November 10th, 2014

Common Curbsides: The Tuberculin Skin Test and IGRA That Don’t Agree

louie may 2014Here’s one I’ve received twice in the past week, plus my answer.

As always, names/some details changed to protect patient confidentiality, plus my annotations in brackets/italics.

Hey Paul,
Quick question [Need I even comment about the “quick question” phrase, and how this unintentionally devalues what ID docs do? OK, I’ve commented, and yes I’m hypersensitive] — one of my patients, a 38-year-old woman from Serbia, is about to start biologics for rheumatoid arthritis [you can see this is going to be a latent tuberculosis testing question from miles away].
She’s not sure if she got BCG as a child [yep, called that one], so I did both [uh-oh] a PPD and sent a quantiferon gold [note this is not the crazy alphabetizing of the branded interferon gamma release assay (IGRA) products, which for some reason is “QuantiFERON®-TB Gold or the other one, which just goes with all-caps, “T-SPOT.TB”, and throws a period in the middle — jeeze, marketers]. The PPD is positive at 20 mm, but the quantiferon is negative [of course — otherwise there’s no question]. Her CXR is negative.
My conclusion is that she does not have TB and therefore does not need preventive therapy prior to starting biologics [that’s notable — putting your money down!]. Is that the correct conclusion?
I’m sure this is a very easy question [ah, not so easy after all] as you must get it all the time [second part is most certainly true].
Thank you very much sir [so formal! or maybe he was in the military] for your time.
Archie [not his real name, but it was the name of a dog we had growing up, a long-haired dachshund]

As noted above, nope, not so easy. Let’s consider the variables:

  • She’s from a part of the world with a higher rate of TB than we have here. So the prior probability of latent TB is greater than if she was US-born, though it’s not as high as this.
  • She’s about to get “biologics”, which by convention means some sort of expensive immunosuppressive drug, probably a TNF-inhibitor. These are of course great potentiators of TB, some worse than others.
  • She may have received BCG, which can give you a false-positive tuberculin skin test. But this effect typically wanes over time, and even if she did get BCG, it’s probably not very effective in preventing adult TB.
  • The sensitivity of the skin test vs IGRA is all but impossible to determine — because there is no gold standard for latent tuberculosis.

To summarize, the positive skin test could be a true positive, or could be a false positive from the (maybe) BCG. And the negative IGRA could be a true negative, or could be a false negative because it’s not 100% sensitive.

So what to do? Here was my answer:

Hi Archie,
The problem is that there is no gold standard — either one could be right. You might consider sending a T-SPOT, since it could be a bit more sensitive than the QF. But since biologics are strong potentiators of active TB, in general I’d recommend preventive therapy for a couple of months before she starts it (then completing a full course) since she’s from a part of the world with more TB than we have here.
A formal consult would be reasonable if this isn’t clear, or if you/she want.
PS: we had a dog named Archie when I was a kid.

So my question for you TB specialists out there — since this is such a common question, why doesn’t managing it appear in all the various guidelines and textbooks? Or am I missing it somewhere?

And speaking of dogs, it’s been a while since I showed a picture of Louie.

19 Responses to “Common Curbsides: The Tuberculin Skin Test and IGRA That Don’t Agree”

  1. Loretta S says:

    Since the stakes are so high with the commencement of a TNF-inhibitor possibly potentiating TB, I would be inclined to toss this one over the fence and have the patient get an actual ID consult. (I work in primary care.) Glad I am not the only one who cringes at the “quick question” intro to what is inevitably a complicated question.

  2. Howard Heller says:

    Check out McGill’s online TST/IGRA calculator

    Per CDC guidelines for IGRA, when results are discordant with the TST and risk for progression is high then the positive test counts. So I do think the guidelines address it clearly though not directly enough.

  3. Tom Rush says:

    Excellent and highly useful discussion of seemingly minor topic. Thanks.

