TUBERCULOSIS


DEFINITION
A terrifying disease that has laid waste to the helpless masses of poor and underprivileged through history, the pathogenesis being the price they paid for protection.

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INCIDENCE

Single most important cause of infectious death on earth (in Robbins' opinion)
Increasing due to HIV, immigration and poverty.
NZ Europeans: 2.7/100,000.
Maori: 18.9/100,000.
PI: 43.9/100,000.
Other: 101/100,000.
~10% are reactivations.
~3% die.

Geography
Developing world (20-50x).
Rampant in AIDS-ridden areas.
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AETIOLOGY

Mycobacterium tuberculosis complex.
- 6 organisms in this group.
- only M. tuberculosis & M. bovis are usually important.
- M avium and M intracellulare have no virulence in normal hosts but can do in AIDS

Characteristics

Strictly aerobic.
Thick lipid-containing cell wall (source of virulence and persistence).
Can survive and multiply intracellularly.
Slow rate of multiplication.
No known exotoxins.
Able to lie dormant for long periods.
Resistant to conventional ABs.
Crucially, induces delayed-type hypersensitivity (type IV)
- this explains the organisms destructiveness
Avoid killing by macrophages
- lipoaribinomannan = endotoxin inhibiting interferon-gamma and promoting systemic reaction via TNF-alpha, and IL-10 suppresses T response.
- cord factor on surface induces granulomas
- complement activated on surface facilitates opsonisation without triggering the respiratory burst for killing them.
- heat shock protein may aid autoimmune reactions
- secretes a urease that helps reduce acidification of lysosomes
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BIOLOGICAL BEHAVIOUR

Natural History
Spread by coughing.
Enters body via inhalation.
The overwhelming preponderance of TB involves the lungs or begins there.
Ingested by alveolar macrophages.
Protected by cell wall.
Grow slowly inside macrophages.
Infectious any time organisms are actively growing in the lungs.

Pathophysiology
“There is perhaps no other infectious disease that so strikingly raises the question of whether pathogenesis is the price one pays for protection.” (Nadles, 1994).

Primary Infection

Bugs arrive in macrophages in lungs.
- non-specific immune response is ineffective.
- bugs spread around a bit through the lung and maybe shower elsewhere via blood, eg deposit brain, kidney, spine, scrotum.
After 2-12 weeks, a specific immune response gets going.
- this response can be either pure TH1 (cell mediated) or mixed TH1 & TH2 (humourally mediated) depending on host factors (key point).
- TH2 response is relatively ineffective and causes severe immune-induced damage
Reaction kills TB via CD4+ mediated IFN-gamma activating macrophages (NO, NO2 and HNO3 intermediates)
- and via CD8+ cells lysing infected macrophages through Fas independent and dependent means.

At this point, one of two things can occur: progression of the primary infection, or latency.
- less than 10% get primary progressively TB (mostly infants & immunocompromised).
- otherwise there is a self limiting course: if TH1 response gets going it is usually good enough to contain the TB.
--> granuloma formation occurs, (Ghon focus), which undergoes central liquefaction (caseastion).
--> a fibrotic calcified scar lesion is left (usually in the apex, as TB likes areas of high oxygen tension).
--> associated with a scarred hilar lymph node visible on CXR - the Ghon complex.
- a small proportion of organisms may remain viable in these scars for years (mostly in the lungs, but perhaps elsewhere).
Symptoms by this stage mild if they occur at all: mostly hilar lymphadenopathy with collapse, or pleural effusion.
Broch’s syndrome is when the collapse does not resolve and bronchiectasis results.

Primary Progression
Body fails to contain primary infection as above.
One of three things happen.
- huge cavitating lesions (mixed TH2 response).
- miliary TB (see below).
- nasty bronchopneumonia.

Secondary TB
May be many years later in 5-15% of self limiting infections
- either due to reactivation of scars or reinfection.
- risk factors for reactivation include: malignancy, alcoholism, diabetes, chronic dialysis, partial gastrectomy (or other malnutrition), immunosuppression, lymphoma, and the frail elderly.
- highest risk is in first 2 years (50% in this time).
Damage relates to a type 4 (cell-mediated) hypersensitivity response - based on an already sensitised immune system.
- the more TH2 the response is, the worse the damage as more mediators are released, yet the bugs are less well contained.
--> greater widespread caseation of the lung.
--> symptoms of primary infection, only worse.
--> symptoms of primary progression.
--> blood borne spread, so miliary TB (see below) or systemic TB.

Miliary TB
The result of acute diffuse dissemination of TB bacilli.
- like a bacteraemia, and they seed everywhere and anywhere.
Common sites include lungs, meninges, bones, joints, lymph nodes, kidneys, adrenals, GI tract (liver, spleen).
Can present pretty non-specifically from here.
- or in a myriad of ways with protean consequences and a menagerie of symptoms.
Hope that wasn’t too flowery. (It was - TB.)

