Tuberculosis

Question 1

Challenges of managing TB in HK

Answer 1

Aging population
Immigrants from countries with hier risk and incidence of TB
Diagnosis and Treatment of LTBI

Question 2

Disease course (exposure, infection, disease). strongest risk factors

Answer 2

Exposure

• contact with individuals with active TB (airborne transmission with high infectivity)
• risk of infection after exposure depends on closeness of contact and infectiousness of source (50% infected if spend 8hr/day for 6mnths with infectious patient)

Infection

• 5-10% lifetime risk of progression to disease after infection
• > 50% active TB occur within 1st 2 yrs of infection
• STRONGEST RISK FACTOR = HIV (5-10% annual risk of progression); other risks e.g. DM, smoking, silicosis, age, co-morbidities

Disease

• progressive primary disease or endogenous reactivation
• pulmonary or extra-pulmonary

Question 3

Mycobacteria general properties - cell wall, staining technique, growth characteristics, molecular methods advantage/disadvantages

Answer 3

Aerobic, non-spore forming, non-motile bacillus
High lipid content in cell wall (mycolic acids, glycolipids etc)
–> thick wall, resistant to chemical agents, drying, very hydrophobic, resistant to lysis and cellular reactions
but sensitive to heat, UV
==> acid-fast

Staining:
- Ziehl-Neelsen staining - Carbol fuschin (red) heated for 5 min –> 3% acid alcohol washing for 2 min –> counterstain with methylene blue for 30 sec –> wash/dry
==> MTB complex resists decolourisation by acid alcohol

Growth characteristics:

• slow growing (3-8 wks)
• special culture required: LOWENSTEIN-JENSON medium (egg based) – gold standard showing morphology, allowing quantification, speciation, susceptibility testing
• rapid culture medium available with radiometric substrate - broth (1-3 wks) with similar sensitivity and specificity to solid media but no quantification/morphology

Nucleic acid amplification:

• TB PCR quick but culture still needed for speciation/susceptibility testing
• Gene Xpert very high sensitivity, detects MTB and rifampicin resistance; limitations as with PCR

Question 4

Pathogenesis of TB

Answer 4

Droplet nuclei as source of infection
1. inhaled bacteria implant in alveolus with subsequent multiplication: primary infection
2. organisms migrate to hilar LN and enter blood to reach other organs
3. subsequent clinical course depends on host immunity
–> absence of response e.g infants, HIV = infection progress to involve more lung parenchyma –> rapid acute disease leading to disseminated infection
–> cell-mediated immunity = halt disease and cause chronic inflammatory reactions with local destruction and necrosis – ASYMPTOMATIC
(–> or organism completely killed by immune response)
4. develop granuloma (caseous necrosis) with fibrosis and calcification to contain organisms
5. mycobacteria remain DORMANT BUT VIABLE and potentially pathogenic for years
6. breakdown of host defenses e.g. age, cancer, HIV = rupture of tubercles and reactivation (usually start at apex-posterior aspect with cavitation)
7. disease can occur in any organ seeded during primary infection
–> local symptoms + general malaise, LOW, night sweats, fever

Question 5

Immunity and Hypersensitivity

Answer 5

CELL MEDIATED immunity (humoural no role)

Host acquires hypersensitivity to tubercle bacilli in the course of primary infection resulting in positive tuberculin reaction

Question 6

Latent TB infection - definition, diagnosis

Answer 6

State of persistent immune response to stimulation by MTB antigens without evidence of clinically manifested active TB

Diagnosis:
- tuberculin skin test
- IFN-gamma release assay
==> doesn’t detect active/latent - judge clinically

Recommend for persons at high risk of developing TB and those with possible latent infection who will require treatment

Question 7

Tuberculin/Mantoux Test - concept, definition of positive test, interpretation of results

Answer 7

Immunological skin test eliciting response by injecting mycobacterial protein into skin of sensitised individuals

• use purified protein derivative; 0.1 ml injected (2TU) intradermally
• delayed HSR

Positive test = INDURATION with edema/erythema 48-72hrs after injection

• • different sizes of cut-off based on risk
• —> >5mm if HIV infected; >10 mm for silicosis, on anti-TNF; >15 mm for immunocompetent household contact >1 yrs old

Interpretation of positive results

• within 4-6 wks after infection
• history of infection
• after BCG vaccination or non-TB mycobacteria (false positive)

Negative results:

• very recent infection (<3wks)
• “anergy” with lack of normal cell mediated immunity due to steroids, AIDS, malnutrition, measles
• after elimination of infection by chemotherapy

CAN’T TELL IMMUNITY VS ACTIVE INFECTION

Question 8

IFN-gamma release assay (IGRA) - method, concept

Answer 8

Quantitative measurement of interferon-gamma in blood
– incubate patient’s blood with MTB antigens and monitor IFN-gamma release

• more sensitive and specific than skin test

Question 9

Symptoms of Pulmonary TB

Answer 9

Early TB: asymptomatic, incidental finding on CXR (Gohn focus, hilar LN)