  4. Ron Karpick, MD says:

    I have been involved with TB work for the past 11 years. Since this woman does come from an area of the world with more TB disease than the USA and since she is going to be treated with one of the biologics which can increase the likelihood of progression from TB infection to TB disease, the question is important. The negative QFT or any IGRA does not rule out TB infection. Recall that 11% of patients with active TB disease have a negative QFT. I would be sure to get a CXR to evaluate for granuloma or more importantly to be sure she does not have a pulmonary infiltrate consistent with active TB. A physical exam should look for active or former TB in the eyegrounds, lymphadenopathy, unexplained hepato or splenomegaly. If the x-ray is abnormal, sputum need to be collected for AFB smear and culture x 3 and if you have it available a GeneExpert MTB/Rif test. If the latter and the AFB cultures were negative, I would err on the side of treating her with INH 5 mg/kg (max 300 mg/day) for a total of 9 months. After 2 weeks of INHK she could be started on the biologic.
    I would monitor signs and symptoms of INH hepatotoxicity at least monthly and to be conservative check at least an ALT monthly.

  5. Loretta S says:

    Thank you, Drs. Heller and Karpick! Great information.

  6. Mike Angarone DO says:

    Dr. Heller
    Excellent link.I get this question and consults to my clinic all the time. I usually defer to the positive test if the person will be immune suppressed in the future (typically I see patients prior to solid organ transplant or prior to biologic therapy). I also subscribe to the school of doing only one test for Latent TB, not multiple.
    Also I prefer using RIF for 4 months or INH/rifapentine weekly for 12 weeks.

  7. Stuart says:

    The calculator is interesting but some sample case results I obtained don’t make decision making any easier. It’s not clear how to balance the risk vs benefit percentages.

  8. John says:

    The reading of the TB skin test is subjective, depending on the ability of the reader to distinguish between induration and swelling. What I have seen in my microcosm is that swelling is often interpreted as induration. Prior BCG almost always results in swelling but not induration in the TB skin test. There are uncommon exceptions. I was taught that swelling is like touching the lips and induration is like touching the tip of the nose. Any feedback?

  9. Holly Gooding says:

    Up-to-date (I know, not a textbook, but it can be so useful!) actually covers this and has a link to the calculator referenced above.

    • Paul Sax says:

      Up-to-date (I know, not a textbook, but it can be so useful!) actually covers this and has a link to the calculator referenced above.

      Holly: First, of course UpToDate is a “textbook” — an electronic one, a Godzilla that has eaten all others! Second, I agree it’s very useful. Third, this exact situation (TST pos/IGRA neg) is not exactly easy to find in there, but maybe I’m not looking in the right place.

  10. Agustín Muñoz-Sanz says:

    Good morning (now in Spain) Dr. Sax:
    It is excellent this provocative ‘Common Curbsides’. This is a good example of ‘problems-still-non-solved’ that we see at the ID consults every day. In my opinion, the Archie’s case can serve to put on the table some interesting questions (What Does Tuberculin Reactivity after Bacille Calmette-Guérin Vaccination Tell Us? Menzie s D. Clin Infect Dis 2000; 31 (Suppl 3: S71-74). For example: A) The age of the Serbian woman when she was vaccinated (less than 1-year-old or more than 1-year-old?). The age of the person when is vaccinated will have in the future a profound influence on the size, pattern, and duration of tuberculin reactions. Otherwise, the immune response to the BCG vaccine is different in infancy than in childhood and adulthood. In this sense, the protective efficacy of BCG vaccine for infants is excellent but is less for older children and adults. In the Archie’s case, a TST of 20 mm of diameter is probably more indicative of TB infection than of a remote BCG vaccination . B) Would be convenient to look for the vaccination scar that could help to sustain a previous vaccination although it is known that until 20%-50% of the persons vaccinated have not scar formation? And, C) Is there the possibility of a ‘booster phenomenon’ in this case, more common in individuals who received the vaccination at an older age? On the other hand, what about her actual immune situation in the context of the rheumatoid arthritis?
    In my opinion, this woman probably has a mycobacterial latent infection (TB infection). So, it is correct to treat her with isoniazide (my preference) as Dr. Karpick say; or RIF for 4 months or INH / rifapentine weekly for 12 weeks as Dr. Angarone suggest. Beginning before starting ‘biologics’, of course.
    Congratulations for your kind initiative and thanks so much, Paul.

