01:28 – Diagnostic Value of Shed Cells – “Epithelial cells, which up until then were considered signs of contamination, are actually a marker of active cystitis.”

FORMATTED TRANSCRIPT

00:00 – Professor Malone-Lee: Epithelial cells, which up until then were considered to be signs
00:03 – of contamination of the urine, we managed to prove they’re
00:06 – coming from the bladder and they are a marker of cystitis going on.
00:24 – Melissa: Let’s go back a little bit to the actual diagnosis. You mentioned that you use a microscope
00:29 – and fresh spun urine. Can you just tell me what you’re looking for there and how that helps you diagnose an infection?
00:33 – Professor Malone-Lee: Right, okay. Well the key, well first of all a caveat:
00:43 – it’s the symptoms that give you the diagnosis. The maths
00:49 – of this is such that the symptoms and the signs over and over again give you the diagnosis. Now
00:56 – if you get an inflammatory reaction in the bladder wall
01:01 – and it’s exuberant enough, then you will leak white blood cells into the urine.
01:08 – Now what we discovered was that those white blood cells will,
01:12 – once they’re into the urine, that they will die quite quickly and then they will
01:19 – lyse, that’s break up, quite quickly. And so if you just send a urine up to the laboratory an awful
01:26 – lot of it will have dissipated. The signal will have dissipated by the time it gets there at these
01:31 – places where they’re sending their urine and it’s examined that the following days it’s useless.
01:38 – We found that within two hours, within two hours the white cell count has dropped to about
01:44 – sixty percent of its starting point. So we instituted this process, now we gotta look at this
01:51 – fresh, absolutely fresh. So we use immediately fresh urine and we copy what was done
02:00 – in 1928. You put a drop of urine onto a special slide that’s got special engravings on it, so
02:09 – it’s called a counting chamber. And then you look down the microscope and you count the white cells.
02:16 – And the thing about counting the white cells is it can be hugely helpful in plotting the course
02:25 – of the disease afterwards. So we will use the white cell count to plot – the graphs of the white
02:32 – cell count – to plot the course of the disease and graphs of the symptom scores to plot the course
02:38 – of the disease. And then while we were doing this work we discovered that the epithelial
02:44 – cell counts in the urine were also elevated in these patients – most of them, not all of them –
02:51 – and that those epithelial cells which up until then were considered to be signs of contamination
02:58 – of the urine, we managed to prove no no no, they’re coming from the bladder and they are a marker of
03:04 – cystitis going on. It’s part of the innate immune response and you’re shedding lots of
03:09 – epithelial cells. So we also count the epithelial cells nowadays. Now the counts are not so important
03:15 – to us. It’s the pattern in the graph that’s really important and that can be important where
03:22 – we got someone on treatment and they say well my symptoms aren’t getting any better. In
03:28 – the past I used to change the medication thinking it wasn’t working, but if we’ve got a graph of the
03:35 – white cells and it shows that it’s going in the right direction we’re then able to say hold it,
03:41 – this is improving and if we stick in here the symptoms will follow. And that’s enabled us
03:48 – to reduce the amount of antimicrobial prescribing that we do.
03:55 – Melissa: Given that the dilution of the urine could impact those cell counts how do you advise patients so that you can get a consistent sample?
04:00 – Professor Malone-Lee: You don’t have to. You see the thing is, gravity comes to your rescue. In fact
04:06 – it’s so important that in the book I have got some drawings to show this of the bladder.
04:16 – When you look into infection in the urine it’s like a snow storm. There are all
04:22 – these cells cascading down and they accumulate at the base of the bladder. So in fact you have
04:29 – these debris all sitting there at the base of the bladder and when you pee it comes right out and so
04:36 – there’s no dilutional effect at all. You just get it coming out.
04:43 – Melissa: Does that mean that you have to catch the first stream rather than the middle?
04:48 – Professor Malone-Lee: Well we’ve studied that as well and we’ve found that the midstream urine specimen is missing a huge chunk of the pathological signal.
