COVID-19 Vaccine allergy, and Improving Leptospirosis diagnostics

We discuss COVID-19 vaccination allergy clinics with Dr Karla Berry and Dr Rebecca Sutherland, and optimisation of leptospirosis diagnostics with Dr David Haake.

COVID 19 vaccination clinics paper can be read here
https://www.sciencedirect.com/science/article/pii/S2590170225001207

The Leptospirosis diagnostics paper is here 
https://www.journalofinfection.com/article/S0163-4453(25)00275-0/fulltext

Dr Haake's paper on Reunion and Mayotte ecology can be found here 
https://pmc.ncbi.nlm.nih.gov/articles/PMC11310630/

One commercially available multiplex PCR panel (BioFire) evaluation can be read about here
https://pmc.ncbi.nlm.nih.gov/articles/PMC9420791/

Thanks for listening to MIC! Feedback is appreciated, email us at journalpodcast@britishinfection.org

Our logo was kindly created by Gabriella Petruso; check out her website at www.gabriellapetruso.com

Transcript

Amy 0:07

Welcome to MIC. More Infection Chat, the podcast for the BIA highlighting articles from the Journal of Infection and Clinical Infection in practice with me, Dr. Amy Bellfield.

Michael 0:19

And me, Dr. Michael Blank, and we're both infection trainees in the uk.

0:24

Today, Amy and I are fortunate enough to be discussing topics as broad as allergy clinics for COVID vaccination and improving diagnostics for leptospirosis. First, let's turn to the paper in the Clinical Infection and Practice Journal, which looked at COVID vaccination allergy clinics

Amy 0:44

Today we've got Dr. Carla Berry, who's a clinical research fellow, and Dr. Rebecca Sutherland, who's an ID consultant, both working as part of the Clinical Infection Research Group at the Western General Hospital in Edinburgh in the UK. So thanks both for joining us.

Becky 1:00

Welcome. Nice to be here.

Amy 1:02

And, we're gonna be talking about your paper, COVID-19 Vaccination in Patients at Higher Risk of Anaphylaxis: A Safe and Pragmatic Approach." and so this is about essentially a COVID-19 vaccine clinic that you introduced during the pandemic. And so what led to you initially introducing the clinic?

Becky 1:21

so we... As an infection group, we had set up a penicillin allergy clinic way pre-pandemic, and we had, got some advice from allergy specialists, and so had got trained in skin testing and were really at the beginning of working out about penicillin allergy de-labeling and as we know, that service has changed direct oral challenge, but we were sort of on that learning curve at the beginning. So pre-pandemic, we had a penicillin allergy de-labeling clinic, and then that was stopped in the pandemic like all non-essential services. And then we all lived through the pandemic, and then the vaccines against COVID-19 were licensed. And very early on, as you probably know, in the first few days, two people had a serious reaction to a vaccine that was described as anaphylaxis, but actually difficult to find granular detail on what happened to those two. But the reaction from the powers that be was, if you have a history of allergy, you shouldn't have a vaccination. now, that is problematic, especially for people working on the front line. and we-- decided that we had this clinic, and we had this expertise. We had the team of, um, nurses who were giving the vaccines, and maybe we could just offer a similar thing because we'd got this I guess, a comfort in challenging allergy in a safe setting with appropriate triaging. And so we wanted to offer this to people who really wanted to have the vaccine but were going to their vaccine hubs in and around Edinburgh, and were told, We can't give you the vaccine because either you have a history of unexplained anaphylaxis or you've had a reaction to the first vaccine already." So we, it to be a safe space for these people to come.

Amy 3:13

Amazing. I think it's, a really brave clinic to set up, I think.

Becky 3:18

Still there, the

Amy 3:22

well done for, for plowing ahead with it. so I thought it was a good place to start talking about vaccine allergy in general, because there was a nice overview in your paper about sort of what constituents of the vaccines were maybe implicated.

Becky 3:38

Yeah, we, we'll have a steep learning curve, so we, we readily had to have a degree of knowledge about vaccine allergy But I have to put the caveat in that, everyone referred to this clinic, it was triaged by an allergy consultant. it's just that our allergy service where we work didn't have capacity to assess all these people. But there was someone with, you know, specialist training in allergy assessing whether it was reasonable for a challenge to be given we of course also wanted to be able to discuss with the people attending this clinic what might be going on. And, the vaccines offered at the very beginning was mRNA technology, so the Pfizer vaccine. And then a little bit later was AstraZeneca, ChAdOx, Oxford, title you want to give it, vaccine. And then a few other vaccines came after. Moderna, another mRNA, and a- actually Novavax that uses a, a different construct altogether. But our clinic was within the time of mRNA and the AstraZeneca/Oxford vaccine. So specifically talking about the mRNA vaccine, that was a brand-new technology, and because of that brand-new technology, they used actually an excipient in the vaccine, which was, rarer um, and that was the PEG, polyethylene glycol, um, which has many different molecular weights is actually relatively, present in medical healthcare. Because it's relatively biologically inert in, in things like laxatives and bowel prep, stabilizers for injections, lubricants and ultrasound gel. So, um, that sounds like it shouldn't be a problem because we use it all the time in hospitals. But it turns out there are different molecular sizes to PEG, and the allergy community felt that different sizes may actually be possible implicators. so the other thing to say is there's this significant population of people who have unexplained anaphylaxis, and they were definitely in the cohort that were wary about receiving vaccines. then if you put this, risk of this molecule that is more associated with allergy, you raise, the anxiety around giving the vaccine. That was the PEG and mRNA story. I think it's really interesting, so PEG is really essential

Amy 5:50

Amazing. Thank you.

