00:00 – Professor Malone-Lee: We hang on the fact that part of the immune response is to shed epithelial
00:07 – cells and that is the way that eventually, the aim is to get rid of those bugs.
00:27 – Melissa: Today I’m speaking with Professor Malone-Lee, a researcher and clinician with a long history of
00:32 – working with recurrent and chronic UTI patients. Thank you so much for taking the time to chat to us today.
00:36 – Professor Malone-Lee: Thanks for inviting me.
00:39 – Melissa: Of course. We got a huge amount of questions from our audience so I do want to jump in, but I think it makes the most sense if you first tell us a little
00:48 – bit about your background and how you came to be working in chronic UTI.
00:54 – Professor Malone-Lee: Okay. After I qualified in the 1970s I went into the army where I worked very very happily as a medical officer.
01:04 – And then at a later stage I decided that I wanted to learn neurology.
01:09 – And because the British army at the time didn’t have a neurologist
01:13 – I managed to persuade them to let me be the neurosurgical registrar for the then
01:20 – neurosurgeon who was at Guy’s Hospital, Peter Schur, who died last year. And for two years he
01:26 – and I worked together very happily and he taught me a vast amount of neurology.
01:33 – And during that time, one of the things that people don’t appreciate is about sixty percent of
01:38 – battle injuries involve a head injury, so that we were dealing with head
01:43 – injuries coming in from various conflicts. I began to notice young squads who were having
01:50 – troubles with bladder control or incontinence and there didn’t seem to be much on offer to them.
01:55 – Anyway, eventually I’d done my time with the army and the authorities felt that it would
02:02 – be unwise for me to stay on and that I would be better off in a university environment.
02:07 – So they helped me in fact and I went to University College London. But by then I wanted
02:13 – to study the bladder and the only way really of a physician, an internist,
02:20 – to study the bladder was to become a geriatrician. So I became an academic geriatrician
02:27 – and in fact 20 years I then worked on urodynamics. And then in about the the mid 90s, early 1990s,
02:39 – I began to, I was working on a means of being able to produce mathematical ways of
02:49 – interpreting the urodynamic data so that we could scrutinize it in relation to the experience of the
02:55 – patient and the pathophysiology. And it took a long time, and these these equations were certainly
03:03 – working but when I applied them to the clinical situation they just didn’t fit, didn’t fit at all.
03:09 – And after a long time I managed to work out that it was urodynamics that was lying and not the patient.
03:16 – And particularly in relation to the overactive bladder, I just
03:22 – said look I think urodynamics has got it all wrong. Which went down like a lead balloon.
03:28 – We conducted a major, major randomized controlled trial in order to to check this and in fact it
03:34 – came out that urodynamics was irrelevant. So at that stage I needed to look for a different
03:41 – means of trying to explain these symptoms of frequency and urgency – the overactive bladder.
03:48 – And I was visiting Palo Alto in order to work with Roche Bioscience on some
03:54 – science and in the evening at dinner somebody made some chance remark that made me think. And on the
04:02 – red-eye flight back I kept on thinking about this. When I got back to London I decided to start looking
04:08 – to see if the culture results were telling us the truth. And in those days I was just using
04:15 – dipstick. And to my horror, just using dipstick I found that the the culture results appeared to be
04:22 – lying and saying that there was nothing wrong with the patient when there evidently was on dipstick.
04:29 – So I started to work on that. Then University College London, it’s got three campuses, and my boss
04:37 – decided that he was going to make me Professor of Medicine on their third campus, Whittington.
04:44 – I moved there as the Professor of Medicine, which is the professor of internal medicine.
04:50 – And in fact I had to sign a letter saying I give up geriatrics.
04:55 – So by then I got to Whittington and continued to beaver away with this. And then I thought, hang on
05:00 – I’m getting even more suspicious now. I think that we need to start looking at the urine under
05:05 – the microscope. So I got hold of some cast off microscopes from the path lab. I mean it was
05:12 – like, it’s like Louis Pasteur. It was going back to when I was a tiny kid, you know the sort
05:17 – of play microscopes with light, from a very odd source. I mean the light source had
05:24 – some kind of electrical box that was incredibly alarming and I thought bloody hell this going to
05:30 – catch fire at some point. It was very difficult. There’s a lot of chromatic aberration and so on, but
05:35 – it was enough to get to really shock me. I began to realize that the dipsticks were
05:41 – lying just as much so I managed to invest in some microscopes and then for a long time
05:47 – I beavered away quietly with my research nurse who happened to be my wife as well. And she and I were
05:53 – doing this and we were gradually building up more and more evidence to suggest that the overactive
05:58 – bladder in many of these cases was being caused by urine infection. And we found that when
06:05 – we treated the infection that was there that god it got easy to treat the overactive bladder. I
06:12 – mean these overactive bladder drugs were just a walk in the park once you cleared the infection.
