Tuberculosis -2 (Latent TB)

Today we’ll discuss specifics in the diagnosis of Latent TB Infection (LTBI) [do read prior post on the natural history of Mycobacterium tuberculosis (Mtb) infection & disease].

Either the purified protein derivative (PPD) or Interferon-Gamma Release Assay (IGRA), diagnose LTBI.  But it’s crucial to ask, how do we know?  In other words, what’s the Gold Standard for identifying LTBI?  And the answer is…

There isn’t any!  LTBI is asymptomatic, CXR is normal, & not even autopsy would ever locate a few microscopic granulomas in a pair of lungs.

Actually, there is a unique Gold Standard — Epidemiology!  Countless studies over the last 100 years, in all sorts of populations throughout the world, have correlated 10 mm of PPD induration with likelihood of future development of Active TB.  The IGRA obviously hasn’t been studied as much (it’s new), but keeps proving valid.

So what does an 8 mm PPD mean, if not LTBI?  Other Mycobacteria species (M. avium, M. gordonae, M. kansasii, M chelonae, & some 60 more) can cause some reaction.  Probably not ≥10 mm, but maybe on occasion.  There’s no way to know.

Therefore (this is real important), to avoid false-positive results (for any test), NEVER screen people with low likelihood of having the target disease.  i.e. DON’T place PPDs or order IGRAs on populations with low-prevalence of Active TB.  Click for a neat, succinct explanation as to why you should NEVER screen low-prevalence populations for anything.

So who should we screen for LTBI?  Easy; anyone in the two following groups:

1. Persons Likely to be Infected with Mtb

  • poor / homeless
  • lived in 3rd World
  • Close contact w/ person w/ Active TB
  • incarcerated / institutionalized
  • Native American / Alaskan
  • Injection Drug Use

Note that Health Care Workers aren’t listed.  Some might be intermediate-risk (maybe in ERs with high active TB incidence); the vast majority are low-risk.

2.  Persons at High Risk of Active TB if Infected

  • HIV
  • Dialysis
  • Silicosis
  • Diabetes (slight ↑ risk)
  • Head & Neck Carcinoma
  • Lymphoma / Leukemia
  • Immunosuppressive Meds (organ transplant meds; prednisone >10-15 mg/d, for >3 weeks;  Tumor Necrosis Factor Inhibitors)
  • Malnutrition (& predisposing illnesses)
  • Tuberculin test converted neg to pos in last 2 yrs

How often should we screen patients?  Not very.  Immigrants who have left their high-prevalence homelands only require repeat testing if they return to the endemic area (perhaps if for over a month).  Persons in institutions or homeless shelters should probably be screened annually, maybe more often if enough active TB has been reported.  Screening teachers, health workers, etc. is an issue of employer liability rather than employee or community health.

Purified Protein Derivative (PPD)

Read the PPD at 48-72 hours after placement.  Record in “mm of induration” [never write “Neg” or “Pos”; that’s the interpretation, not the objective reading].  If placing the PPD on a Thursday, it’s OK to return the following Monday (96 hours).

Diagnose LTBI in any of the above at-risk persons if the PPD produces 10 mm of induration.  But note the following considerations:

  • Non-specific irritants cause induration <48 hrs: Ignore!
  • Induration appearing after 72 hrs counts as Positive
  • Any vesicles make it a Pos (regardless of mm induration)

5 mm induration is considered positive if:

  • HIV (weak T-cell response)
  • Contact tracing of active TB index pt (maybe infected <10 wks)
  • Abnormal CXR compatible with “Old Scar”

Demand at least 15 mm of induration for anyone without risk factors (i.e., for the majority of Americans).  Actually, as we noted above, don’t even test people without risks.  For a long time, to the dismay of TB experts, the American Academy of Pediatrics recommended routine tuberculin testing for all children.  They stopped a few years ago.

Major urban Health Departments usually consider 10 mm to be positive for all residents, even though many of them aren’t actually high risk.  Fair enough; simplifies population-wide decision-making.

Causes of False-Negative PPD:

  • Injected too deep (didn’t raise an intradermal bleb)
  • PPD solution sat at room temp >30 min
  • Pre-filled syringe (PPD solution adsorbs into plastic)
  • Anergic (immunocompromised) —  no way to identify (tough for us)
  • Recent infection (takes 10 wks for immune system to react)
  • Recent live virus vaccine [place PPD simultaneously, or 3 mos. later]
  • Remote Mtb infection: immune response waned

Waning of the immune response is why we do initial 2-Step Testing, placing a 2nd PPD, 1-3 weeks later, on all new health workers & anyone who can expect to receive annual testing.  It’s to seek a Booster Response; click for explanation.

Causes of False-Positive PPD:

  • Read before 48 hrs.
  • Other Mycobacteria species (no way to determine)
  • NOT the BCG vaccine!!!

