Professor Guy Thwaites is the Director of Oxford University Clinical Research Unit (OUCRU), Vietnam. He is trying to improve outcomes for patients with tuberculous meningitis, the most severe form of tuberculosis. 100, 000 people a year get tuberculous meningitis and without treatment 100% of people with the disease will die.
The number of people who die of tuberculous meningitis reduces depending on how early you get treatment for the disease. There are therefore two approaches to improving clinical outcomes, the first is to diagnose the condition faster so clinical intervention can happen sooner. The second is to improve treatments so that they are more effective.
Ultimately, medical research must translate into improved treatments for patients. At the Nuffield Department of Medicine, our researchers collaborate to develop better health care, improved quality of life, and enhanced preventative measures for all patients. Our findings in the laboratory are translated into changes in clinical practice, from bench to bedside.
Q: How many people does tuberculous meningitis affect?
Guy Thwaites: It is a little difficult to be absolutely sure but there are around 9 million people a year who get TB and tuberculous meningitis is the most severe form of it – about 1% get it. It is around 90 to 100,000 people a year who get tuberculous meningitis.
Q: Why is early diagnosis of tuberculous meningitis important?
GT: Tuberculous meningitis (TB meningitis) is one of those unusual infections that if you don’t treat it then it is invariably fatal. There are not many infections like that. If you delay treatment or if you don’t give it at all then 100% of people will die. The number of people who die reduces depending on how early you get treatment for the disease. If you get TB meningitis very early, after a few days of symptoms, when the patient is reasonably OK, then only about 5% of people will die. If the patient doesn’t get treated then coma will set in and the patient will lose consciousness – about 50% people will then die. It is very important to get treatment in early otherwise the patient will do very badly.
Q: How is your research helping to improve outcomes for patients with tuberculous meningitis?
GT: We have two approaches. The first one is to make the diagnosis quickly. Diagnosis is difficult because there isn’t a single diagnostic test available that is 100% accurate. We try and do it in a couple of different ways. We try and work out what it is about the patient, the different features of the disease that make it distinguishable from other causes of meningitis. We investigate new laboratory tests that might help us make the diagnosis better than the currently available tests.
The other way of improving outcomes is to improve treatment. TB drugs have been around for about 60 years - the first one was discovered in 1948. It was at that point that TB meningitis went from being a universally fatal condition to being one that was actually treatable. The drugs have a problem: they are given by mouth or by vein but they have to be able to get into the brain, where the disease is actually causing the problems. In order to do that we need to know what sort of dose we need to give and what sort of route we need to give it by to get the drug in to the brain to kill the bugs – that’s difficult! The work that we have been doing has been to try and get the best doses and the best regimens to get the best killing of the bugs in the brain, so that the patients get better.
Q: What are the most important lines of research that have developed over the past 5 or 10 years?
GT: We have been using that same framework of improving outcomes for this disease. We have looked at new diagnostic methods and new treatment methods. I think that some of the most interesting avenues for improving diagnosis have been through the simplest techniques. Very simply identifying what it is about the clinical features of the disease that allow you to discriminate it from other causes. It doesn’t require any special equipment to ask patients the right questions and then get some very simple laboratory tests together. That has been very fruitful and a very important avenue of research.
We’ve also taken the diagnostic test that has been available since about 1880, discovered in Germany by Ziehl and Neelsen and adapted it to make it work even better than it was 120 years ago. Just by doing simple things, we have been able to make the diagnosis much quicker and easier.
I think that some of the most exciting things recently have been around treatment of the disease. We did a trial in Vietnam about 10 years ago that showed that if you control the inflammatory response in the brain by giving steroids to patients you improve survival. Unfortunately when we tried to look for the mechanism for how that drug improved the outcome we just weren’t able to find it. This was until we discovered that there was a particular gene that the patients did or didn’t have that determined response to the steroids. This was the first time that anyone’s really shown in this disease that there may be some patients who, because of their specific genetic makeup, should get one treatment and other patients who should get another treatment. We are exploring that now and it’s really exciting because we might be able to predict by a rapid genetic test what sort of treatment the patient should get. It also opens new doors for new treatments because it seems that different patients are responding in different ways to the infection. This offers new hope to patients that aren’t responding to the treatments that we have.
Q: Why does your research matter, why should we put money in to it?
GT: TB meningitis matters because if you get it wrong and you don’t get treatment then it kills you. As the figures suggest about 100,000 people a year get this disease. At the moment around half of those are dead or very severely disabled from the infection. This is a really important question: how can we improve outcomes for this infection?
It is also an infection that affects the poorest regions of the world, which are least able to cope with it. If we can make some very simple improvements, through the research that we do, in terms of diagnosing and treating this infection, then potentially we will have a really big impact on the outcomes fof patients on those regions of the world which are getting the disease most. The research that we do aims to do that, and if we can achieve better outcomes for patients that will be a good thing.
Q: How does your research fit in to translational medicine within the Department?
GT: Translational medicine is all about taking the best science to patients and improving their outcomes. I think that this is what we do continually with our research on tuberculous meningitis. We take the patients and describe them as accurately and as well as we possibly can. We apply the best and most technologically advanced science to try and improve outcomes. For example, we have a gene that we think may influence response to treatment, and we are able to take that genetically based science back to the patient and try to understand what it means to them and other patients in the future, in terms of improving their outcomes. We are continually doing almost model translational science: starting with the patient, going to the lab and then going back from the lab to the patient, in this continual cycle in an effort to try and improve outcomes for this infection.