Non-specific constitutional symptoms e.g. LOW, fever, chills, night sweats
Productive cough +/- other respiratory symptoms e.g. SOB, sputum, chest pain (if extend to parietal pleura)

Haemoptysis from caseous sloughing is minor but suggests advanced disease

Question 10

Primary TB in childhood - symptoms, progression

Answer 10

Diagnosis relies on symptoms, positive tuberculin skin test/IFN-g, hx of contact with active disease and CXR

Gastric aspirate for AFB smear and culture
Initial focus MC as mid-lung zones

CXR: regional lymphadenitis
–> compress central bronchi (brassy cough) or atelectasis or may rupture into a bronchus and seed infection distally to cause pneumonia

<5 yrs old: progressive lymphato-haematogenous dissemination with miliary meningeal disease
5-12 yrs: relatively disease resistant period, usually non-progressive

Question 11

Diagnosis of TB infection - clinical, lab 1st line, other additional methods

Answer 11

Clinical signs and symptoms, history
Radiological (CXR)
- primary: hilar LN, generally normal
- secondary: apical-posterior segment of lung, cavitation, patchy pneumonitis, fibrosis

1st line: EARLY MORNING SPUTUM
- microscopy (AFB)
- culture (LJ media/ rapid)
[- molecular (PCR)]

If patient can’t produce sputum or AFB negative but still suspect clinically:

• sputum induction by hypertonic saline aerosols
• fiberoptic bronchoscopy with biopsy and BAL
• granuloma formation on histological exam of biopsy

Question 12

Extra-pulmonary TB - possible manifestations, diagnosis

Answer 12

Local symptoms pertaining to site of disease - can occur in any organ seeded

Meningitis
Lymphadenitis (MC non-pul TB; cervical LN more involved - painless, slowly progressive)
Genitourinary - sterile pyuria
Skeletal - osteomyelitis, arthritis; >50% in spine leading to back pain (destroy IVD and then adjacent vertebral bodies - Pott’s disease)
GI - caecum MC, enteric ulceration/perforation/mass formation
Peritonitis (in AIDS)
Percarditis, laryngeal, anal etc

Miliary TB if severely immunocompromised

• numerous millet seeds in lungs and organs
• usually tuberculin negative

Diagnosis: PET-CT aids in diagnosis

Question 13

Treatment - aims

Answer 13

Aims:

• reduce number of ACTIVELY growing bacilli –> decrease severity of disease and halt transmission
• eradicate PERSISTING bacilli to prevent relapse after completion of therapy
• prevent acquisition of drug resistance during therapy

Overall:

• combination therapy (prevent MDR)
• prolonged course (6-9 mths; up to 2 yrs)
• directly observed therapy (DOT) to ensure compliance and lower risk of MDR

Question 14

Treatment regimen - drugs and duration

Answer 14

Intensive phase for 2 months:

• Isoniazid
• Rifampicin (KEY DRUG)
• Pyrazinamide
• Ethambutol (or streptomycin IM)

Continuation phase for 6 months:

• Isoniazid
• Rifampicin

Can check for sputum smear/culture conversion after 2 months and 6 months of therapy

Extension of therapy may be needed:

• e.g. additional 3 months continuation if positive culture after 2 months + cavitation on initial CXR or DM or HIV
• 3 HRZE + 9 HR if CNS involvement, miliary
• 10 month continuation if bone/joint

Question 15

Use of Dexamethasone in TB treatment

Answer 15

Suppress inflammation which may be caused by TB treatment initially –> more neurological damage with raised ICP/ hearing loss etc

Question 16

Drug interactions with TB drugs, adverse drug events

Answer 16

Concentrations reduced by Rifampicin

• warfarin, phenytoin, erythromycin
• contraceptive pills
• many others

Adverse drug events:

• GI upset – exclude hepatitis, take drug with food
• non-petechial rash – exclude other causes, antihistamines for mild, suspend tx if severe
• drug fever
• hepatotoxicity – underlying risk factors, withhold tx if ALT 3xULN

Question 17

MDR and XDR tuberculosis

Answer 17

MDR = resistance to at least both isoniazid and rifampicin

XDR = MDR + any fluoroquinolone + one of amikacin/capreomycin/kanamycin

(overall: isoniazid resistance highest)

Question 18

Treatment of resistant TB

Answer 18

Isoniazid resistant TB

• replace with levofloxacin
• 6 months

MDR-TB

• levofloxacin, bedaquilline, linezolid
• clofazimine/ terizidone

Question 19

Treatment of latent TB

Answer 19

Isoniazid monotherapy for 6 months

Question 20

Prevention of TB spread

Answer 20

Notifiable disease!

Negative pressure isolation rooms
N95 masks

Question 21

Vaccinations

Answer 21

BCG vaccine
- non virulent bovine strain

Reduce incidence of clinical disease but no protection against post-primary TB in adults

Offered to infants