LTBI: igra false positives

a recent article found the disturbing result that the Interferon-γ release assays (IGRAs)​ for tuberculosis seems to have many false positive results (see tb igra false pos amjrespcare2013​ in dropbox, or DOI: 10.1164/rccm.201305-0831OC). this is particularly disturbing since there is a national shortage of PPD testing reagents, leading many institutions to rely heavily or exclusively on IGRAs [70 have adopted QuantiFERON-TBGold (QTF)]. I sent out a blog a couple of years ago questioning the validity of IGRAs at the Cleveland clinic.  The current study is more impressive and with larger numbers of health care workers.  For background reference, MMWR did a full issue on PPD vs IGRAs in 2010 (see http://www.cdc.gov/mmwr/pdf/rr/rr5905.pdf. ).  There was some concern voiced to me by a TB specialist member of the committee involved in producing this paper at that time, stating that most of the committee members voicing approval for IGRAs (not including him) were receiving funding from producers of the tests, and that he felt that there was insufficient data to endorse IGRAs at that time. (of course, one of the issues is that there is no good gold standard – the comparison is with PPDs, which can have false pos and neg results). the current study was at Stanford (which adopted serial QFT screening in 2008, with more than 10,000 employees).  Baseline at Stanford:

--611-bed hospital with mean of 14 cases of pulmonary TB/yr between 2006-2011

                --surrounding community with estimated TB rate of 10.7-10.9 cases per 100K people

                --from 2008-2010, all employees were screened annually with QFT, independent of prior PPD status or if had received therapy for LTBI (latent TB infection)

                --analyzed 9153 health care workers with at least 2 results over time from QFT, 72% female, man age 43

Results:

                --overall 13.9% of QFT tests were positive

                --of 1223 individuals initially with positive QFT, 67.5% remained positive (“persistently positive”)

                --of 8227 initially negative, 4.4% converted to positive (which was 11x the rate of prior conversions with PPDs!!)

                --of those whose QFT reverted from positive to negative, 73.9% had titers between 0.35 and 1.0 IU/ml (0.35 being the cutoff value for positive), vs that titer in 62.4% going from negative to positive and 27.8% of persistently positive

                --of the 361 workers who converted to positive, repeat testing was done in 60 days in 261 of them and 64.8% reverted to normal.

                --in 16 low-risk workers with conversions from negative to positive who were persistently positive after the repeat test, 12 (75%) reverted ultimately to negative

                --if change cutoff for positive increased to be 1.0 IU/ml, that would eliminate 67% of discordant repeats, but fail to pick up 33.7% of persistently positives

                --and one interesting analysis: if one were to assume that the PPD conversion rate at the institution (0.4%) were a true reflection of LTBI (and it has the longest track record with such repeat testing), that would translate to a QFT cutpoint of 5.3 IU/ml to get the same 0.4% conversion rate. In that case the persistent positive QFTs (who presumably have the highest likelihood of real LTBI) would be reduced by 68.6%

So… one would have thought (including me) that this more specific test (the IGRAs) would be great, esp for those of us working in communities with a high prevalence of prior BCG vaccination and a moderately high rate of TB. This article is pretty impressive in demonstrating the variability of QFT results. Not sure if this applies to other IGRAs (the MMWR considers the QFT and T-SPOT as pretty equivalent), or if QFT would really be more accurate with a higher cutoff value for positive (again, hard to assess directly since there is no great gold standard. and, would one then miss a lot of true positives??). Also would have been interesting to know what % of workers at Stanford with positive PPD had negative QFT, but this was not reported in this article.  Bottom line: probably best to stick with PPDs as the test-of-choice (though a bit of a snafu now with the short supply, the second time this year, though the CDC does think PPD will be available in October)