Latent tuberculosis infection

Background

• Prior exposure to TB leading to persistent latent tuberculosis, usually contained within lung granulomas
• Goal is to identify those who are at increased risk of developing active TB and would benefit from treatment to prevent future reactivation
• Use the TST in 3D calculator and the BCG World Atlas for risk estimation
• Standard prescription is 4 months of rifampin 10 mg/kg/day (up to 600 mg); counsel patient on side effects and monitor liver enzymes weekly to start

Epidemiology

• One quarter to one third of the world population has LTBI (estimated at 1.7 billion people)
• More prevalent in the same countries as active tuberculosis, and is highest in South-East Asia, Pacific, and African regions
• More common in older patients who would have been exposed when active tuberculosis was more prevalent

BCG Vaccination

• Done routinely in tuberculosis-endemic countries
• Commonly causes an elevated scar as site of inoculation (often on the deltoid)
  • Compared to smallpox, which forms a crater
• Receipt of the BCG vaccine affects interpretation of the tuberculin skin test

Risk for Progression to Active Tuberculosis

• HIV
• Transplantation
• End-stage renal disease
• Specific biologics, including TNFa-α inhibitors
• Corticosteroids

Diagnosis

Tuberculin Skin Test (TBST/TST)

• Sn 90%, Sp >95
• Lower specificity after BCG vaccination, which can cause false positives
  • Especially if received after age 5 years
  • Also if received after age 1 year, or received multiple times

Scenario	TST Cutoff (mm)
High Risk
people living with HIV	≥5
Contact with infectious TB within last 2 years	≥5
Fibronodular disease on CXR	≥5
Transplant patient	≥5
Immunosuppression with biologics or other, including prednisone ≥15 mg daily or higher	≥5
CKD stage 4 or 5	≥5
Moderate Risk
TST conversion within last 2 years	≥10
Diabetes mellitus	≥10
Malnutrition (<90% IBW)	≥10
Current tobacco smoker	≥10
Alcohol >3 drinks daily	≥10
Silicosis	≥10
Hematologic malignancy	≥10
Solid-organ malignancy of head-and-neck, lung, or GI tract	≥10
Low Risk
Any low-risk population	≥10

Interferon-Gamma Release Assay (IGRA)

• Sn 95%, Sp >95%
• Doesn't crossreact with BCG (uses ESAT-6 and CFP-10) but can crossreact with other non-tuberculous mycobacteria (most likely Mycobacterium marinum, Mycobacterium kansasii, Mycobacterium szulgai, and Mycobacterium flavescens)
• Preferred for those who have received BCG after infancy
• May be more useful in patients who are unlikely to follow up in 48 hours, or who need urgent immunosuppression and need a faster result
• QuantiFERON-TB Gold Plus (QFT-Plus) likely has better PPV than TST in a low-prevalence population

Choice of Test

• Either can be used in most situations
  • Historically, there has been a slight preference for TST because of long history of use
  • Now, more and more leaning towards IGRA (though barriers due to cost)
• IGRA specifically preferred when the patient has received the BCG vaccine after 1 year of age, received BCG in infancy but age 2 to 10 years, has received multiple BCG vaccines, or is unlikely to follow up to have their TST read
• TST still preferred for serial testing, such as in healthcare, corrections, or prisons
• Positive predictive value of both for the development of active TB is still quite poor

Sequential Testing

• May be indicated in some situations
• If high risk, but the initial test was negative, then the alternative may be ordered to increase sensitivity
• If low suspicion of LTBI but TST positive (i.e. possible false-positive), follow-up IGRA may be reasonable
• Patients with discordant results are still at higher risk of progression to active TB

Evaluation of a Positive TST

1. Is it truly positive?
   • Consider IGRA
   • BCG vaccine can be considered a cause of false positive when
     • vaccine given after 12 months of age, and
     • patient has no risk factors, and
     • either Canadian-born non-Aboriginal, or not from endemic country
2. Rule out active TB
   • signs/symptoms
   • CXR or CT chest
   • Sputum x3 if coughing or cavitary lesions
3. Evaluate risk of reactivation treatment
   • INH 300 daily x9 mo with pyridoxine
   • baseline liver enzymes and vision testing

Management

Regimen	Duration	Dose	Adverse Effects and Notes
First-Line
3HP	3 months	isoniazid 15 mg/kg weekly (max 900 mg) rifapentine weekly 10-14 kg: 300 mg 14.1-25 kg: 450 mg 25.1-32 kg: 600 mg 32.1-49.9 kg: 750 mg ≥50 kg: 900 mg	flu-like reaction, drug-drug interactions heavy pill burden difficult to access in Canada needs Public Health for DOT
4R	4 months	rifampin 10 mg/kg daily (max 600 mg)	rash, drug-drug interactions
Second-Line
9H	9 months	isoniazid 5 mg/kg daily (max 300 mg) pyrixodine 25 mg daily	hepatotoxicity, peripheral neuropathy
Alternatives
6H	6 months	isoniazid 5 mg/kg daily (max 300 mg) pyrixodine 25 mg daily	hepatotoxicity, peripheral neuropathy
9H (intermittent)	9 months	isoniazid 15 mg/kg twice weekly (max 900 mg)	hepatotoxicity, peripheral neuropathy
3HR	3 months	isoniazid 5 mg/kg daily (max 300 mg) rifampin 10 mg/kg (max 600 mg) pyridoxine 25 mg daily	hepatotoxicity, peripheral neuropathy, drug-drug interactions
Under Development
1HP	1 month	isoniazid and rifapentine daily

Timing of Treatment

• For pregnancy, either delay treatment until after delivery or prefer 4R regimen
• For medical immunosuppression, most guidelines recommend delaying immunosuppression until after the first month of LTBI treatment, where possible, though there is variation in this recommendation1
• For transplantation, guidelines recommend starting treatment while they are still on the transplant list, and that treatment should not delay transplantation1
• For patients with HIV, no specific recommendations, likely can start LTBI and HIV treatment concurrently1

Further Reading

• TBST vs. IGRA for latent TB
• Canadian TB Standards, 8th Edition. Chapter 6: Tuberculosis preventive treatment in adults Canadian Journal of Respiratory, Critical Care, and Sleep Medicine. 2022;6(sup1):77-86. doi: 10.1080/24745332.2022.2039498

Tools

• TST in 3D online TBST/IGRA Interpreter
• BCG World Atlas, which has a listing of every country's BCG vaccination policies