Spectrum of infection

Diagnosis

• Microscopy: ZN stain, acid-fast bacilli (AFB). Specific, not sensitive. Negative (none in 100 field); +1 (<1 /field); +2 (<10/field); +3 (>10/field)

• Culture: Most sensitive/specific. Species, resistance. Traditional (4-8 weeks) vs. liquid (3 weeks, expensive) culture.

• Drug sensitivity testing (DST): Genotypic: Line Probe Assay (LPA); 1st/2nd line drug mutations , takes 48 hours, e.g. MODS. Phenotypic: conventional culture-based, around 6 weeks

• Nucleic acid detection: Gene Xpert (tests for rifampicin resistance). Also Xpert Ultra (more sensitive, more false positive), Xpert Omni (closer to POC test).

• Interferon Gamma Release Assay (IGRA) e.g. QuantiFERON / T.spot-TB. Principle: interferon gamma is a cytokine that is critical for innate and adaptive immunity, produced by T helper (CD4) white blood cells. Immune response to antigen derived from M.Tb: antigen presentation will release interferon gamma. Fresh blood samples mixed with antigens and controls. Test of “exposure”: does not distinguish active vs. latent disease. Prior BCG vaccination does not cause a false-positive.

• Tuberculin (Mantoux) skin test” purified protein derivative (PPD). Delayed hypersensitivity reaction. Test of “exposure”: does not distinguish latent from active. If positive need to screen for active disease. False positive if previous BCG (in children: >5 BCG; >10 no BCG). False negative: HIV, miliary, ....

• Urine: Lateral Flow Strip (LAM). Immunochromatographic, point-of-care, test. M.Tb antigen in urine. Good for disseminated TB (sens=45%; spec 92%) and HIV especially if CD4<200 or no sputum. Use with Xpert increases diagnostic yield from 50 to 80%.

Treatment

• R: Rifampicin (orange urine, hepatitis, ?reduced BMD)

• H: Isoniazid (peripheral neuropathy)

• Z: Pyrazinamide (arthralgia, increased uric acid)

• E: Ethambutol (optic neuritis)

First line: RHZE for 2 months, then continue with RH for 6 months

CNS: 12 months treatment (2-months steroids)

MDR

• Resistance to rifampicin and isoniazid

Second-line treatment (needs updating)

Pyrazinamide PLUS 4 core second-line drugs e.g. Levofloxacin, Kanomycin, Cyloserine, Ethionamide

Intensive phase (6M), continuation phase (20-24 months). Bangladesh 9-12 months.

• Group A: Fluoroquinolone e.g. levofloxacin

• Group B: injectable e.g. kanamycin, streptomycin (renal, ototoxicity)

• Group C:

• Group D:

• Pre-XDR: above PLUS resistance to fluroquinolone OR injectable

• XDR: above, PLUS fluoroquinolone (Group A) AND second-line injectable (Group B)

• TDR: all

Directly Observed Treatment (DOTS): Suspected case; confirmed cases; default; failed; relapse (same strain)

When to start TB treatment if HIV +? If CD4<50 ART within 2 weeks. If CD4 >50, start within 8 weeks.

Prevention

BCG (Bacillus Calmette Guerin): live vaccine, protects against severe forms in children e.g. miliary, disseminated. Protection against leprosy/buruli ulcer?? (sustained infection-local lyphadenitis)

IPT (Isoniazid Preventative Therapy): 6-12 months treatment to eradicate latent TB infection

TB worldwide

• Top 10 causes of death worldwide.

• In 2015, 10.4 million people fell ill with TB and 1.8 million died from the disease (including 0.4 million among people with HIV). Over 95% of TB deaths occur in low- and middle-income countries.

• Six countries account for 60% of the total, with India leading the count, followed by Indonesia, China, Nigeria, Pakistan and South Africa.

• In 2015, an estimated 1 million children became ill with TB and 170 000 children died of TB (excluding children with HIV).

• TB is a leading killer of HIV-positive people: in 2015, 35% of HIV deaths were due to TB.

• Globally in 2015, an estimated 480 000 people developed multidrug-resistant TB (MDR-TB).

• TB incidence has fallen by an average of 1.5% per year since 2000. This needs to accelerate to a 4–5% annual decline to reach the 2020 milestones of the "End TB Strategy".

• An estimated 49 million lives were saved through TB diagnosis and treatment between 2000 and 2015.

• Ending the TB epidemic by 2030 is among the health targets of the newly adopted Sustainable Development Goals

Historical aspects

• Robert Koch

• Surgical treatments e.g. Plombage 'collapse' therapies

• 1944: discovery of streptomycin and first ever RCT

Cutaneous TB