04:55 – So nowadays we just say look here’s a bowl, pee into it, all right. And that’s what we use. And in fact
05:03 – it’s amazing, the thing is that we have all grown up with habits of peeing and most people are very
05:12 – consistent in the way that they pee. They do the same thing every time and as a result of that an
05:18 – individual’s accounts can be hugely consistent and enable us to monitor the progress of the disease.
05:26 – So we don’t, oddly enough, the dilutional effect doesn’t come through, isn’t that nice?
05:31 – Melissa: That is interesting. A lot of people can’t access this kind of diagnostic method, so in that case can they use symptoms alone?
05:38 – Professor Malone-Lee: Yeah, in fact in my view the symptoms
05:45 – are, I keep saying it, the symptoms are the best guide to all of this. Now the trouble is that
05:52 – it’s nerve-wracking. I’ve got to give that while COVID broke we were not able
05:58 – to get the microscopy that we could do, so we were managing on symptoms a great deal.
06:05 – 80 percent of the time that was great but where we ran into difficulties was with the patients who
06:11 – were getting acute flares or feeling it wasn’t going fast enough or were distressed and so on.
06:18 – I was finding that I was changing the antibiotic and after a while when we looked
06:24 – back and looked at our data on aggregate I could see clusters of shuffling antibiotics.
06:31 – And I realized that the problem was that we were not getting the urine analysis
06:36 – and that if I’d seen the plots of the urine I wouldn’t have changed the treatment.
06:43 – So what we instituted was to say okay, send your urine off to the local laboratory.
06:49 – Send us back the report, please ignore the culture result, but tell us
06:56 – what the white cell and epithelial cell count showed. And it’s a very crude, very crude option
07:03 – but we’ve been able to muddle through a bit using that. And some labs have cooperated by
07:10 – taking the urine, you know allowing people to provide the urine fresh and they run it through the machines and we get an early answer.
07:15 – Melissa: What advice do you have for patients who
07:20 – do have plenty of UTI tests but they always come back negative and they don’t have access to a protocol or an approach like yours?
07:25 – Professor Malone-Lee: I understand that. I mean, this is the problem about
07:32 – progress, is that we’re a specialized scientific unit and at the moment, as far as I can make
07:40 – out, we seem to be the only clinical scientific unit really working on this big time in the world.
07:45 – That’s why I wrote the book in fact, was to try and encourage my profession to recognize
07:52 – that the tests are non-starter and you’ve got to go by the symptoms and I’m hoping that that
07:59 – will change. The advice that I can give people at the moment is to take Hiprex – methenamine. Now
08:08 – the point being is you can get Hiprex over the counter, you don’t need a prescription
08:12 – and it’ll work. It’s incredibly slow in its working but it does the right thing.
08:20 – And the reason for this is that it turns your urine into a disinfectant
08:27 – and if you’ve got a chronic infection and you’re shedding the epithelial cells that’s great.
08:33 – That’s the immune system doing what you want it to do. Now if you turn your urine into a
08:40 – disinfectant it means that when you’ve shed these cells and the microbes wake up and try and mount
08:46 – an escape they will be confronted with a urine that’s disinfectant and that will curtail a lot of
08:53 – their escape attempts. Now it’s not, it’s imperfect, it hasn’t got the power of the penetration of the
08:58 – antibiotics, but if you stick at it that can make an enormous difference.
09:06 – Melissa: Hiprex is actually prescription only in some places in the world. I know it’s available in others
09:11 – over the counter, but not everywhere, so there are issues accessing that. Maybe we can
09:16 – talk a little bit more about your actual treatment approach? You touched on the fact that you tend to
09:21 – use first generation, narrow spectrum antibiotics. I wanted to just confirm that that is at a full dose not a prophylactic dose.
09:26 – Professor Malone-Lee: Yes. The other thing is that the prophylactic dose, and
09:32 – years ago I started with the prophylactic doses and the results were atrocious –
09:40 – absolute atrocious – and there’s no two ways about it, it’s not going to work.
