Latent tuberculosis infection: Difference between revisions

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== Background ==
−
= Latent tuberculosis infection (LTBI) =
  
  +
*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 '''[http://tstin3d.com/en/calc.html TST in 3D calculator]''' and the '''[http://www.bcgatlas.org/ 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)
−
== Definition ==
  
  +
*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===
−
* Prior exposure to TB
  
−
* Goal is to identify those who are at increased risk of developing active TB and would benefit from treatment
  
   
  +
*Done routinely in tuberculosis-endemic countries
−
== Investigations ==
  
  +
*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===
−
* Tuberculin skin test (TBST)
  
−
** Sens 90%, Spec >95
  
−
* Interferon-gamma release assay (IGRA)
  
−
** Sn 95%, Sp >95%
  
−
** Preferred for those who have received BCG after infancy
  
   
  +
*HIV
−
== Positive TBST ==
  
  +
*Transplantation
  +
*End-stage renal disease
  +
*Specific biologics, including TNFa-α inhibitors
  +
*Corticosteroids
   
  +
==Diagnosis==
−
# Is it truly positive?
  
  +
===Tuberculin Skin Test (TBST/TST)===
−
#* 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
  
   
  +
*Sn 90%, Sp >95
−
== Reading ==
  
  +
*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
  +
{| class="wikitable sortable"
  +
!Scenario
  +
!TST Cutoff (mm)
  +
|-
  +
! colspan="2" |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
  +
|-
  +
! colspan="2" |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
  +
|-
  +
! colspan="2" |Low Risk
  +
|-
  +
|Any low-risk population
  +
|≥10
  +
|}
   
  +
===Interferon-Gamma Release Assay (IGRA)===
−
* [http://blogs.jwatch.org/hiv-id-observations/index.php/common-curbsides-the-tuberculin-skin-test-and-igra-that-dont-agree/2014/11/10/ TBST vs. IGRA for latent TB]
  
   
  +
*Sn 95%, Sp &gt;95%
−
== Tools ==
  
  +
*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 ===
−
* [http://www.tstin3d.com/en/calc.html TST in 3D online TBST/IGRA Interpreter]
  
  +
  +
* 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 ===
  +
#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
  +
  +
==Management==
  +
{| class="wikitable"
  +
!Regimen
  +
!Duration
  +
!Dose
  +
!Adverse Effects and Notes
  +
|-
  +
! colspan="4" |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
  +
|-
  +
! colspan="4" |Second-Line
  +
|-
  +
|9H
  +
|9 months
  +
|[[isoniazid]] 5 mg/kg daily (max 300 mg)
  +
[[pyrixodine]] 25 mg daily
  +
|hepatotoxicity, peripheral neuropathy
  +
|-
  +
! colspan="4" |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
  +
|-
  +
! colspan="4" |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 recommendation<ref name=":0">Hasan T, Au E, Chen S, Tong A, Wong G. Screening and prevention for latent tuberculosis in immunosuppressed patients at risk for tuberculosis: a systematic review of clinical practice guidelines. BMJ Open. 2018 Sep 12;8(9):e022445. doi: [https://doi.org/10.1136/bmjopen-2018-022445 10.1136/bmjopen-2018-022445]. PMID: [https://pubmed.ncbi.nlm.nih.gov/30209157/ 30209157]; PMCID: [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc6144320/ PMC6144320].</ref>
  +
* For transplantation, guidelines recommend starting treatment while they are still on the transplant list, and that treatment should not delay transplantation<ref name=":0" />
  +
* For patients with HIV, no specific recommendations, likely can start LTBI and HIV treatment concurrently<ref name=":0" />
  +
  +
==Further Reading==
  +
  +
*[http://blogs.jwatch.org/hiv-id-observations/index.php/common-curbsides-the-tuberculin-skin-test-and-igra-that-dont-agree/2014/11/10/ 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: [https://doi.org/10.1080/24745332.2022.2039498 10.1080/24745332.2022.2039498]
  +
  +
==Tools==
  +
  +
*[http://www.tstin3d.com/en/calc.html TST in 3D online TBST/IGRA Interpreter]
  +
*[http://www.bcgatlas.org/ BCG World Atlas], which has a listing of every country's BCG vaccination policies
  +
  +
[[Category:Tuberculosis]]

Latest revision as of 10:13, 15 April 2024

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 recommendation[1]
  • For transplantation, guidelines recommend starting treatment while they are still on the transplant list, and that treatment should not delay transplantation[1]
  • For patients with HIV, no specific recommendations, likely can start LTBI and HIV treatment concurrently[1]

Further Reading

Tools

  1. ↑ 1.0 1.1 1.2 Hasan T, Au E, Chen S, Tong A, Wong G. Screening and prevention for latent tuberculosis in immunosuppressed patients at risk for tuberculosis: a systematic review of clinical practice guidelines. BMJ Open. 2018 Sep 12;8(9):e022445. doi: 10.1136/bmjopen-2018-022445. PMID: 30209157; PMCID: PMC6144320.

References

  1. ^  Canadian Tuberculosis Standards. 7th edition. ed. Template:ISBN. OCLC 978699031.

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