Secondary Systemic TB
This is reactivation of a primary infection outside the lungs (see above).
Can be isolated extrapulmonary manifestation.
- any of the locations mentioned for miliary and more.
Presents non-specifically.
Or as chronic infection of the target organ.

TB And HIV
Primary infections do not regress as occurs in people with good immune function.
Of those HIV pts with latent infection, 5-10% will develop secondary TB per year.
Nasty combo.

Complications
Short Term
Pleural effusion.
Empyema.
Bronchopneumonia.
Sinus tract formation.
Lymph node rupture.
Long Term
Bronchiectasis.
Cor pulmonale.
Mycetoma.
Adrenal insufficiency.
Sterility.
Bronchostenosis.
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MANIFESTATIONS

Symptoms
Primary Infection
Usually a silent disease early on.
Cough, perhaps fixed wheeze (atelectasis due to hilar lymphadenopathy).
Pleural effusion.
Rash (erythema nodosum due to allergy to infection).

Progression / Reactivation / Miliary
Target organ damage will raise suspicion relevant to clinical context.
Cardinal features are tiredness, malaise, anorexia, weight loss, fever and cough.

TB peritonitis
TB enteritis
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INVESTIGATIONS

Mantoux Testing

A large topic.
Essentially, it’s only a guide to diagnosis, based on other clinical data.
The result is the horizontal diameter of the area of induration not the area of inflammation.
A positive response means a pt has had a dose - either infection with one of the complex or a non-TB mycobacterium.
If the clinical circumstances are appropriate, then an interpretation of active TB can be made.

Examples of clinical use

>5mm - May be active +ve in HIV pts, children, adolescents with recent contact, fibrotic CXR changes, major immunosuppressive pts.
>10mm - previous residence in high incidence country, IV drug users, TB lab personnel, adult with recent TB contact, conditions with increased risk of infections or children exposed to adults with high risk.
>15mm - people with no risk factors & past vaccination.

Microbiology
Send a sample off.
3 sputum samples initially.
Smear test and staining with fluorochrome and ZN stain.
Culture - gives identification in 1/52 and sensitivity in 2/52.
Molecular DNA probes - rapid identification in ccultures.
PCR - does not differentiate live and dead organisms.

Induced sputum

Inhale hypertonic saline.
Superior to bronchial washing.

Other

MSU - if sterile pyuria, then AFB stain and culture.
FNA of enlarged lymph nodes for AFB and cytology.

Imaging
CXR.
Apical shadowing.
Cavitation.
Miliary shadowing.
TB is a great imitator with respect to cx-rays.
Bronchoscopy
With bronchial washings.
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MANAGEMENT

Control of infection

Screening contacts and migrants from high incidence countries.
Vaccination (BCG) in neonates - reduces risk by about 50%.
Chemoprophylaxis is limited drug treatment to eradicate latent TB infection (LTBI) - traditionally 6-12/12 isoniazid.
Treatment of active cases - doctor delay of 7/52 was shown in a recent Auckland study.
General containment - isolation, masks, etc...

Control in hospital
Think of TB - high index of suspicion.
Isolate infectious cases in ventilated, negative pressure rooms (at GLH).
Face masks for patient and/ or medical staff - must be the special 3M ones.
Pre-employment screening for staff - 2 step Mantoux + CXR if positive.
Investigation and surveillance, annual questionnaire.

Medical
Team approach, pt cooperation is essential.
Principles
4 drugs.
Always use at least 2 meds, because of natural resistance (1 resistant AFB/10).
Never add a single drug to a failing regimen.
Factors Important to tx
Longer duration of tx if extensive disease (ie lots of bugs).
Sites - if low perfusion sites, need a longer course.
Resistance to drugs means longer course now needed.
First & Second Line
Rifampicin (R), Isoniazid (H), Pyrazinamide (Z), Ethambutol (E).
Second line agents include aminoglycosides, ethionamide, capreomycin, para-amino-salicylic acid.
Regimens
May be self-administered.
Or given by a health professional - DOT (Directly observed therapy) - once daily, twice weekly or thrice weekly.
For a non extensive disease by a fully sensitive organism:
Daily RHZ for two months, then RH for four months.
-> 2RHZ + 4RH.
Resistance Factors
Primary resistance refers to original organism transmitted from a known resistant index case.
Secondary resistance results from inadequate treatment.
10% of NZ isolates have some resistance - isoniazid and streptomycin most commonly.
MDR (multi drug resistance) refers to isoniazid and rifampicin or just more than 1 drug.
1% of NZ isolates are multi-drug resistant.
Most multi drug resistant TB can be cured with medication, although a long, hard and expensive course is necessary.

Surgical
Resection of localised severe disease is sometimes needed.

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