1. Tuberculosis
Prof David Dockrell

2. Introduction Tuberculosis is a clinical disease
pulmonary
extra-pulmonary
Caused by Mycobacterium tuberculosis (hominis)
or M. bovis
Second leading cause of infectious death
WHO declared TB a global public health emergency in 1993.

3. Epidemiology One third of worlds population infected.
9 million cases per year with 2 million deaths.
Risk factors;
Foreign born e.g. Sub-Saharan Africa
HIV+
IVDU
Homeless
Alcoholic
Prisons

4. Estimated TB incidence rate, 2005
No estimate
0–24
50–99
100–299
300 or more
25–49
Estimated new TB cases (all forms) per population
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Dotted lines on maps represent approximate border lines for which there may not yet be full agreement.
 WHO All rights reserved

5. Microbiology
M. tuberculosis complex, includes M. tuberculosis and M. bovis.
Aerobic, non-spore forming non-motile bacteria with high content of high molecular weight lipids in its cell wall.
Slow growing; doubling time hours so takes 3-8 wks to grow on solid media

6. Pathogenesis Clinical
Spread in aerosol from infected individual’s lung to another lung,
or via spitting or sneezing on plates or hands
Person becomes infected
PTB disease
cough
Bacilli enter the lung
aerosol droplets of about 5 microns contain a few bacilli and lodge in alveolae or small airways

7. Infectivity
If smear positive 27-50% of household contacts become positive
If smear negative ≤5%
No more infectious if HIV+
If have fully sensitive TB become non-infectious after approximately two weeks of therapy

8. Immunonolgy T-cell responses (3-9 wks after exposure)
Ingest by alveolar Mf
Survives in phagosome
Prevents acidification
Inhibits reactive oxygen species
Limits antigen presentation.
T-cell responses (3-9 wks after exposure)
Manifest as delayed type hypersensitivity
CD4 T-cells activate Mf via IFN-g prime Mf killing of bacilli but also release of tissue damaging enzymes
CD8 T-cells can lyse infected cells
Key role for IFN-g and IL-12
Ongoing T-cell response keeps infection quiescent but may cause reactivation disease

9. Immunology
Granulomata formation with activated epithelioid Mf and Langhan’s giant cells control infection in an organised reaction
Exudative reactions occur when more bacilli and less organised reaction without epithelioid cells or Langhan’s cells. If necrosis results:
Caseous necrosis with bacilli
Cavitation with bacilli
If little hypersensitivity non-reactive tuberculosis just a few immune cells without cavities or granulomata

10. Pathogenesis
Subpleural Mf in midzone of lung ingest bacilli but fail to contain (primary focus). Lymphocytes and Mf recruited to lesion and Mf traffic to regional Lymph nodes
Lymphohaematogenous spread and replication apices of lungs, LNs, kidneys, subarrachnoid space etc.
In young or immunocompromised may get miliary spread to lungs and other organs e.g. meninges
Clinical features of cell-mediated immunity Erythema nodosum, Phlyctenular conjunctivitis
Cell-mediated immunity and healing (usually not visible) may produce:
Ghon focus in lung
Ranke complex (calcification in lung and hilar LN)
Simon’s focus in apices

11. Natural History Infection
Majority of people mount an effective immune response that encapsulates and contains the organism for ever.
circa 95% do not have any disease
Disease develops in 5-10%, half in first year
Favored by;
Age (infants, young adults, elderly)
Immunosuppression e.g. AIDS
Malnutrition
Intensity of exposure

12. Clinical Terms Primary Tuberculosis Progressive primary Tuberculosis
Post Primary Tuberculosis (usually endogenous reactivation but also reinfection)

13. pulmonary infection only
Macrophages + lymphocytes
seal in and contain and kill
Infecting bacilli
Bacilli settle
in lung Apex
The Lungs