06:18 – And this was really a sort of one man, well one man and his wife, show for a long time. And
06:26 – the other thing is when we were presenting the results at the conferences and so on, I was already
06:31 – in bad odor because I said that urodynamics was crap. And so I was even more bad by coming up with
06:37 – all these stupid ideas about cultures missing it and things. So really I was absolutely living
06:45 – the life. Really we were not making much of an impact. But in 2007
06:50 – I got more serious and brought Raj Khasriya in as a PhD student and from that moment on I
06:57 – started bringing in more and more doctors to do PhDs with me. And we started building up the
07:02 – data set more and more. Then in around about 2018 we started to attract more
07:12 – patients who had long histories of chronic bladder pain, or you know the favorite diagnosis,
07:20 – interstitial cystitis. And applying the principles of fresh urine microscopy which
07:27 – you know was developed in 1928, was nothing new, we were discovering that these people
07:33 – were very very similar to overactive bladder in the sense that there was an infection there. And
07:42 – the only signal was a pus cell signal in the urine but there’s a really the most probable
07:47 – explanation for that is infection. So we treated them with antibiotics and they all got better,
07:53 – and then we stopped the antibiotics and they all got worse again, so we started them again.
07:58 – And you end up with this cycle of what we call evolutionary epistemology built up.
08:06 – And it was becoming increasingly clear to us that these patients were not going to function unless
08:10 – we were using really very protracted antibiotics. And I then became an incredibly worried person.
08:18 – Very very terrible times of deep worry because I was having to use extended courses of antibiotics.
08:24 – It was quite clear that the the cultures were half the time not telling us what’s going on
08:31 – and I was desperately worried about causing side effects and so on and so forth.
08:37 – And then around about 2013 new data started to come available
08:44 – using 16s ribosomal rna studies of patients and normal controls. And
08:51 – it deeply shocked us to see that in fact the cultures were… If we, in the
09:01 – nine percent of patients, if we got a positive culture we were treating on the sensitivity,
09:06 – and we believed that that was the right thing. But her data showed that this is not
09:11 – right and that these bugs that they’re isolating, it may well not be the cause.
09:19 – And one of the facts of it is, if you go by cultures, it’s a Darwinian
09:25 – principle this, that what happens is the spectrum of the antibiotics that you use
09:31 – keep increasing they get gradually more powerful. So I remember this, in Christmas over the
09:39 – Christmas holiday 2013, I decided right, we’re going to abandon cultures absolutely. I came back and
09:45 – said well we’re just not going to treat on cultures anymore, we’re just going to go on the symptoms – the
09:50 – white blood cells. And we’re going to try and stick to first generation urinary antibiotics.
09:57 – And we never looked back. It was just amazing, and the resistance rate dropped.
10:06 – Since then we’ve been working on on trying to make sure that we stick to really
10:12 – really simple first generation bug antibiotics, you know the ones that were invented when I was
10:17 – at school. So you know they’re really elderly, very elderly, and if something’s old and been
10:23 – around a long time then we know it to be safe. And also that the first antibiotics that come out in
10:29 – any group are usually quite narrow spectrum. And nowadays we’re functioning with
10:35 – urinary antibiotics, I mean they’re no use to anything else than treating the urine and
10:41 – they’re narrow spectrum. And I think it’s crystallizing and we’ve gone through,
10:47 – I don’t know whether you know it but Judea Pearl who is an outstanding academic who’s
10:55 – in California, he cracked the problem of causation which is a really difficult one. And not
11:01 – only that, he produced an equation, a mathematical equation that proves the point. And so that
11:09 – gave us something to explore causation when you’re dealing with these diseases. And we follow
11:21 – Judea Pearl’s principles in testing whether infection is the causative element in this condition.
11:29 – And he’s got three rungs, one two three. We’re on the third rung at the moment. We’ve done the
11:34 – first two experiments of the third rung and we’re going to move on to do a major randomized controlled trial that will clinch it.
11:39 – Melissa: I think it would be helpful if we take a step back and
11:44 – maybe you can explain to us the difference between a recurrent UTI and a chronic UTI so
11:48 – that people have more context for the work you do.
11:57 – Professor Malone-Lee: Right, well the the difficulty there is that acute UTI, chronic UTI and recurrent UTI are all categories, okay.
12:08 – Now if you, Richard Dawkins wrote an utterly brilliant essay called the
12:15 – tyranny of the discontinuous mind,
12:21 – which was derived from a chapter in his book. I think it was the Salamander’s Tale in
12:31 – the Ancestor’s Tale. And it makes the point that categories, biology does not exist in categories.
