moderate
Moderate
Pleural biopsy
Low (10-50%)
High
Pericardial biopsy
High
Invasive tissue biopsy
Low
moderate
Skin biopsy
Low
Low
Abscess
Low
Moderate
Stool
Low
Low
Slide 24
Slide 25
What if it doesn’t culture?
Slide 26
Mantoux test
Equivalent to 5IU worldwide. From Denmark
If BCG
>15mm
No BCG >5mm
Weak +ve
Atypical mycobacteria.
BCG
False –ve
HIV
Prednisolone>20mg OD
Old age
Immunosuppression
Overwhelming TB
Slide 27
Factors leading to negative Mantoux
• The person being tested
– Infections
• Viral (measles, mumps, chickenpox)
• Bacterial (typhoid fever, brucelosis, typhus, pertussis, overwhelming TB,
• Fungal (South American blastomycosis)
–
–
–
–
–
–
Live virus vaccinations (MMR)
Metabolic derangements (chronic renal failure)
Nutritional factors (severe protein depletion)
Diseases of lymphoid organs (Hodgkin’s lymphoma, CLL, sarcoidosis)
Drugs (corticosteroids, other immunosuppressive agents)
Age (newborn, elderly)
– Recent overwhelming infection with M. tuberculosis
– Stress (surgery, burns, mental illness, graft versus host reactions)
• Tuberculin used
• Method of administration
• Reading the test and recording results
Slide 28
Interferon Gamma Release Assay
THEORY:
A person’s T-cells that previously were sensitized to TB
antigen produce high levels of IFN-gamma when reexposed to the same mycobacterial antigen.
Slide 29
Specific antigens in IGRA
Not present in BCG
Slide 30
Mycobacteria & IGRA antigens
Slide 31
Available IGRA tests
T-SPOT TB®
• The peripheral blood mononuclear cells (PBMC) are washed,
isolated and stimulated with ESAT-6 & CFP-10.
• Incubate overnight: number of T-cells producing IFN-γ “counted”
• Not many indeterminates: more laboratory intensive
Quantiferon Gold®
–
–
–
–
Blood exposed to ESAT-6, CFP-10 and TB7.7 antigens.
Incubated overnight
Plasma removed and assayed for IFN-γ levels by ELISA.
Arbitrary cutoff for level of positives: more indeterminate results.
Slide 32
Uses of IGRA testing
• Detection of mycobacterium tuberculosis infection
• Useful in
– Immunocompromised (indeterminate results in lymphopoenia)
– HIV
•
•
•
•
•
Not useful to diagnose active disease
May help to exclude active disease
Not useful in monitoring disease response
May differentiate non-tuberculous mycobacteria from TB
Useful in outbreak investigations (contact tracing)
Slide 33
Latent TB infection
Slide 34
Risk factors for drug resistance
•
•
•
•
•
•
•
•
History of prior TB drug treatment
Prior TB treatment failure
Contact with known case drug-resistant TB
Birth / residence county with high incidence resistance
HIV infection
Residence in London
Age: highest rates age 25-44
Male gender
Slide 35
Drug resistance by age group
Age Group
Isoniazid
Multi-drug
Resistant to any
resistant
resistant
first line drug**
Total*
n
%
n
%
n
%
0-14
6
6.3
1
1.1
6
6.3
95
15-44
302
9.0
73
2.2
337
10.0
3,368
45-65
61
6.2
7
0.7
67
6.8
989
65+
19
2.8
0
0.0
21
3.1
675
*Culture confirmed cases with drug susceptibility results for at least isoniazid and rifampicin
**First line drugs - isoniazid, rifampicin, ethambutol, pyrazinamide
Slide 36
Drug resistance after previous diagnosis TB
Isoniazid
Multi-drug
Resistant to any
Total**
Previous history TB
resistant
resistant
first line drug***
n
%
n
%
n
%
Yes
26
11.1
13
5.6
31
13.3
234
No
338
7.4
61
1.3
371
8.2
4549
*Cases with unknown previous history of tuberculosis are excluded.