14. Natural History 2-5 % develop clinically evident primary disease,
in PTB bacilli are engulfed by alveolar macrophages in which they multiply killing the cells.
Phagocytic blood borne lymphocytes and macrophages aggregate around infection and form a granuloma
This is called the PRIMARY FOCUS

17. Natural History
Some bacilli are transported to the regional lymph nodes
(mediastinal or hilar, paratracheal and supraclavicular)
Here secondary lesions develop

18. Primary Tuberculosis In apex of lung there Is more air and less
Blood supply
(fewer defending
White cells to fight)
Bacilli settle
in apex and granuloma forms
Bacilli taken in lymphatics
to hilar lymph
nodes
The Lungs
Granuloma + Lymphatics + Lymph nodes = Primary Complex

20. Natural History
If not contained there is haematogenous dissemination which often leads to serious non pulmonary disease
This may happen after primary infection or after reactivation
If there is reactivation after a dormant period it is known as
POST PRIMARY DISEASE
as most often dormant bacilli are in the lungs, so post primary disease occurs in the lungs

21. TB spreads beyond lungs
TB Meningitis
Miliary TB
Bacilli settle
in lung Apex
Bacilli taken
to hilar lymph
nodes
Pleural TB
The Lungs
Bone and Joint TB
Genito urinary TB

22. PTB Presentation of TB Systemic features: Weight loss* cough > 3/52
most other causes
resolve by then
Maybe haemoptysis
Systemic features:
Weight loss*
Low grade fever
Anorexia
Night sweats*
Malaise
*Most predictive of TB

23. Pulmonary TB Primary disease chest pain, dyspnoea
upper lobe consolidation: dull apex with bronchial breathing
compression by LN; collapse, cough etc
Features of cell-mediated immunity
Progressive primary disease
Usually primary disease is self limiting but may progress in a no of ways, within the lung or cause MILIARY disease.

24. Post-primary disease
Asymptomatic presenting as nodules, fibrosis or cavity
Systemic presentation
Haemoptysis
Pneumonic presentation
Pleurisy

26. EPTB Presentation of TB Lymph node TB swelling +/- discharge Bone
Pain or swelling of joint, Potts disease with spinal cord lesion
Abdominal TB
Ascites, abdominal lymph nodes, ileal malabsorption
Genito-urinary TB
epididymitis, frequency, dysuria and haematuria.
Systemic features:
Weight loss
Low grade fever
Anorexia
Night sweats
malaise

27. Miliary TB

31. EPTB Presentation of TB TB Meningitis. Bacilli in CSF and on meninges.
Meningeal inflammation produces
thick exudate, which leads to stran-
gulation of cranial nerves +raised
ICP. Thus a low grade meningitis,
random cranial nerve palsies and
symptoms of raised ICP: headache,
vomiting, confusion, coma.
Systemic features:
Weight loss
Low grade fever
Anorexia
Night sweats
malaise

33. Remember Miliary TB Pleural TB Hilar lymphadenopathy
all involve lungs but classed as EPTB

37. Pott’s disease = spinal/vertebral TB

38. Acid fast stain Ziehl-Neelsen stain
Fixed smear stained with carbol fuchsin, heated, rinsed, decolorized with acid-acohol and counterstained with methylene blue
Detects 10,000 organisms per ml
Smear positivity most likely for cavitatory disease
Sensitivity 60%.Increases to 72% with three samples.

