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Different screening strategies (single or dual) for the diagnosis of suspected latent tuberculosis: a cost effectiveness analysis

Anil Pooran, Helen Booth, Robert F Miller, Geoff Scott, Motasim Badri, Jim F Huggett, Graham Rook, Alimuddin Zumla and Keertan Dheda*

BMC Pulmonary Medicine 2010, 10:7  doi:10.1186/1471-2466-10-7

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Comments on the paper “Different screening strategies (single or dual) for the diagnosis of suspected latent tuberculosis: a cost-effectiveness analysis”

Albert Nienhaus   (2010-05-19 12:57)  University Clinics Hamburg Eppendorf, Institute for Health Service Research in Dermatology and Nursing email

This is the second analysis of the costs of a screening programme based on UK data [1]. The first paper was published by Hardy et al. 2010 and compared NICE recommendations for TB screening in immigrants from high-incidence countries with a strategy that performed IGRA in emigrants from countries with a TB incidence of >200/100,000 and carried out chest x-rays (CXR) on those positive in IGRA (Quantiferon-Gold-in-Tube) [2]. The second strategy was less expensive than the NICE strategy.

Cost-effectiveness analyses are crucial because recommendations on the use of IGRA in TB screenings are currently being revised in several countries (e.g. US, UK, Germany, Switzerland). Revision or drafting of guidance will to a large extent be based on economical considerations, which makes cost-effectiveness analyses very important.

Pooran and colleagues present a cost-effectiveness analysis of tuberculosis (TB) screening from a UK healthcare perspective [1]. A hypothetical cohort of 1,000 close contacts was followed for two years. The prevalence of latent tuberculosis infection (LTBI) is assumed to be 30% and the probability of post-exposure TB is assumed to be 0.025 in two years. This paper is unique because it is the first to compare the costs of the two different commercially available interferon-γ release assays (IGRA). The cost-effectiveness of five strategies is compared: TST alone, Quantiferon-Gold-in-Tube (QFT-GIT) alone, T-SPOT.TB alone, QFT-GIT in TST+ves or T-SPOT.TB in TST+ves.

The strategies using an IGRA are more cost-effective than the strategy using a TST alone, and the strategies using IGRA in TST+ves possess higher cost-effectiveness than the IGRA-alone strategies. Therefore, the NICE recommendation (IGRA in TST+ves) appears to be reinforced by this paper [3].

However, the results of cost-effectiveness analyses depend on the assumptions made regarding sensitivity and specificity of the applied tests and on the assumptions about progression from LTBI to active TB. These assumptions therefore should be based on the most actual evidence. Because the evidence concerning IGRAs is growing very fast, we think it is important to note that Pooran et al. [1] did not use the best available evidence in their analyses. Most crucial for cost-effectiveness analyses are assumptions about the specificity of a test. Here the authors assumed specificity for the T-SPOT.TB of 100%, for the QFT-GIT of 95% and for the TST of 80%. Due to these assumptions, costs incurred on false positives were GBP 55,090 for TST and GBP 16,313 for QFT-GIT while for T-SPOT.TB these costs were zero. In a systematic review of the specificity of the two IGRAs, the specificity of the QFT-GIT was found to be higher than the specificity of the T-SPOT.TB (99% versus 86%) [4]. An earlier systematic review including pre-commercial IGRAs also found the specificity of the QFT-GIT to be higher than the specificity of the T-SPOT.TB (99% or 96% depending on BCG vaccination versus 93%) [5]. Therefore, assuming a lower specificity of QFT-GIT than of T-SPOT.TB clearly goes against the published evidence. The surprising result that, despite the higher units costs, the strategies involving T-SPOT.TB were less expensive than the QFT-GIT-based strategies is explained by these faulty assumptions. Assuming at least equal specificity of QFT-GIT and T-SPOT.TB, the QFT-GIT-based screenings become less expensive than the T-SPOT.TB-based strategies regardless of considerations of differences in sensitivity of the two IGRAs.