** Culture confirmed cases with drug susceptibility testing results for at least isoniazid and rifampicin
***First line drugs - isoniazid, rifampicin, ethambutol, pyrazinamide
Slide 37
Where Drug resistance comes from
Place of birth
UK born
Non-UK born
Central Europe
East Asia
East Europe
East Mediterranean
North Africa
North America and Oceania
South Asia
South East Asia
South, Central America & Caribbean
Sub-Saharan Africa
West Europe
Isoniazid
Multi-drug
resistant
n
%
resistant
n
%
72
295
9
4
20
3
4
0
160
20
7
63
2
6.1
8.0
7.7
6.2
38.5
7.5
11.8
0.0
7.4
12.8
11.1
7.2
2.7
4
76
1
2
14
0
0
0
43
2
1
12
0
0.3
2.1
0.9
3.1
26.9
0.0
0.0
0.0
2.0
1.3
1.6
1.4
0.0
Resistant to
any
first line
drug***
Total**
n
%
79
326
9
4
20
3
4
0
181
21
7
72
2
6.7
8.8
7.7
6.2
38.5
7.5
11.8
0.0
8.4
13.4
11.1
8.3
2.7
1187
3689
117
65
52
40
34
2
2157
157
63
873
74
Slide 38
Multi-drug-resistant TB
Slide 39
Extensively
drug resistant
TB
Slide 40
Drug resistance therapies
Slide 41
Isolation and
infection control
Slide 42
Any questions?
Tuberculosis
Dr Anindo K. Banerjee
Consultant Respiratory Physician
Southampton General Hospital
Slide 2
History repeating itself
“The weariness, the fever and the fret
Here, where men sit and hear each other groan;
Where palsy shakes a few, sad, last grey hairs,
Where youth grows spectre-thin, and dies.”
Ode to a nightingale
Slide 3
TB incidence
Slide 4
TB regional
incidence
Slide 5
Southampton incidence
140
TB Notification rate
120
100
80
60
40
20
0
'6
4
'6
8
'7
2
'7
6
'8
0
'8
4
'8
8
'9
2
'9
6
'0
0
'0
4
'0
8
Slide 6
TB incidence by ethnic group 2011
1,800
300
1,600
Rate (per 100,000)
244
250
1,200
200
152
1,000
150
130
800
600
52
43
100
UK-born
Non-UK-born
Place of birth/Ethnic group
0
Mixed/other
Chinese
Bangladeshi
Pakistani
Indian
8
Black
8
White
Bangladeshi
64
50
6
Mixed/other
23
Pakistani
Indian
0
35
3
Black
200
31
Chinese
400
White
Number of cases
1,400
Rate (per 100,000)
256
Number of cases
Slide 7
800
40
700
35
600
30
500
25
400
20
300
15
200
10
100
5
0
0
Age group (years)
Male cases
Female cases
Rate in males
Rate in females
Rate (per 100,000)
Number of cases
TB incidence by age 2011
Slide 8
1,100
1,000
900
800
700
600
500
400
300
200
100
0
130
120
110
100
90
80
70
60
50
40
30
20
10
0
Age group (years)
Non-UK-born cases
Non-UK-born rate
Rate (per 100,000)
Number of cases
Non-UK born incidence by age 2011
Slide 9
200
10
180
9
160
8
140
7
120
6
100
5
80
4
60
3
40
2
20
1
0
0
Age group (years)
UK-born cases
UK-born rate
Rate (per 100,000)
Number of cases
UK born incidence by age 2011
Slide 10
Slide 11
TB site of disease 2011
Site of disease*
Pulmonary
Extra-thoracic lymph nodes
Intra-thoracic lymph nodes
Other extra-pulmonary
Pleural
Gastrointestinal
Bone – spine
Cryptic/miliary
Bone – other
CNS – meningitis
Genitourinary
CNS – other
Laryngeal
Unknown extra-pulmonary
Number of cases
4603
1906
919
633
668
436
378
268
205
191
145
87
14
15
*With or without disease at another site
**Percentage of cases with known sites of disease (8916)
CNS - Central Nervous System
Total percentage exceeds 100% due to infections at more than one site
Percentage**
51.6
21.4
10.3
7.1
7.5
4.9
4.2
3.0
2.3
2.1
1.6
1.0
0.2
0.2
Slide 12
TB pathogenesis
Slide 13
Natural
history
Live inside cells including
Type II pneumocytes
Lifelong risk 5-10%
Greatest in first 2 years
Slide 14
Natural history of active TB infection
Slide 15
Non-UK born incidence TB
by time after entry to UK
700
600
Number of cases
500
400
300
200
100
0
0
5
10
15
20
25
Years since entry to diagnosis
30
35
40
45
50+
Slide 16
Incidence of TB in exposed patients
Slide 17
At risk patients (latent TB)
•
•
•
•
•
•
•
•
•
HIV positive
IVDU
Solid organ transplant
Haematological malignancy
Jujunoileal bypass
Chronic renal failure or haemodialysis
Gastrectomy
Anti-TNF therapy
Silicosis
Slide 18
Symptomatology of TB
Slide 19
What do you do next?