39. Stains pink with alcohol and acid fast ‘Zeil-Neelsen’ stain

40. Culture Solid media take 3-8 wks to grow Lowenstein-Jensen (egg based)
Middlebrook 7H11 (agar)
Liquid 1-3 weeks to grow
Middlbook 7H12
Automated systems BACTEC Mycobacterial growth indicator tube (MGIT) fluorometric detection in liquid media
Microscopic-observation drug-susceptibility allows identification of drug resistance in liquid media

41. Diagnosis: TST Tuberculin skin test or Mantoux
protein derived from organism
injected intradermally (technically difficult)
stimulates type 4 delayed hypersensitivity reaction
not sensitive: immunosuppressed or miliary TB wont react (false negatives)
only moderately specific (false positives)
won’t easily distinguish infection from disease

42. QuantiFERON®-TB Test Method
Stage 1 Whole Blood Culture
Nil
Control
Avian
PPD
Human
PPD
Mitogen
Control
Transfer undiluted whole blood
into wells of a culture plate
and add antigens
Culture overnight at 37oC
TB infected individuals respond by secreting IFN-g
Heparinised whole blood
Stage 2 IFN-gamma ELISA
IFN-g IU/ml
OD 450nm
Standard Curve
Harvest Plasma from above settled cells and incubate 60 min in ‘Sandwich’ ELISA
Wash, add Substrate,
incubate 30 min
then stop reaction
Measure OD and
determine IFN-g levels
From’ BMA Feb Tuberculosis in the UK what is being done

43. Table of drugs used for the treatment of tuberculosis.
First line drugs
Second line drugs
Essential
Other
Old
New
Isoniazid  Rifampicin   
Pyrazinamide
Ethambutol Streptomycin
Ethionamide Cycloserine Capreomycin Amikacyn  Kanamycin PAS Thiocetazone
Quinolones
ofloxacin ciprofloxacin moxifloxacin
Macrolides
clarithromycin
Clofazimine Amoxycillin & Clavulanic acid
Lanizolid
New rifamycins    Rifabutin    Rifapentine
From’ BMA Feb Tuberculosis in the UK what is being done

44. Treatment of fully sensitive tuberculosis
Isoniazid (H) and Rifampicin (R) for duration 6 mo unless CNS then 12 mo.
+Pyrazinamide (Z) x2 mo
+Ethambutol (E)/Streptomycin (S) x 2mo or till sensitivities known

45. Side effects
Isoniazid; hepatitis, peripheral neuropathy (give with pyridoxine), psychosis, haemolytic anemia, lupus like syndrome, gynecomastia, pellagra
Rifampicin; fever, rash, hepatitis, discolouration of secretions, blood dyscrasia, abdominal and respiratory symptoms, drug interactions (inducer of P450 hepatic enzymes), renal failure, thrombocytopenia
Prazinamide; hepatitis, hyperuricemia, arthralgia, rash
Ethambutol; optic neuritis

46. DOTS Directly observed therapy.
Give meds in supervised fashion 3 or more times a week
Aids adherence

47. Resistance Single agent 15-20%
Multi drug resistance; Isoniazid and rifampicin
XDR; Isoniazid, rifampicin, injectable (aminoglycoside) and fluoroquinolone

48. Drug resistance CHECK SENSITIVITIES IN ALL ISOLATES! RISK FACTORS
Previous treatment especially if prolonged or exposure to somone who has had prior treatment
Contact with known drug resistant patient
Originates from or travelled to area of high incidence e.g. Russia, China, SE Asia, Latin America
HIV
History non-adherence
Substance abuse and homelessness
Remains smear positive after 2 mo therapy

49. Management drug resistance
Assess risk.
Treat with Isoniazid and rifampicin plus four new agents
Never add one or two agents to a recycled regimen
Assess susceptibility on culture ± MODS ± NNAAT (PCR) for Rifampicin or any any other resistance mutations

50. Prevention
CXR
Skin test± Interferon gamma release assay for susceptible groups e.g. anti-TNF treatment
If > 5mm mantoux and exposed, skin test conversion, old fibrosis immunocompromised > 10mm born in endemic area, IVDU or health care worker TREAT
Isoniazid 300mg x 6-9 mo guidelines vary

51. Routine BCG Discontinued in teenagers July 2005
Continue neonatal BCG in high risk groups
Family history
Ethnic minority groups
High incidence areas
From’ BMA Feb Tuberculosis in the UK what is being done