Differential diagnosis of tuberculosis, other granulomatous diseases and oncology

Professor Dr. Graham Bothamley

EACCTB, Rotterdam 2019

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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

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SymptomsEpidemiology; sensitivity and specificity

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Presenting symptomsCommon

• Cough

• Sputum

• Fever

• Malaise

• Loss of appetite

Uncommon

• Haemoptysis

• Night sweats

• Weight loss

• Lymphadenopathy

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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

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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)

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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)

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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

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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?

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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

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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

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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

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Physical examinationThe cold lymph node

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Primary TB Post-primary TB

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Skin sarcoid

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Uveitis

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Radiology

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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

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PET-CT

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BHL

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Pulmonary infiltrates

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Gallium scan

Lacrimal glands

Parotid glands

Bilateral hilar lymphadenopathy

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PET scanning and sarcoidosis

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Case detectionSputum smear Sputum culture

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Mtb DNA amplification

Genotype MDRTBPlus

Xpert MTB/RIF

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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

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GranulomasInflammation; collection of immune cells (macrophages always present)

Wall off foreign material that can’t be eliminated

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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

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Shah KK, et al. J Clin Tub Other Mycobact Dis 2017; 7:1-12

Granulomas

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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)

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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

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Chung C-L et al. BMC Infect Dis 2018; 18: 530

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Patient 2

TaiwanHisto+ve,Micro –ve

Chung C-L et al. BMC Infect Dis 2018; 18: 530

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63 MNTM noduleVATSCoincident ACA

Watanabe et al.Mol Clin Oncol 2017; 6: 839-45

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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

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Problematic cases

• Mediastinal lymphadenopathy

• Generalized pulmonary infiltration

• Pulmonary scarring

• Intestinal complaints (Crohn’s or TB)

• Anterior uveitis

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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!)

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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

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