Slide 20
Clinical specimens for TB
Microscopy
Culture
Sputum natural
High (50-80%)
High (>80%)
Sputum induced
Moderate
Moderate
Bronchial wash
Moderate
Moderate (25-90%)
Nasopharyngeal asp
Moderate
Moderate
Pleural fluid
Low (<5-10%)
Low (<25-50%)
CSF
Low (<5-10%)
Moderate (30-90%)
Peritoneal fluid
Low (<5%)
Low (20%)
Pericardial fluid
Low
Low
Synovial fluid
Low
Moderate (<80%)
Blood
Not applicable
Low
Bone marrow
Not applicable
Moderate-high
Slide 21
CSF in meningeal TB
Clear
80-90%
Pressure>25
50%
White cells
5-1000 x103ml-1
Neutrophils
10-70%
Lymphocytes
30-90%
Protein
0.45-3
Lactate
5-10
CSF / blood glucose
<95%
Slide 22
To help diagnosis: meningeal TB
•
•
•
•
10ml CSF for analysis (at least 6ml)
Long look at smear (45mins)
Image chest and abdomen: other signs TB
PCR: good sensitivity if smear positive, not evaluated
in smear negative disease
• Not useful
– CSF Adenosine deaminase
– Tuberculin skin test
– Interferon assay
Slide 23
Biopsy for TB
Microscopy
Culture
Peripheral lymph node
Moderate
Moderate
Pleural biopsy
Low (10-50%)
High
Pericardial biopsy
High
Invasive tissue biopsy
Low
moderate
Skin biopsy
Low
Low
Abscess
Low
Moderate
Stool
Low
Low
Slide 24
Slide 25
What if it doesn’t culture?
Slide 26
Mantoux test
Equivalent to 5IU worldwide. From Denmark
If BCG
>15mm
No BCG >5mm
Weak +ve
Atypical mycobacteria.
BCG
False –ve
HIV
Prednisolone>20mg OD
Old age
Immunosuppression
Overwhelming TB
Slide 27
Factors leading to negative Mantoux
• The person being tested
– Infections
• Viral (measles, mumps, chickenpox)
• Bacterial (typhoid fever, brucelosis, typhus, pertussis, overwhelming TB,
• Fungal (South American blastomycosis)
–
–
–
–
–
–
Live virus vaccinations (MMR)
Metabolic derangements (chronic renal failure)
Nutritional factors (severe protein depletion)
Diseases of lymphoid organs (Hodgkin’s lymphoma, CLL, sarcoidosis)
Drugs (corticosteroids, other immunosuppressive agents)
Age (newborn, elderly)
– Recent overwhelming infection with M. tuberculosis
– Stress (surgery, burns, mental illness, graft versus host reactions)
• Tuberculin used
• Method of administration
• Reading the test and recording results
Slide 28
Interferon Gamma Release Assay
THEORY:
A person’s T-cells that previously were sensitized to TB
antigen produce high levels of IFN-gamma when reexposed to the same mycobacterial antigen.