09:45 – And then when we started doing the real heavy duty science we realized that there was an enormous
09:51 – problem with penetration of the antibodies. So we’re going to use the full dose and in fact,
09:58 – that we will try and use the the maximum permitted dose within the tolerance of the patient. And
10:08 – I’ll tell you something, that when we start on the full dose we’ll sometimes see patients who
10:14 – will describe trough effects. So I have patients coming in saying, oh well, you know everything’s
10:21 – all right until I’m coming up to my next dose and then I feel awkward. Then I take the dose and then
10:27 – my symptoms clear again. Initially I thought that this is just wacky, I don’t believe this
10:32 – and so on, but eventually when we realized, my god these people are talking
10:36 – correct. So we dealt with that partly by splitting the doses up so they go four times
10:44 – a day over the day. But when we see trough effects in people nowadays we’ll increase the dose
10:50 – because it’s a signal we’re just not giving enough and it’s wearing off. So you’ve got to get a real grip on it. So yes, it is the full dose.
10:55 – Melissa: In what percentage of patients would you combine the antibiotic with Hiprex which I know is often the approach?
11:01 – Professor Malone-Lee: 100% nowadays, if we can. So
11:08 – what we’ll do now, the trouble with Hiprex is, if you’ve got a rampant inflammation going in your
11:13 – urinary tract and you take Hiprex then it burns you, because it’s an acidic drug. So we always start
11:21 – the antibiotic first and then we get the people to accommodate to that and then after two weeks we
11:29 – ask them to make their first attempt with the Hiprex. Now some of them can take to it like a
11:34 – duck to water, it doesn’t bother them. But quite a lot of people say, oh crap, god that causes burning. So we
11:40 – say fine, don’t do anything more with Hiprex for four weeks and then try it again and stay with one
11:47 – tablet and build on it. And then you keep on. Trial and error elimination is the thing. And in the
11:54 – past I made mistakes by just sort of writing, can’t tolerate Hiprex and now I learned the
12:00 – hard way that in fact that’s not the case. You can eventually allow them to get onto it because
12:06 – it’s an important drug. And the other thing about the Hiprex is, it enables
12:12 – us to get them off antibiotics much quicker than we did before we were using Hiprex in 100%
12:18 – Melissa: Are there any antibiotics that you cannot take with Hiprex?
12:25 – Professor Malone-Lee: Sulfonamides. It’s not a good idea to take them because they can crystallize in the urine and so that there’s a risk of
12:33 – forming stones. And in fact it’s quite interesting this. We’ve tumbled into this recently because
12:40 – in the UK there’s been a deficiency, or there’s a supply problem with Trimethoprim and so as
12:46 – compensation we will forced back onto Ceptrin and Bactrim which consists of trimethylamine.
12:53 – And the sulfonamide itself or methoxazole and we’d completely forgotten about this contraindication.
13:00 – So we got various sort of, are you sure you know what you’re doing, type emails and said
13:06 – no actually I’m not sure. We got this wrong. It can crystallize. So don’t take sulfonamide with it. But otherwise that’s it.
13:13 – Melissa: We often get the question about Hiprex forming formaldehyde
13:20 – in the bladder. Do you have any concerns around that?
13:26 – Professor Malone-Lee: No. The thing is that once again this formaldehyde can have carcinogenic properties on the bladder, but this was noticed in
13:36 – in people working in an industry where they were exposed to extraordinarily high concentrations
13:41 – of formaldehyde. And the formaldehyde excretion in the urine was extremely high.
13:47 – Nothing, not anything like the small amounts that appear in the urine and Hiprex has been
13:55 – around for a very long time. 1889 it first got invented by the French.
14:07 – It was then used throughout the first half of the 20th century as the only means
14:14 – used in urine infection and it was used quite a lot after that. No incidents of cancers have come
14:20 – out of that and the manufacturers don’t believe this is a risk and I agree with them. I don’t
14:25 – think that there is. It’s a remarkably safe drug actually remarkably safe.