الرحيم الرحمن الله بسم

A 25 year old Saudi male applied to work as paramedic. He has no symptoms or history of contact with sick patients. His physical examination is unremarkable. His CBC, U&E, LFTs, urinalysis and CXR were all normal. Tuberculin skin test led to an induration of 12 mm after 48 hours.

What is your diagnosis? What is your plan of management?

Latent Tuberculosis

Outline:During this talk the following will be discussed:• Pathogenesis of latency in tuberculosis• Diagnosis of latent TB infection (LTBI)• Role of interferon gamma assays in the diagnosis

Latent Tuberculosis

• Very common (2 billion people)• Asymptomatic ( dormant )• A major source of active TB• In healthy; risk of reactivation is 0.1% /yr• In recent converters; risk is 5 – 10% in 2-5 yrs• Risk is increased by immunosuppression and chronic

diseases• Diagnosis is difficult to confirm

Latent Tuberculosis: Pathogenesis

• After infection: 10% develop active TB• Primary infections leads to hematogenous

dissemination and metastatic foci• Is post primary TB always due to reactivation?

Evidence of latency

• Autopsy studies• PPD and CXR surveys• Lower rate of drug resistance in elderly• Relapses after effective chemotherapy• INH prohylaxis decreases reactivation

Evidence of latency

MacCune et al experiment on Cornell model: - Infected mice treated for 12 weeks with INH & PZA - At end of therapy: no m. TB could be cultured - after 3 months: m. TB cultured from 65% of mice ( 100% if given cortisone for 3 wks )

Latent Tuberculosis: Pathogenesis

• But: most primary foci become sterile in few years

• Within granuloma: environment is microaerophilic, acidic & & &

contain toxic oxygen and nitrogen radicals

• How does M. TB survive such stressful environment?

Latent Tuberculosis: Pathogenesis

• Studies showed that m. TB cannot survive anerobic conditions for prolonged periods

• Possibly: m. TB can go into a state of dormancy with low metabolic activity for a long time

• How to explain INH effect?

Latent TB : Diagnosis

• TST is the standard test for diagnosis• PPD contains > 200 antigens• BCG vaccinated: more likely to have +ve TST • Low specificity in BCG vaccinated• Low sensitivity with impaired immunity• Interpret in view of pretest risk

Table 1. Interpretation of Tuberculin TestingDiameter of Induration Groups Considered Positive (CDC)

Alternative tests

• No gold standard to diagnose LTBI• Test performance in high risk individuals• IGRA tests: - T-spot TB assay - Quantiferon TB test• Specific IGRA tests: - Quantiferon TB Gold

IGRA Tests

• Quantiferon TB evaluated in 216 healthy Japanese nursing students , no TB exposure. All had BCG.

- TST +ve (>10 mm) in 64.6% - Quantiferon TB +ve in 1.9%

• Quantiferon TB Gold studied in 99 healthy Korean adults, no TB exposure. BCG in 90% .

- TST +ve in 51% - Quantiferon TB +ve in 4%

IGRA tests in contact tracing

• T-spot TB test evaluated in 535 secondary school students exposed to infectious TB case . Most had BCG .

- T-spot TB test was as sensitive as TST. - It correlated better with degree of exposure.

Can IGRA tests predict development of TB

Diel et al evaluated 601 contacts of TB patient: 278(46%) had BCG. TST +ve in 243(40%). Quantiferon +ve in 66(11%). INH offered to contacts with +ve Quantiferon. 41 contacts declined to take INH. FU for 2 years : 6 contacts developed TB, all were Quantiferon +ve

Can IGRA tests predict development of TB

Higushi et al: 88 TST +ve contacts were followed up for 3.5 years.

Only 4 were quantiferon +ve . None of 84 Quantiferon -ve contacts

developed TB.

Role of IGRA tests in diagnosis of LTBI

• Do IGRA test replace or complement TST?• IGRA tests are more expensive ($40/test)• More specific• CDC suggested replacing TST by Quantiferon • In UK (and Europe) IGRA tests are used as

confirmatory in TST +ve s.• Most cost effective approach in contact evaluation.• Other areas remain controversial.

Thank you

Latent Tuberculosis: Pathogenesis

Latent Tuberculosis

Latent Tuberculosis