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Differential diagnosis of tuberculosis, other granulomatous diseases and oncology
Professor Dr. Graham Bothamley
EACCTB, Rotterdam 2019
1
Disclosure of speaker’s interests
(Potential) conflict of interest None
Potentially relevant company relationships in connection with event 1
NA
▪ Sponsorship or research funding2
▪ Fee or other (financial) payment3
▪ Shareholder4
▪ Other relationship, i.e. …5
None
Plan of talk
• Symptomatology
• Physical examination
• Radiology
• Histopathology
• Laboratory tests
• Summary
3
SymptomsEpidemiology; sensitivity and specificity
4
Presenting symptomsCommon
• Cough
• Sputum
• Fever
• Malaise
• Loss of appetite
Uncommon
• Haemoptysis
• Night sweats
• Weight loss
• Lymphadenopathy
5
Hackney Borough Council: active screening
• Survey attached to payslip
• Symptoms of TB
• TB risk: previous TB, contact with TB
• Date of screening at place of work
6
Hackney Borough CouncilSymptoms Non-smokers (n = 785) Smokers (n = 173) Total (%)
None 486 (62) 108 (63) 594 (62)
Cough > 3 week 52 (6.6) 19 (11) 71 (7.4)
Sputum >3 week 50 (6.4) 22 (13) 72 (7.5)
Night sweats >3 weeks; fever >3 weeks 16 (2.0); 3 (0.4) 5 (2.9); 1 (0.6) 21 (2.2); 4 (0.4)
Unexpected weight loss > 5% 15 (1.9) 4 (2.3) 19 (2.0)
New lumps/swellings 15 (1.9) 3 (1.7) 18 (1.9)
Loss of appetite 11 (1.4) 4 (2.3) 15 (1.6)
Haemoptysis 6 (0.8) 4 (2.3) 10 (1.0)
Previous TB 7 (0.9) 3 (1.7) 10 (1.0)
Contact TB 2 (0.3) 0 2 (0.2)
3 symptoms or more 10 (1.3) 0 10 (1.0)
7
Incomplete forms: 16TB cases: 0Rate of smoking: 24%
Hackney Borough CouncilSymptoms Non-smokers (n = 785) Smokers (n = 173) Total (%)
None 486 (62) 108 (63) 594 (62)
Cough > 3 week 52 (6.6) 19 (11) 71 (7.4)
Sputum >3 week 50 (6.4) 22 (13) 72 (7.5)
Night sweats >3 weeks; fever >3 weeks 16 (2.0); 3 (0.4) 5 (2.9); 1 (0.6) 21 (2.2); 4 (0.4)
Unexpected weight loss > 5% 15 (1.9) 4 (2.3) 19 (2.0)
New lumps/swellings 15 (1.9) 3 (1.7) 18 (1.9)
Loss of appetite 11 (1.4) 4 (2.3) 15 (1.6)
Haemoptysis 6 (0.8) 4 (2.3) 10 (1.0)
Previous TB 7 (0.9) 3 (1.7) 10 (1.0)
Contact TB 2 (0.3) 0 2 (0.2)
3 symptoms or more 10 (1.3) 0 10 (1.0)
8
Incomplete forms: 16TB cases: 0Rate of smoking: 24%
Cough clinic• Part of cancer program
• Cough > 3 weeks
• Primary care action• Check medication (ACE-inhibitors)
• Antibiotics if indicated (check TB risk)
• Smoking cessation advice
• Assess for asthma
• Trial of anti-reflux (PPI 1st m; PPI + metoclopramide 2nd if no response)
• CXRTurner & Bothamley. npj Primary Care Resp Med 2016; 26: 15081
9
Outcomes of cough clinic Diagnosis Number (%)
Asthma 75 (29)
Gastro-oesophageal reflux 56 (22)
ACE-inhibitor use 37 (14)
Post-infective 30 (12)
Smoking 23 (8.8)
Upper airway pathology (e.g. rhinosinusitis) 17 (6.5)
COPD 5 (1.9)
Lower respiratory tract infection 4 (1.5)
Voluntary coughing/throat clearing 3 (1.1)
Malignancy 2 (0.8)
Bronchiectasis 1 (0.4)
Pulmonary fibrosis 1 (0.4)
Other (half resolved with time) 31 (11.8)
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Turner & Bothamley. npj Primary Care Resp Med 2016; 26: 15081
Unexpected weight loss• 5-10% over 6 months
• Cancer diagnosis in >60 year olds (systematic review; GP coding)
• 3-7% women; 11-14% men• acute and chronic leukaemia and non-metastatic colorectal cancer
• 2nd most powerful predictor of cancer (Swedish registry) after• rectal bleeding in colorectal cancer• haemoptysis in lung cancer• rib pain in myeloma• jaundice in pancreatic cancer• haematuria in renal tract cancer
Nicholson BD et al. BMJ; 5 October 2019: 31-33.