12:40 – It just doesn’t. And if you try and categorize biology you’re going to
12:46 – get into terrible difficulties. So let me give an example: using categories like that, this
12:52 – is like saying the rainbow is either blue, it’s either violet or red and anyone who
12:59 – argues about it can shove off. So the thing to do is
13:07 – recognize categories as, they’re there, they’re crude tools, they’re imagined by the
13:15 – human being, they don’t exist, but they’re there to give us a vague understanding of what’s going on.
13:20 – But in fact what you have is a continuum from no infection whatsoever
13:28 – through to a chronic life-threatening infection that can’t be winkled out of the individual. And
13:38 – we’re in our infancy in trying to work out what’s going on, all right. My view on
13:44 – urine infection is we’ve got to start all over again, that our understanding of it is
13:50 – incredibly naive and we’ve got to cast off all the old assumptions and just start
14:00 – thinking about it much more carefully. And I think the illustration of this is that that there’s a
14:08 – most important piece of research that’s about to start off in our unit,
14:14 – which is in fact to study the stories that patients produce
14:25 – in order to try and find better ways of measuring the disease.
14:31 – Because in all the work that we’ve done, I’ll come back to your question, don’t worry I haven’t
14:35 – forgotten it… In all the work that we’ve done we’ve discovered that the tests are
14:41 – a really whopping great letdown. Of the tests of the bladder, all of them,
14:48 – I would give them a D minus, frankly. They are terrible. But one of the things, absolute star
14:55 – turner – the patient’s history and story. And in fact one of the things that helped
15:01 – us make a lot of these discoveries was a symptom score that took us 20 years to develop.
15:07 – But as I’ve been working more and more with the patients I’ve noticed that
15:13 – they have some pretty quirky symptoms. So someone will come to you and say well when I have white
15:19 – wine it’s shit, the whole thing blows up and I’m in terrible pain. Whereas other people say
15:24 – oh no I can drink it by the bucket load, nothing happens, but if I have a peanut then all hell
15:30 – breaks loose. Now the point being is, individual patients have their own experience of the disease
15:38 – and we have to learn to measure that or we’re not going to identify the fact that there’s
15:44 – active disease. Now the scale that we developed was based partly on, well no, it’s based wholly on
15:52 – patients telling me their story spontaneously and me constructing a scale about it, but I was using
15:59 – symptoms that were very very common to all people and worked on it with the context. Now we’ve got
16:06 – to find ways of measuring using the individual experience and there are ways of doing it. Now why have
16:13 – I gone into that? Well the reason is, the spectrum exists. So someone gets an acute urine infection
16:21 – and you get all the classic experiences of one time to another simple acute urine cystitis and
16:28 – you look at the urine and the dipsticks are positive and you might get a positive culture
16:33 – and you look down the microscope and they’re all the white cells. And then those peter out
16:39 – first. So the first thing that clears is the test, then the patient’s symptoms as you measure
16:46 – them stop, and if I go and then say to the patient right that’s it, you’re better, they’re going to go but, but, but
16:55 – if I have a peanut… Okay, so that there’s this other area where the symptoms that are peculiar
17:02 – to the patient are continuing and in my view the person has not got better until those have cleared.
17:12 – So the first thing to say is that the acute cystitis is not the sort of, you
17:20 – have it and then you don’t, it’s a quite complicated thing with a very slow process of clearance. Now,
17:29 – a very significant proportion of patients will get better spontaneously because their immune system
17:35 – clears it. And that’s where you get people saying well I drink lots and
17:40 – I do this and I do that and so on. Now the drinking lots, do this and do that,
17:45 – it’s not having any effect whatsoever. It’s simply the immune system that’s clearing it.
17:51 – Then you’ve got a group of patients who really do need an antibiotic to help,
17:56 – And we can put on an antibiotic and we know because it’s constantly
18:05 – published in all the randomized controlled trials on antibiotics for urine infection that
18:12 – there’s a failure rate of between
18:16 – 23% and 37%, so I say 25% to 35%, just don’t respond. But the difficulty
18:26 – is, their tests are negative. So you’ve got the ones that just get better.
18:32 – 65% to 75% get better, so you’ve got around about 25% to whatever it is, not better. And the trouble
18:41 – is that their tests are negative, so people say you haven’t got an infection. Now they can go on
18:48 – chronically and as it goes on various people will drop off that
18:57 – set because the innate immunity somehow manages to get rid of it.
19:03 – But there are others who just don’t shake it off and they end up with a chronic
19:10 – urine infection. So you go from an acute cystitis, and there are all those different
19:18 – colors on the way, until eventually you go into that group who have a chronic urine infection.
19:24 – These bugs have had millions of years to evolve and they’re absolutely amazingly sophisticated.
