It's all about Progression.

I think I finally have managed to put the pieces together to really understand what this whole thing is about. (It has only taken me 9 or so years to get to this point!). It's a bit complex so I hope I can translate the thoughts in my head into the written word in a way that makes sense.


Let's start with a little diversion.


Cellestis' corporate motto is "Changing the way the world looks at TB" I'm sure we've all seen this on their website and documentation. Perhaps we've even thought that it's a pretty good motto. But look at it very closely and you can see that there are two messages contained in that one little precise statement. Firstly we can substitute the reasonably close synonym of "diagnoses" for the phrase "looks at". That is, to diagnose something, one would "look at" it. So the motto is saying "Changing the way the world diagnoses TB" 


However, the motto says something else as well. Just take the whole message as it is written. They are saying that they are changing the way that TB people actually understand TB. The QuantiFERON TB Gold diagnostic is doing more than just providing a new way of diagnosing TB - it is actually changing the dynamics of this whole field of endeavor. It is this second meaning that I believe is of huge importance.


Naively, when I first became involved in this my thoughts were along the line of "Well, the existing test is not very good, QuantiFERON-TB  is demonstrably much better. Just replace the existing (TST) test with QuantiFERON-TB. Job done".  Both from the evidence (10 years!) and the knowledge that I (we?) have gained, it is now clear that that was truly naive and incorrect. It's not that simple. In the following I hope that I can explain both why that is so and, more importantly (even though we have been waiting for 10 years), the positives for us of the real situation.


We know that QFT-TB Gold has at least as high a sensitivity as the TST and, most importantly, a much higher specificity (ability to not report false positives). I have said much about this in the past but it has primarily always been from the perspective of patient outcomes and the costs of current TB programs. That is, the low specificity of the TST results in huge numbers of people being treated with (quite nasty) antibodies when they weren't actually infected. This treatment comes at a financial cost to the TB program (both the cost of the actual treatment and the cost of monitoring same).


In the rest of this discussion I will rely heavily upon the following findings of Diel.

Title: Predictive value of a whole blood IFN-gamma assay for the development of active tuberculosis disease after recent infection with Mycobacterium tuberculosis.

Authors: Diel R, Loddenkemper R, Meywald-Walter K, Niemann S, Nienhaus A

Journal: Am. J. Respir. Crit. Care Med.

Publication Date: Volume 177 - Issue 10 - May-2008

PubMedID: 18276940

RATIONALE: Numerous studies have been published on the new Mycobacterium tuberculosis (MTB)-specific IFN-gamma release assays. However, their prognostic value for progression from latent tuberculosis infection (LTBI) to active TB has yet to be established. OBJECTIVES: To compare the QuantiFERON-TB Gold In-Tube assay (QFT) with the tuberculin skin test (TST) in recently exposed close contacts of active TB cases with respect to their development of TB disease within 2 years. METHODS: Close contacts (n = 601) of MTB-positive source cases underwent both TST and QFT testing and were subsequently observed for 103 (+/-13.5) weeks. Risk factors for MTB infection were evaluated by multivariate analysis. MEASUREMENTS AND MAIN RESULTS: For the TST, 40.4% (243/601) of contacts were positive at a 5-mm cutoff, whereas only 66 (11%) were QFT positive. QFT positivity, but not TST, was associated with exposure time (P < 0.0001). Six contacts progressed to TB disease within the 2-year follow-up. All were QFT positive and had declined preventive treatment, equating to a progression rate of 14.6% (6/41) among those who were QFT positive. The progression rate for untreated TST-positive subjects was significantly lower (P < 0.003), at 2.3% (5 of 219), and one subject who progressed was TST negative. CONCLUSIONS: Results suggest that QFT is a more accurate indicator of the presence of LTBI than the TST and provides at least the same sensitivity for detecting those who will progress to active TB. The high rate of progression to active TB of those who are QFT positive (14.6%), which is far greater than the 2.3% found for those who are TST positive, has health and economic implications for enhanced TB control, particularly if this higher progression rate is seen in studies of other at-risk populations.

It's all about Progression.


The implementation of medicine is impacted by the cost of achieving outcomes as much as it is about pure patient outcomes. This may, at first thought, seem a slightly sad situation but it really doesn't take much thought to see why it is so and always will be so. 


In the specific field of TB control there is much consideration of the cost of achieving outcomes. The current TB control programs implemented around the world (as different as each may be) have been developed to utilize financial resources in the most efficient way (at least we would hope that is the case). 


Let's take the (slightly unscientific) step of assuming that the results of the Diel paper above apply universally. We know that that is probably not the case and different studies with different population groups may find different results. However, whilst the metric of the differences between TST and QFT may vary, the principles below will hold true.


The results of the Diel paper are:


- QFT did not miss a single case of latent TB (as defined by progression to Active TB within 2 years) whereas TST missed one. (that's sensitivity). This is good (for QFT) but more importantly (in the context of this post);


- 1 in 6 (14.6%) of the QFT positives went on to develop Active TB within 2 years, whereas only 2.3% of TST positives did so. Thats specificity as elicited by Progression.


Note that those results were over a two year period. Common wisdom (and you know that I dislike "common wisdom") says that the chances of progressing from latent TB to active TB are greatest in the first 2 years after exposure. True? Untrue? I'm not sure and I will do a separate post on that issue at another time, rather than distracting from the aim of this post.


Let's try to be very targeted with our thinking here. To do that forget about the sensitivity issue - let's forge ahead even assuming that TST is as sensitive as QFT (it's clearly not but it involving it in this discussion would make the argument more difficult to clearly fix in our heads - well, mine, anyway). So, we are talking purely about specificity or, more specifically (!), Progression.


Remember that we said that TB Control Programs are impacted by costs - actually "cost/reward". Complex costing models involving the cost of diagnosis, the cost of treatment and the cost of having potential TB patients wandering around the community will impact exactly how a TB Control Program is implemented. We are getting close to the nuts and bolts of this now. Implementing QuantiFERON TB Gold diagnosis totally changes those costing models and therefore the content, implementation and value of TB Control Programs. (That is my take home message).


Using the Diel results, we know that of the 601 contacts, 66 (11%) were diagnosed as having latent TB by QFT, whereas 243 (40%) were diagnosed as having latent TB by TST. Of the 66 diagnosed by QFT, 6 subsequently progressed to Active TB, whereas of the 243 TST positives only 5 (2.3%) progressed to Active TB. It is patently obvious that when you factor those figures into the costing model of a TB Control Program, the program will change completely. Suddenly, in at least some circumstances, the costs of not testing (and leaving potential TB vectors in the community) becomes a higher relative cost than testing. Or, in really simple terms, whereas it may be that under a low progression regime (TST) it may not be financially efficient to test certain populations in certain situations, if your diagnostic (QFT) has a much higher progression rate then it becomes financially effective to diagnose that population. 


Suddenly, armed with this new tool, those who manage TB Control Programs have the opportunity (even necessity?) to reshape their programs to achieve better outcomes at a lower cost (as Dr. Masae Kawamura seems to have implemented in San Francisco).


It's a huge thing. Whilst CST are making ever growing sales into the current scenario, in time (and the CDC Guidelines will provide impetus to this), I believe that we will see these changes to TB Control Programs happen. Ultimately, it may even mean that more more people will be tested and/or existing testing regimes will be performed more frequently. 


Cellestis - Changing the way the world looks at TB.