Aspirin for Tuberculous Meningitis

How one of the most successful and cheapest drugs ever made - aspirin - can make a dent in the morbidity and mortality of one of the manifestations of one of the world’s most common infections, TB, as Chris Smith hears from Oxford University's Guy Thwaites...

Guy - TB tuberculous meningitis is when TB, which is a common and well-known infection throughout the world affects the brain. It's a very serious infection. It kills or disables around half of people who get it. And what we wanted to work out was whether if we added aspirin to the standard treatment of this infection it stopped bad things happening as a consequence.

Chris - First of all tell us what is the treatment for tuberculosis meningitis and what is the rationale for adding aspirin? Why might that change the outcome for people?

Guy - Well there's two ways of treating tuberculous meningitis. The first way is to kill the bacteria that cause the infection, and to do that we give four or five different antibiotics or anti-TB drugs. These drugs are very effective but, when we start killing the bacteria in the brain, it causes the brain to get inflamed and that can cause really bad things to happen that can can harm patients. So the other thing that we have to do is to control that inflammation; and studies that we've done in the past have shown that if we give an anti-inflammatory agent, or steroids as they're called, in addition to the anti-TB drugs, we get more survival from this infection and better outcomes. So what we hypothesised was that we could further improve the outcome of these patients with this very severe infection by giving a very old drug called aspirin as an anti inflammatory agent. Aspirin has two  effects. The first is anti-inflammatory - and that might help because if you kill the bacteria you get inflammation - and the second way is to prevent strokes, because of clots in the brain and those are the two reasons why we thought that aspirin might help people with TB meningitis.

Chris - So how did you do this. Is this a clinical trial that you did on patients who were diagnosed with tuberculous meningitis?

Guy - Yes this was a randomised controlled trial. So what we did is that we got adults, with TB meningitis, who were admitted to our hospital in Vietnam. We gave them the standard treatment, and we randomly allocated them to either receiving aspirin or receiving placebo; and the other thing that we did is that we wanted to see whether low dose aspirin was as effective as high dose aspirin,

Chris - And is the reason for looking at different doses of aspirin that, obviously, all drugs come with side effects and aspirin is no exception to that rule?

Guy - That's right. So one of the common side effects of aspirin, which many people will know because it's a very commonly taken drug, is that it can cause stomach upsets and more seriously it can cause bleeding from the stomach. And so we were a little nervous that if we added very high doses of aspirin particularly we'd get more bleeding from the stomach. So this was one of the primary outcomes from the trial. We really wanted to make sure that it was safe for patients to receive this drug in addition to the other drugs that they were receiving.

Chris - So what were the outcome measures of this study? You've taken the patients you've randomised them to aspirin at high dose aspirin at low dose or placebo. What are you looking for over the follow up period?

Guy - So this is what we would describe as a Phase 2 study. So this is a study that explores whether it's safe to give a particular drug or treatment and whether it's likely to be effective. But it gives doctors an idea and it gives researchers an idea whether or not this is going to be a safe and effective treatment. So we had two measures that we were interested in. The first one was whether or not it caused increased bleeding from the stomach. And the second one was whether it reduced the number of brain infarcts - or dead areas of the brain - as a consequence of the infection, and survival from the infection itself in the first 60 days of treatment.

Chris - What was the result. That's the key thing. What did you find?

Guy - Well the result was that it's appeared to be safe. There was a very small - probably just occurring by chance - increase in the number of small minor stomach bleeds; but what it did do, it seemed, particularly in those people who definitely had TB meningitis - in that we were able to grow the bug from the brain fluid - in that group it seemed to reduce the number of brain infarcts, and it seemed to increase survival.

Chris - Do you still think on the basis of the measurements you've now made that the aspirin is working the way that you thought it might?

Guy - Well one of the things that we did is that we measured the substances in the brain fluid that might go up or down when you give aspirin. And what we found was very very interesting, because we found that the substances that might reduce the body's ability to clot blood, that substance was very very low and those people who had high dose aspirin, suggesting that that was one of the mechanisms by which aspirin was having its effect. The other really interesting thing - and this is a completely new mechanism really for how aspirin might help people with TB and TB meningitis - is that it increases the amount of substances that help inflammation resolve. People have known for a long time that aspirin has an effect on inflammation and it reduces inflammation, but it's only been very recently that they've discovered these new molecules that help the body resolve inflammation, and we think that it's probably this way that aspirin had its really quite dramatic effects particularly at a high dose and this is really fascinating, because no one's ever shown this before in any form of TB but certainly not in TB meningitis.