  11. Kevin says:

    Every time some health care provider says “Quick question,” to me, I reply, “There are no quick questions.” And — in the case of this one statement, if nothing else — I’m always right! Perhaps it is time for a national campaign to get providers to stop saying, “quick question.”

  12. Gordon says:

    The best part is the pic of Louie. What kind of dog is he? Does he shed?

  13. Donald Steinmuller says:

    Use the algorithm, consult up to date, and get a formal consult. As a nephrologist for 40 years, I have seen several young patients die from TB diagnosed too late after immunosuppression for transplantation and lupus. We waste so much money on unnecessary testing, procedures and care. This decision can be life or death in a young person with otherwise a good prognosis. The cost is well worth it.
    Quick questions and curbside consults are extremely irritating to me as well. I was even more upset when my daughter during Family Practice residency would be encouraged by fellows to just get a curbside consult with no documentation of the discussion and then later rebuke because the intervention “wasn’t what I told you.”
    It is a bother and time consuming but let’s document our consults for the record and better care in the long run.

  14. Gillian Arsenault says:

    Based on the 2006 review by Farhat et al ( ): “In 24 studies involving 240,203 subjects BCG-vaccinated as infants, 20,406 (8.5%) had a TST of 10+ mm attributable to BCG, but only 56/5639 (1%) were TST-positive if tested > or =10 years after BCG. In 12 studies of 12,728 subjects vaccinated after their first birthday, 5314 (41.8%) had a false-positive TST of 10+ mm, and 191/898 (21.2%) after 10 years.”


    the 2002 meta-analysis by Wang et al ( ): “Patients who had received BCG vaccination were more likely to have a positive skin test (5 TU PPD: relative risk (RR) 2.12 (95% confidence interval (CI)1.50 to 3.00); 2 TU RT23: 26.50 (95% CI 1.83 to 3.85). The effect of BCG vaccination on PPD skin test results was less after 15 years. Positive skin tests with indurations of >15 mm are more likely to be the result of tuberculous infection than of BCG vaccination.”

    one is led to the conclusion that this 38 year old lady, who is at least 20 years past childhood even if we count age 18 as the end of childhood, with a PPD positive at 20 mm and a negative chest X-ray, is highly likely to have latent TB.

    Gotta love these “quick” questions . . . .

  15. Alan A. Pollock, M.D. says:

    Several points to make:
    1. BCG in childhood certainly fades with time and by adulthood, it would be quite unlikely to result in an unequivocally positive PPD of at least 10 mm.
    2. A properly performed positive PPD trumps the Quantiferon every time. I’ve lost count on how many “indeterminate” Quantiferon tests have been reported at our hospital. It has to do with rapid mixing after phlebotomy and timely processing of the specimen. If the PPD were not performed properly, it wouldn’t be positive in the first place, so I would consider a clearly positive result as reliable.
    3. INH/B6 should definitely be given with the TNF inhibitor. A negative chest x-ray is not reassuring. The absence of a calcified granuloma certainly does not preclude latent TB.

  16. Alyssa says:

    This is an excellent discussion. I wonder what we should be recommending to providers screening patients prior to immunosuppression. An IGRA is convenient as it doesn’t require an additional visit for reading. In this case, if she only had an IGRA she would have screened negative and started immunosuppression without any latent TB therapy. Guidelines would suggest that she undergo IGRA testing instead of PPD given her potential history of BCG vaccination.

    As always, great topics, Paul. I hope you are doing well!

  17. Marshall Kubota says:

    I assume the need for the biologic is clear. The common HIV coinfection of HCV may result in a positive RA in the absence of rheumatoid arthritis.

HIV Information: Author Paul Sax, M.D.

Paul E. Sax, MD

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