BCG vaccine (click link for definition + blurb) is a source of contention among foreign health workers who are told they need chest x-rays & even INH Tx.  BCG can cause <10 mm of induration to the PPD, but that’s interpreted as negative.  It might occasionally cause 10-15 mm, and extremely rarely > 15 mm.  So…

If the foreign professional came from a country with high prevalence of TB, it’s much more likely that 10 mm represents true LTBI than a false-pos BCG effect.  Simply a question of numbers — mere probabilities.  So the CDC says to ignore a history of BCG vaccine when interpreting PPDs.

Interferon-Gamma Release Assay (IGRA)

Brand names are QuantiFERON® and T-Spot.TB®.  As noted, they detect γ-interferon released from lymphocytes when incubated with an Mtb antigen.  The IGRA requires special handling which many labs can now do.  The CDC recommends performing either PPD or IGRA, not both.  European counterparts say it’s fine to do both, drawing the IGRA at time of PPD reading (drawing it later might cause a false-positive IGRA).

IGRA results are either “positive,” “negative,” or “indeterminate.”  The latter means that either the negative control reacted inappropriately, or that the positive control didn’t.  It does NOT mean “intermediate” (like for culture & sensitivity).  “Indeterminate” means “non-interpretable”.

The IGRA’s advantage is that it’s much more specific for Mtb.  It’s main bragging right is that it won’t react to BCG effect.  So it would be the ideal option for foreign professionals (and anyone else who’d received the vaccine).  Another invaluable virtue is that it doesn’t require a return visit (PPD reads are notorious for no-shows, & studies show patients’ own interpretations are horrid).

A nurse adopted a 2 year-old child from China, whose PPD was positive.  She tried giving INH, the kid spit it out, bonding was at stake.  So she had an IGRA drawn, which was negative.  Fair enough to presume the PPD induration was a BCG effect, and INH treatment was cancelled.

But the IGRA is NOT more sensitive than the PPD.  People intuitively suppose that, because it’s a blood test, it has to be better.  Not so!  They’re both the same in terms of sensitivity (likelihood of false-negatives).

If the PPD is negative, and the IGRA positive, you don’t know which to believe.  There are reports of repeated IGRAs that “wobble” back & forth between positive & negative.  Over-testing can be worse than no testing.

What to Do for Patient with Positive PPD / IGRA

Obtain a PA chest x-ray (for children, a lateral view too, since active TB can present with paratracheal adenopathy alone).  It’ll probably be normal, since the screened patient is asymptomatic.

Any infiltrates, nodules, or cavities require work-up for Active TB.  Send to TB control through the local health dept., which has the knowledge base & resources.  If AFB cultures remain negative for 2 months, and a repeat CXR shows no changes, you can diagnose TB-4 (“Old Scars;” see last posting).  The infection is latent, non-contagious, but at such high risk of reactivation that it warrants INH Tx.

The only CXR abnormality you can ignore is a “calcified granuloma” (maybe called a “Ghon” or “Ranke” lesion or complex).  These are burnt-out scars from where Mtb first entered the lungs, got attacked by innate immunity and transported to nodes in the hilum.  No risk for reactivation.  The operative word is “calcified.”  Other “granulomas” need W/U.

If CXR is normal, explain to patient they have Latent TB Infection:

  • Mtb is inside them, asleep
  • They’re not ill & not contagious
  • They should NEVER get another PPD / IGRA (we already know they’re infected, won’t get any new info, but their arm’ll itch something fierce)

Do they ever need another CXR?  Only if:

  • They have a cough lasting ≥3 weeks without any improvement
  • They get hemoptysis, night sweats, chronic fevers, or weight loss
  • They need clearance for work, school, etc.

How often do they need a CXR for clearance?  Every 10 years.  Or 20?  This is a loaded question — medically speaking, they NEVER need a CXR unless they’re ill.  It’s purely a liability issue.  Clear them for as long as you want, & wait for company lawyers to complain.

Many (but not all) tuberculin-positive persons should take INH to prevent reactivation.  This Blog is about Diagnosis; if interested, click for a brief take on Who Should Get INH Tx.


1.  Latent TB Infection (LTBI) is diagnosed by a positive PPD or a positive IGRA blood test.
  • False-positives (less common with the IGRA) may be due to other Mycobacterium species.

2.  Avoid false-positives by only testing the following persons:

  • Persons Likely to be Infected with Mtb
  • Persons with Conditions Conferring High Risk of Active TB (if infected with Mtb)
3.  Patients with Pos PPD / IGRA need a CXR to r/o Active TB
  • Pos PPD / IGRA and normal CXR = Dx LTBI
  • Calcified granulomas also = LTBI [do not require work-up]
  • Cavities, nodules, infiltrates, “fibrotic scars” require W/U
    • 3 sputums for AFB; if Neg at 60 d, repeat CXR
    • Neg sputums + no change CXR = Latent TB (TB-4)
    • See prior posting TB-1 (Intro)
4.  Teach patients with LTBI:
  • Never receive another test
  • No more CXRs unless a) symptomatic; or b) required by job
  • Persons with LTBI may be Candidates for INH Tx

Next time we’ll conclude with the CXRs & Sputums for Active TB.

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