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Haemoptysis
• When did it start?
• What time of day?
• How much?
• Bright or dark red?
• Streak or blob?
12
Differential diagnosis of haemoptysisDiagnosis Cough Purulent
sputum
Fever Chest
pain
Quantity
Nose bleed - - +
Pulmonary embolus - - + dark
Lung cancer + - - streak
Tuberculosis + + + to +++
Bronchiectasis + + - to +++
Aspergilloma + + - - +++
Foreign body + + + - +
Anticoagulation + - - - to +++
Rare:
Polyangiitis syndromes
Goodpasture’s
Hereditary telangiectasia
+
-
-
-
-
-
-
-
-
+
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Low specificity symptoms for TB
Common
• Cough
• Sputum
• Fever
• Malaise
• Loss of appetite
Uncommon
• Haemoptysis
• Night sweats
• Weight loss
• Lymphadenopathy
14
TB, sarcoidosis or lymphomaTB Sarcoidosis Lymphoma
None (7%) None (80%) None (40%)
Cough with phlegm Dry cough Breathlessness
Haemoptysis Breathlessness Fever (B)
Fever Red eyes Night sweats (B)
Night sweats Skin lesions Weight loss (B)
Weight loss Thirst, polyuria (Ca2+) Malaise
Malaise Arthritis Itching
Lymph node Neurological Lymph node
15
Likelihood of diagnoses (Europe)
Lung cancer Tuberculosis Sarcoidosis Lymphoma Polyangiitis
Non-Hodgkin’s Hodgkin’s
Age (yr) > 50 20-35; >70 25-45(also F, 50-70)
>60 15-35; 70-90 40-60
Incidence 23.1 10.7 (2 – 40) 7 (5 – 40) 6 - 12 2.7 0.3 - 1.4
Most common symptom
Smoker High incidence(Night sweats)
Dry cough Lymph node;liver, spleen
LN (CXR); spleen
Haematuria
16
Physical examinationThe cold lymph node
17
Primary TB Post-primary TB
18
Skin sarcoid
19
Uveitis
20
Radiology
21
Lung cancer screening
• Dutch-Belgian Randomised Lung Cancer Screening (NELSON):• > 50 years• Smoking: >15/d for >25 yr or 10-15/d for 30 yr; current or <10 yr quit• 15,822 enrolled• not calcified, lentiform or triangular pleural, < 5mm or 80 mm3
• Brock criteria: • spiculation; F>M; upper lobe; larger (older, FH, emphysema, part-solid, fewer)
• S Korea: 313 nodules in 53,036; 179/186 transient; 2/7 TB
• S Korea: 118/1587 nodules; 4 lung cancers; false-positives 96.6%
• Mumbai: 191 PET scans: 144 cancer, 16 TB (overlap in uptake)
Han S, et al. IJTLD 2019; 23(6): 698-706
Kim HJ et al. ERJ 2016; 47(5): 1510-7. Ju SM et al. Thorac Canc 2013; 4: 405-9
Purandare MC et al. Indian J Cancer 2017; 54: 271-5
22
PET-CT
23
BHL
24
25
Pulmonary infiltrates
26
Gallium scan
Lacrimal glands
Parotid glands
Bilateral hilar lymphadenopathy
27
PET scanning and sarcoidosis
28
Case detectionSputum smear Sputum culture
29
Mtb DNA amplification
Genotype MDRTBPlus
Xpert MTB/RIF
30
Common testsSarcoidosis Lymphoma TB
Symptoms Rare EtOH and sweats NS, WL
Examination Eye, skin Other LN; liver, spleen Thin
Fbc Normal Normal or lymphocytes+ Normal
Calcium Raised Normal raised
CRP Normal Normal 10-70 mg/L