Slide 29
Specific antigens in IGRA
Not present in BCG
Slide 30
Mycobacteria & IGRA antigens
Slide 31
Available IGRA tests
T-SPOT TB®
• The peripheral blood mononuclear cells (PBMC) are washed,
isolated and stimulated with ESAT-6 & CFP-10.
• Incubate overnight: number of T-cells producing IFN-γ “counted”
• Not many indeterminates: more laboratory intensive
Quantiferon Gold®
–
–
–
–
Blood exposed to ESAT-6, CFP-10 and TB7.7 antigens.
Incubated overnight
Plasma removed and assayed for IFN-γ levels by ELISA.
Arbitrary cutoff for level of positives: more indeterminate results.
Slide 32
Uses of IGRA testing
• Detection of mycobacterium tuberculosis infection
• Useful in
– Immunocompromised (indeterminate results in lymphopoenia)
– HIV
•
•
•
•
•
Not useful to diagnose active disease
May help to exclude active disease
Not useful in monitoring disease response
May differentiate non-tuberculous mycobacteria from TB
Useful in outbreak investigations (contact tracing)
Slide 33
Latent TB infection
Slide 34
Risk factors for drug resistance
•
•
•
•
•
•
•
•
History of prior TB drug treatment
Prior TB treatment failure
Contact with known case drug-resistant TB
Birth / residence county with high incidence resistance
HIV infection
Residence in London
Age: highest rates age 25-44
Male gender
Slide 35
Drug resistance by age group
Age Group
Isoniazid
Multi-drug
Resistant to any
resistant
resistant
first line drug**
Total*
n
%
n
%
n
%
0-14
6
6.3
1
1.1
6
6.3
95
15-44
302
9.0
73
2.2
337
10.0
3,368
45-65
61
6.2
7
0.7
67
6.8
989
65+
19
2.8
0
0.0
21
3.1
675
*Culture confirmed cases with drug susceptibility results for at least isoniazid and rifampicin
**First line drugs - isoniazid, rifampicin, ethambutol, pyrazinamide
Slide 36
Drug resistance after previous diagnosis TB
Isoniazid
Multi-drug
Resistant to any
Total**
Previous history TB
resistant
resistant
first line drug***
n
%
n
%
n
%
Yes
26
11.1
13
5.6
31
13.3
234
No
338
7.4
61
1.3
371
8.2
4549
*Cases with unknown previous history of tuberculosis are excluded.
** Culture confirmed cases with drug susceptibility testing results for at least isoniazid and rifampicin
***First line drugs - isoniazid, rifampicin, ethambutol, pyrazinamide
Slide 37
Where Drug resistance comes from
Place of birth
UK born
Non-UK born
Central Europe
East Asia
East Europe
East Mediterranean
North Africa
North America and Oceania
South Asia
South East Asia
South, Central America & Caribbean
Sub-Saharan Africa
West Europe
Isoniazid
Multi-drug
resistant
n
%
resistant
n
%
72
295
9
4
20
3
4
0
160
20
7
63
2
6.1
8.0
7.7
6.2
38.5
7.5
11.8
0.0
7.4
12.8
11.1
7.2
2.7
4
76
1
2
14
0
0
0
43
2
1
12
0
0.3
2.1
0.9
3.1
26.9
0.0
0.0
0.0
2.0
1.3
1.6
1.4
0.0
Resistant to
any
first line
drug***
Total**
n
%
79
326
9
4
20
3
4
0
181
21
7
72
2
6.7
8.8
7.7
6.2
38.5
7.5
11.8
0.0
8.4
13.4
11.1
8.3
2.7
1187
3689
117
65
52
40
34
2
2157
157
63
873
74
Slide 38
Multi-drug-resistant TB
Slide 39
Extensively
drug resistant
TB
Slide 40
Drug resistance therapies
Slide 41
Isolation and
infection control
Slide 42
Any questions?