19:31 – Some of the bugs that have attacked you, they’re causing symptoms because they’re invading
19:37 – the tissue of the bladder and the urethra and the inflammatory signal makes
19:45 – your tissues terribly inflamed and sore and smarting. Now, while they’re doing that
19:52 – some of the bugs can get inside a cell and find the environment really rather congenial.
19:59 – And they become dormant. And what their role is, is to become, they’ve got to
20:07 – dig a trench and become surrogate, they’ve got to be camouflaged. They must not be
20:19 – detected, they gotta not create a storm, to shut up, all right. And what happens is, then
20:24 – the whole acute inflammation and so on dies down and you’ve got these little sleepers sitting there.
20:31 – Now they can sit in those cells for a long, long time and one of the big mysteries for us
20:39 – is that, certainly our clinical data suggested, that people can have them living in those cells
20:44 – for years and years and years and we don’t understand that because we know that the
20:50 – cells of the bladder are dropping off. So the maths is that eventually they’ve got to get rid of them.
20:56 – And our thoughts were well if the bugs are going to
21:00 – move from one cell to the other they’ve got to wake up, start dividing, burst out of the cell and
21:05 – go and find new cells. And that’s going to cause an acute cystitis. In the book I published,
21:13 – Harry Horsley got this microcosm that’s amazing, and you can see a bug coming out of the cell
21:20 – and the little shite’s dressing itself in cell membrane. It’s quite extraordinary. So it covers
21:26 – itself in cell membrane and it looks like cell and that way it sneaks off and finds a new home
21:34 – without attracting any immune attack. So these bugs can sit inside your cells as sleepers
21:42 – waiting for a day when they decide to create some havoc. And on occasions
21:53 – one of them, for various reasons, will wake up, start dividing and then it feeds
21:59 – on the contents of the cell to sustain that division to feed it, and they divide, divide,
22:06 – divide and they eventually kill the cell because they just strangle it and then they burst out
22:15 – of the cell. And you get this planktonic flare, an acute urine infection. Now that
22:23 – secret little beast hiding there not being detected, bursting out from time to time
22:31 – are the recurrent urine infections. So you can have chronic and
22:39 – recurrent and then you’ve got a spectrum and it can vary an enormous amount.
22:46 – Melissa: You mentioned that you’ll often have a flare-up of your symptoms with the planktonic bacteria that escape into the
22:51 – urine. Some people say that they just have pain throughout treatment. Is this why that is
22:57 – happening even when they’re taking antibiotics and do antibiotics exacerbate that in some way?
23:03 – Professor Malone-Lee: No. What it is, is that the thing is that in some people, do you remember on a scale? Some people
23:10 – have a low level action where the bugs in a low level way, one or two of them will wake
23:18 – up, start dividing and break out. And in a rather low level way go and find other cells. Or
23:27 – that they’re dividing in a way so that they are stimulating an immune response.
23:33 – It just keeps it going so those patients have a low level chronic immune response that
23:41 – gives them symptoms all the time. Now there’s a point about those bugs inside the cell. Antibiotics will
23:45 – only work against bugs that are dividing.
23:54 – Secondly, the bugs are protected inside the cells, and thirdly they will form themselves inside the
24:04 – cells inside a biofilm that is impenetrable to a large extent. So when it’s in that state,
24:13 – you have a urine infection that is resistant to antibiotics. You can’t treat it with an antibiotic.
24:21 – The way we work is where, we hang on the fact that part of the immune response
24:28 – is to shed epithelial cells and that is the way that eventually the aim is to get rid of those
24:37 – bugs that are sitting inside the cells. Now, we now know that if you perturb any of these cells
24:44 – in the laboratory, if you so much as tickle them with a feather, the bugs wake up, start
24:48 – dividing and mount this escape through a planktonic flare. So if we put them on treatment
24:58 – that the bugs when they come out of the cells are greeted with, this treatment sitting there
25:03 – in the urine, it kills them and it curtails the escape route for the bug. So then you hang on
25:10 – the patient shedding all the cells until eventually by a process of constant shedding and
25:16 – so on, so forth, the numbers of parasitizing bugs reduces and you gradually shake off the disease.
25:22 – Melissa: How long does that usually take for someone? How long will they need to be on antibiotics?
25:27 – Professor Malone-Lee: In our unit the average seems to be sort of around about a year with a huge variation.
25:35 – Melissa: Does it correlate to how long the person has had the infection previously?
25:40 – Professor Malone-Lee: It’s a very good question. Now, and in fact I’m quite pleased because we thought we knew the answer that
25:45 – the longer you had it the worse it was. So we in fact in good time measured it this year
25:50 – and do you know there’s no relationship whatsoever, none at all. So you can
25:56 – have had it for years and years and years and you’re better in a fortnight,
26:00 – or you can have had it for a few weeks and it’s the devil’s own job to get out.