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

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

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

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

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

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

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

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
Rule out active TB
- signs/symptoms
- CXR or CT chest
- Sputum x3 if coughing or cavitary lesions
Evaluate risk of reactivation treatment
- INH 300 daily x9 mo with pyridoxine
- baseline liver enzymes and vision testing

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

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

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

a b c Tasnim Hasan, Eric Au, Sharon Chen, Allison Tong, Germaine Wong. Screening and prevention for latent tuberculosis in immunosuppressed patients at risk for tuberculosis: a systematic review of clinical practice guidelines. BMJ Open. 2018;8(9):e022445. doi:10.1136/bmjopen-2018-022445.