Testing the test: Tuberculosis Diagnostics

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Naman pointed me to a really interesting study out of Hopkins on evaluating the cost-effectiveness of potential new TB diagnostics tests. Since I’m currently developing one of said potential new TB diagnostic tests, this was of particular interest.

Global Health is really an engineering field: its all about optimization. With a limited set of resources and finite demand and a limited set of tools available to us, what is the most efficient way to spend our resources to maximize impact? Granted this depends on your definition of impact, but thankfully the DALY is a pretty well accepted metric when it comes to infectious diseases.

In the case of TB, we have a fairly narrow assortment of tests: sputum smear microscopy, mycobacterial culture and PCR. Some folks (I’m looking at you, FIND!) are working on antibody based rapid tests, but these aren’t due out for 2-3 years, optimistically speaking. When you add latent TB to the mix, a couple other techniques come into play including products based on ELISA and ELISPOT, but we’ll leave out latent TB for now.

The three cornerstones of TB diagnostics (yes, yes, I’m leaving out chest X-rays, but that’s screening not diagnostics. Any… stuff… in your lungs will show up right away, but without any of these other techniques, you’d never know if it were TB or nearly any other pulmonary disease) each have their own challenges:

Microscopy is, well, microscopy. Its manual, time-consuming and error-prone. There’s some push to phase out bright field microscopy for fluorescence, but the improvement is relatively incremental. You’re still fundamentally limited by the human operator and how much time he or she is willing to put into scanning a smear at 1,000x (bright field) or 450x (fluorescence) magnification. The up-side? Its the cheapest method we have at around $1.45 a test and even though its pretty hard to become a master microscopist, it doesn’t take much to become proficient.

PCR is God’s Gift to the Geneticists. Its also an amazingly powerful diagnostic tool. The problem? Its way too expensive- if the developing world were to perform as many PCR tests as they do sputum smears it would cost over $4 Billion at $50 a pop… 4x current global TB control expenditures. Infrastructure is also a bit of a problem since reagents are typically temperature sensitive and the assay’s need pretty clean water (heaven forbid any DNase gets in there!).

The basic premise behind culture is fairly straightforward: if you don’t have enough bugs in the sputum to see easily, give em some food and let them grow till there are enough! Unfortunately, M. TB happens to be one of the slowest growing microorganisms out there with a life cycle of about 15-20 hours so it can take up to 6 weeks for enough to grow out… yikes. The good thing is that TB doesn’t kill you very fast and while culture takes a pretty good amount of infrastructure to support, its a lot less than PCR and each test weighs in at around $3-4 per test. On the other hand, every day that a patient walks around un-diagnosed could mean dozens of future cases, not the ideal situation.

So what are Hopkins’ thoughts on this? Basically, if you were to try to introduce a high specificity (95%) test with a fairly high per-test cost ($20) that is somewhat more sensitive than microscopy (70%) its not going to be very cost-effective. In fact, they found that specificity coupled with price was the single most important factor in a new diagnostic test being able to beat the cost-effectiveness of microscopy. Find the people that are very sick very quickly, get them out of the public and on treatment before they spread more and you’re going to get the most bang for your diagnostic buck. Good advice that FIND, the WHO and the Gates Foundation need to hear more of: PCR and antibody tests may be extremely impressive, but until they can become drastically cheaper they’re still likely to be beat out by a cool blue LED and a $20 camera sensor.