How do you use a tool you don’t know you can trust? Issues with diagnosing latent TB

I attended an excellent talk a while back by Dr. Jason Stout, the TB medical director for the state of NC. The talk was entitled TB Diagnostics: New Tools, New Dilemmas, and dealt primarily with the challenges we see in attempting to diagnose and treat latent mycobacterial infections. While active TB infections are still a primary health concern for much of the world (roughly 90% of active TB cases occur in the developing world), the biggest challenge facing the developed world in TB control is going to be the risk posed by latent infections.

The latent infection itself is not directly a health concern- it is the risk of conversion, which occurs in an estimated 5% of patients, from a latent to an active infection that worries most health professionals in the developed world. With an estimated prevalence of about 10-15 million individuals in the US alone, this represents over 500,000 potential future active cases even without direct contact or transmission. These numbers are pretty rough estimates though, when it comes to diagnosing latent TB we’re pretty much flying blind. Almost everyone is familiar with the Tuberculin Skin Test (TST), the standard for diagnosing latent TB. By injecting a cocktail of proteins from sterilized cultures just under the skin, we expect to see a patient that has been exposed to TB to mount an immune response and cause swelling at the site of the injection. Given the complexity of the human immune system and how little we really know about it, it isn’t surprising that the test isn’t very reliable. Everything from the BCG vaccine to exposure to non-TB mycobacteria can throw off the results of the test.

Unfortunately, most modern latent tests haven’t improved significantly over the TST like how PCR is revolutionizing active TB diagnosis in the US and other developed countries. Some technologies based on using ELISA to monitor production of the cytokine interferon gamma (IFN-γ) by immune cells in human blood have been brought to market and approved for use. The problem is an extremely complex one, however, and breakthroughs are likely to hinge on a better quantitative understanding of the immune system itself. According to Dr. Stout, while these tests do seem to fare better in patients that have had a BCG vaccination, the root problem still exists.

We don’t know how many people have latent TB. We don’t know how good our tests are because we have no way of knowing how many patients our tests miss. Our tests rely on a somewhat arbitrary cut-off that patients often fluctuate around. In the end, developing a sane policy for dealing with the danger that latent TB poses is going to depend heavily on developing innovative and effective new diagnostics for the infection.