More important than the question of which IGRA to use is the question of whether the IGRA alone or the IGRA in TST+ves screenings are the most cost-effective. In the paper by Pooran et al. [1] the two-step strategies were the most cost-effective even though costs for TST non-returns were considered. In the literature, six other cost-effectiveness analyses comparing IGRA as a confirmatory test in TST+ves with strategies using IGRA alone are available [6-11]. Three support an IGRA in TST+ves strategy [6-8], one found the strategy using IGRA alone advantageous by a very small margin [9], and two found the IGRA-only approach clearly more cost-effective [10, 11]. How do these two works differ from the one by Pooran et al. and from the other three papers mentioned above?

The most striking difference for the Japanese paper is the high rate of repeated BCG vaccination in the cohort inflating the number of TST+/IGRA- contacts [10]. The impact of BCG vaccination in the UK was not considered by Pooran et al. [1]. In the German study supporting IGRA alone, the most noticeable difference is the assumption of the progression rate [11]. While all other studies besides the work of Pooran et al. [1, 6-10] assume progression to active TB to be independent of the applied test, Diel et al. [11] used different progression rates for TST+ves and IGRA+ close contacts. These progression rates were based on observations made in German close contacts. Out of 42 close contacts positive in QFT-GIT and not treated, six developed active TB within two years after contact (14.6%). Of the 200 close contacts positive in TST and not treated, five developed active TB (2.2%). Taking these different progression rates into account explains the higher cost-effectiveness of the IGRA-alone screening in the latest German cost-effectiveness analysis. This still leaves us with the question of whether the high progression rate observed in Germany pertains also for close contacts in the UK. At the annual meeting of the British Thoracic Society in 2009 the results of a contact tracing in Leicester were shown. The study is comprised of 2,204 contacts. In those contacts positive in QFT-GIT and not treated, 17.2% developed active TB within two years after the positive QFT-GIT [12]. This is a progression rate even higher than that assumed in the German study (14.6%).

In the sensitivity analysis of their study Pooran et al. varied the incidence of post-exposure TB (progression rate) within two years between 1% and 5%. This variation did not influence the ranking of the five different strategies. However, it would be instructive if the variation of the progression rate were to be performed on a wider range (up to10% or even 15%) and if different progression rates were used for TST and IGRA. The higher the progression rate, the bigger the increase in costs for untreated contacts. As this rate is higher in TST-based screenings, IGRA-only strategies will become the most cost-effective.

Literature

1 Pooran A, Booth H, Miller RF, Scott G, Badri M, Huggett JF, Rook G, Zumla A, Dehda K: Different screening strategies (single or dual) for the diagnosis of suspected latent tuberculosis: a cost-effectiveness analysis. BMC Pulmonary Medicine 2010,10:7 doi:10.1186/1471-2466-10-7
2 Hardy AB, Varma R, Collyns T, Moffitt SJ, Mullarkey C, Watson JP: Cost-effectiveness of the NICE guidelines for screening for latent tuberculosis infection: The QuantiFERON-TB Gold IGRA alone is more cost-effective for immigrants from high burden countries. Thorax 2010, 65:178-80
3 National Institute for Health and Clinical Excellence, Eds: Clinical Guidelines 33. Tuberculosis: clinical diagnosis and management of tuberculosis, and measures for its prevention and control, London, March 2006 [http://guidance.nice.org.uk/CG33/costreport]
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12 Diel R, LoddenkemperR, Meywald-Walter K, Niemann S, Nienhaus A: Predictive Value of a Whole Blood IFN-g Assay for the Development of Active Tuberculosis Disease after Recent Infection with Mycobacterium tuberculosis AJRCCM 2008, 177(10): 116470
13 Haldar P, Thuraisingham H, Hoskyns W, Woltmann G: S13 Contact Screening with single-step TIGRA testing and risk of active TB infection: The Leicester cohort analysis. Abstract of the oral presentation on the annual meeting of the BTS. Thorax, 2009, 64:A10-A13

Competing interests

None declared

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