SACE > 52 IU/mL Normal Normal
CXR BHLMid zones
BHL BHLUpper zones
Tuberculin response Negative (BCG+) Negative Positive (75%)
IGRA 5% +ve Negative 80% +ve
31
GranulomasInflammation; collection of immune cells (macrophages always present)
Wall off foreign material that can’t be eliminated
32
Some common causes of granulomas
Infections - lung Infections – usuallyoutside lung
Immune Other
TuberculosisSarcoidosisAspergillosisNon-tuberculous mycobacteriaNocardiaHistoplasmosisCoccidiomycosisBlastomycosisAspiration pneumoniaPneumocystis pneumonia
Cat scratch diseaseToxoplasmosisCryptococcusRheumatic feverSchistosomiasisLeishmaniasisListeriaLeprosyPlagueTularaemia
Rheumatoid arthritisCrohn’sPolyangiitis (WG, CS)Behçet’s
Foreign bodyKeratinNecrobiosis lipoidicaBerylliosisChronic granulomatous disease
33
Shah KK, et al. J Clin Tub Other Mycobact Dis 2017; 7:1-12
Granulomas
34
Granulomas in Taiwan
Treated (n=40)Number (%)
Untreated (n=67)Number (%)
Age yr: mean (SD) 55.5 (12.4) 56.8 (14)
Female 14 (35) 29 (43)
PMH TB 2 (5) 10 (15)
Caseation 31 (78) 24 (36)
Malignancy 6 (15) 31 (46)
Later TB 0 1 (2)
Follow-up (yr); mean (SD) 3.94 (0.23) 3.75 (0.72)
35
Chung C-L et al. BMC Infect Dis 2018; 18: 530
Granulomas
Treated (n=40)Number (%)
Untreated (n=67)Number (%)
Age yr: mean (SD) 55.5 (12.4) 56.8 (14)
Female 14 (35) 29 (43)ns
PMH TB 2 (5) 10 (15)ns
Caseation 31 (78) 24 (36)
Malignancy 6 (15) 31 (46)
Later TB 0 1 (2)
Follow-up (yr); mean (SD) 3.94 (0.23) 3.75 (0.72)ns
36
Chung C-L et al. BMC Infect Dis 2018; 18: 530
37
Patient 2
TaiwanHisto+ve,Micro –ve
Chung C-L et al. BMC Infect Dis 2018; 18: 530
38
63 MNTM noduleVATSCoincident ACA
Watanabe et al.Mol Clin Oncol 2017; 6: 839-45
39
Tomlinson G et al.Transcriptional profiling…Chest 2016; 149: 535
“Diagnosis” of sarcoidosis
Clinico-radiographic data
Clinical diagnosis:
• BHL
•Löfgren’s: BHL, EN, fever + arthritis
•Heerfordt: parotid, uveitis, feverBiopsy
Exclude other causes of granuloma
>1 organ
Exclude other multisystem
granulomatous disease
MRI (gadolinium)
PET
40
Problematic cases
• Mediastinal lymphadenopathy
• Generalized pulmonary infiltration
• Pulmonary scarring
• Intestinal complaints (Crohn’s or TB)
• Anterior uveitis
41
Anterior uveitis
Clinical Sarcoidosis Tuberculosis
Risk factors for TB: e.g. contact or high incidence country
No Yes
Uveitis Symmetrical Asymmetrical
Schirmer’s test Reduced tear production Normal tear production
PPD No response Positive
IGRA Depends on country of birth Positive (80%)
Other possible tests CT chest/PET scan Culture (sputum>LN>>eye!)
42
Exclude syphilis and toxoplasmosis
Petrushkin H et al. Eye 2019; doi: 10/1038/s41433-019-0543-7
Summary
• Assess likelihood and risk factors
• CXR
• Send sputum early for TB
• Biopsy with culture
• Interpret in the light of simple blood tests
43