TB or not TB, That is the Question

Quick Facts!

In 2018, there were an estimated 10 million new active TB cases worldwide, including 1 million children; of these people, 1.45 million died. 

1.7 billion people are infected with latent TB worldwide, meaning that about 1 in 3 people in the world have latent TB!

ANYBODY can get TB. Some famous names include Desmond Tutu, Nelson Mandela, George Orwell, Tina Turner, Ringo Starr, Cat Stevens, and Carlos Santana, among many others.

Source: WHO 2020 Global Tuberculosis Report
Source: Rhode Island Department of Health

Cases of multi-drug resistant TB (MDR-TB) are increasing, especially in former Soviet countries, Asia, and South Africa. 

Source: WHO 2018 Global Tuberculosis Report

Guidelines: 2016 American Thoracic Society / Infectious Diseases Society of America / CDC Guidelines for Diagnosis of TB in adults and children

The Spectrum of TB Disease

Although TB disease can be viewed as a dynamic continuum from Mycobacterium tuberculosis infection to active infectious disease, patients are categorized as having either latent TB infection (LTBI) or active TB disease for simplicity in clinical and public health settings. Individuals can advance or reverse positions, depending on changes in host immunity and comorbidities.

Source: Pai et al. Tuberculosis. Nat Rev Dis Primers. 2016 Oct 27;2:16076.
Source: Drain et al. Incipient and Subclinical Tuberculosis: a Clinical Review of Early Stages and Progression of Infection. Clin Microbiol Rev. 2018 Jul 18;31(4):e00021-18.

Clinical Suspicion

  • Age (infant vs adolescent vs adult vs elderly)
  • Clinical symptoms: 
    • PNA that is not getting better
    • Fever, cough, hemoptysis (rare), night sweats, fatigue, loss of appetite, weight loss, wasting
    • Symptoms can be subtle!
  • Exposure history: place of birth, possible contacts, travel, workplace, friends, habits
  • General health: HIV, DM, immune system, smoking

Microscopy & Culture

  • Critical to do even when we have PCR tests
  • Smear positivity is used to assess bacterial burden and risk of transmission of TB
  • The sensitivity of smear microscopy is around 60-70% (in adult pulm disease), which is more sensitive than PCR-based testing!

Who to test?

  • Household or known contact to active TB disease
  • Immigrants from high-burden countries (>20 / 100,000)
  • Residents and employees of high-risk congregate settings
  • Patients with autoimmune disease at diagnosis
  • Mycobacterial lab personnel

Immune-based tests

TST and IGRA test for the diagnosis of TB infection, but cannot differentiate between infection and disease.

  • A negative TST or IGRA does NOT exclude active disease!!
  • Sensitivity in active disease is 70-85%
  • Test positivity can decline with the severity of active infection

How to test?

For the tuberculin skin test (TST), remember that correct interpretation is based on size of induration, not erythema. As the cutoff for mm of induration increases, the sensitivity decreases and the specificity increases. A positive test depends on risk factors:

  • ≥15 mm (sensitivity = 50-60%):
    • healthy individuals ≥4yo with no known risk factors
  • ≥10 mm (sensitivity = 90%):
    • Foreign-born individuals from high-risk countries who have spent <5yr in the US
    • Persons with clinical conditions that increase the risk of reactivation [e.g. silicosis, CKD requiring dialysis, DM, some malignancies (leukemias, lymphomas, carcinoma of the head, neck, or lung), underweight, jejunoileal bypass, and persons who inject drugs]
    • Residents and employees in high-risk settings, such as prisons, jails, healthcare facilities, mycobacteriology labs, and homeless shelters
  • ≥5 mm (sensitivity = 98%):
    • HIV infection
    • Close contact of active contagious case
    • Abnormal CXR with fibrotic changes consistent with old TB
    • Immunosuppressed patients [e.g. TNF-alpha inhibitors, chemotherapy, organ transplantation, glucocorticoid treatment (equivalent of ≥15 mg/day prednisone for ≥1 month)]

Causes of false-negative tests: infections (e.g. active TB, HIV, measles, etc), recent MMR vaccine, immunosuppressive drugs, age extremes

Causes of false-positive tests: NTM infection, prior BCG vaccination (check out this map for country-specific information)

  • BCG vaccination in the first year of life may produce low-level TST reactivity in adults; such reactions are typically <10 mm and rarely persist past the age of 10yo. Vaccination after the first year of life may cause a stronger and longer-lasting effect on TST; as many as 20% of individuals remain TST positive ≥10 years after vaccination at this age
  • Most persons with a history of childhood BCG vaccination have a lasting scar, typically found over the deltoid

One helpful way to read a TST is using a ballpoint pen, with which it is easier to feel a subtle change in skin induration. Remember to measure the transverse diameter. 

Interferon gamma release assays (IGRAs) have sensitivity similar to the TST but greater specificity for the diagnosis of TB infection. IGRA is preferable to TST in

  • Patients >2yo
  • Patients likely to be infected (e.g. from an endemic country)
  • Low to intermediate disease progression
  • When testing is warranted
  • History of BCG or if patient is unlikely to return

IGRA should be collected by a person trained to collect the test. Improper collection can greatly influence the test.

IGRA interpretation

IGRA requires careful interpretation. We must read the full results–don’t stop thinking when you see the word “positive”! Check out the examples below using the following information:

  • Mitogen is the positive control; an appropriate mitogen level is ≥0.5 IU/mL
  • Nil is the negative control; it adjusts for background, heterophile antibody effects, and non-specific IFN-gamma in blood samples; an appropriate nil level is ≤8 IU/mL
  • TB Antigen levels are significant if ≥0.35 IU/mL, but there is no difference in disease for levels above this threshold

Try doing all 3 cases before clicking on the answers. 

Case 1

  • TB Quantiferon Gold Plus: POSITIVE
  • TB Antigen 1 minus Nil: 3.67
  • TB Antigen 2 minus Nil: 3.50
  • Mitogen minus Nil: >10
  • Nil Control: 0.41

Case 2

  • TB Quantiferon Gold Plus: INDETERMINATE
  • TB Antigen 1 minus Nil: 0.00
  • TB Antigen 2 minus Nil: 0.00
  • Mitogen minus Nil: 0.01
  • Nil Control: 0.03

Case 3

  • TB Quantiferon Gold Plus: POSITIVE
  • TB Antigen 1 minus Nil: 0.01
  • TB Antigen 2 minus Nil: 6.18
  • Mitogen minus Nil: 0.03
  • Nil Control: 0.04

How to proceed?

  • Symptom screening should be performed on everyone prior to testing. In presence of symptoms, there is no need to test for infection; proceed with CXR and referral.
  • Following +TST or +IGRA, check CXR (mask patient in presence of cough). If abnormal, refer to the RISE clinic.

Treatment regimens for LTBI

  • Isoniazid x 9mo, daily
    • Preferred treatment for persons with HIV, 2-11yo children, and pregnant women
  • Isoniazid + rifapentine x 3mo, once weekly
    • Preferred treatment for persons ≥12yo
  • Rifampin x 4mo, daily

Blog post based on Med-Peds Forum talk by Natasha Rybak, MP Class of 2011 and Combined Infectious Disease / TB specialist

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