Becky 5:55

a lipid nano particle that protects mRNA. So mRNA is, like, a really unstable molecule And you need something to protect it, and that is the role of PEG is to protect the mRNA, so you wouldn't You can't have an RNA vaccine without PEG in it cause it's, the basis of the technology. And the other excipient we were gonna mention is- Mm polysorbate 80, is more common because it's in most of the other vaccines we use. I am generalizing, and, I'll give this all with a big caveat if there are any, super specialists in this area, but, but our approach was that polysorbate 80 is present in Hep B and flu and vaccines people may have seen. there was another discussion, wasn't there, with allergy saying that there may be cross-reactivity between PEG and PSA, PS 80. PS 80. Thank you. What's What am I thinking of I

Amy 6:46

Thinking about prostates.

Becky 6:48

Ah, thinking about prostates. There were no prostates on show in this clinic. Um, yeah, so then there was this concept that there might be overlap, and at that point, I had to put in my sort of pragmatic oar and say, Come to the clinic, and you will be seen." And I'll go on and describe how we, did the clinic. But essentially, yeah, there's, there were two probable major players of excipients that might trigger allergy in certain populations, and, we really didn't know whether they were the players or not, but that was the hypothesis at the time.

Amy 7:21

And so in order to, determine whether they were a potential risk to patients, usually you'd mentioned before that skin prick testing is something that is used in allergy clinics. but there was a decision not to do that in this clinic. Is there a reason? Was that because of the triage system, or was there a different reason for that?

Becky 7:42

Yeah. the reason behind that is when we did penicillin allergy de-labeling skin testing, you could only really see four or five patients in a morning, and this clinic it had a big spike of people that wanted to enter into the clinic, so we wouldn't really be adding much if we adopted approach. Skin testing couldn't be offered by- Any other service within the hospital, and so we did that, and I'm flying the flag for infection doctors and general medical doctors here, where you did that pragmatic, "Well, we'll just do it. It's something to do with infection." and then the other thing to say is When you do skin prick testing, you give sort of small doses, and some people think maybe you should try all the molecular weights of PEG, or you should work your way up. and in the end, you're slightly thinking, "Well, if I'm injecting this person anyway, maybe I should just give a little bit more and give the whole vaccine and see what happens." Because we can't even definitely correlate a skin test reaction and an actual systemic reaction. obviously, as long as the person attending clinic is fully consented, was felt that we would skip that and go straight to challenge. following consent, resus trolley nearby and triage approved by the allergist. interestingly, we've had a good look, Carla particularly, uh, at the evidence of skin testing and, there isn't a lot out there. it's generally considered now in hindsight you didn't need to do it, and the other thing is that, you couldn't actually do skin testing with the mRNA vaccine, so they actually used a different form of PEG to do the skin testing, which was a, higher molecular weight, so more associated with reactions, and it wasn't the same formulation in that it was the PEG bound to a lipid nanoparticle. So it's actually a d- totally different type of skin testing that they did to test. As we said, in hindsight, There's been a meta-analysis of this, and the official guidance has changed to you shouldn't be using skin testing assess patients for allergy.

Amy 9:40

So you were right. The gift of hindsight there, hey?

Becky 9:44

Luckily.

Amy 9:45

And so we've sort of alluded bit to the pathway that patients came through, but I wondered if you could make it a bit more clear for people listening, what was the pathway through your clinic and, and what were the potential sort of outcomes for them?

Becky 10:01

with the support of colleagues in public health and, our allergy specialist in dermatology, a protocol that GPs could refer into the clinic. if you had any history of allergy or anaphylaxis, if you had a systemic reaction to a biologic, so that's hinting at you might have a PEG allergy, it was suggested that we would avoid mRNA vaccines but come to clinic and get the AstraZeneca vaccine. if you had unexplained anaphylaxis or you had anaphylaxis to multiple drug classes, avoid the mRNA vaccine, but come to a monitored clinic for Chadox. And if you'd already had a reaction to one of the vaccines, then come to our clinic, and we'll give you the one you haven't had. And by then we had the data from Com-COV to show that it was safe, if not beneficial, to mix your vaccines to have an even, more optimal immune response. Um, and so then you would come to our clinic, and we would consent the patients because although I'm being a little light about this subject, these were people who really wanted to have the vaccine. It was a great clinic to run because you got to meet members of public who hadn't been able to come out because they thought, "I'll never be able to get this vaccine." so we would consent them, and then we would simply their obs at the beginning, give the vaccine, and then we would, I have to say, chat to them, bore them, give them cups of tea, observe them, but not observe in a you alone in a room kind of way. We were pretty much hovering, and we had a sort of daybed where we were walking around, especially at the beginning, where we were sense checking whether this was a good plan or and then after thirty minutes they would have their obs repeated. This was documented, and then we gave them some, worsening advice. then if nothing happened, you know, by the evening, they were then safe to go on and receive vaccines in the community. I had two staff nurses with me and the resus trolley, but we also drew up adrenaline and had it ready in the unlikely event we would need to use it And then there were also some patients, weren't there, that were advised by your triaging or allergy specialist to give oral antihistamine on the day before they came to clinic, as a pre-medication before they got their vaccine. Oh, yeah. Thanks for reminding me. The rashy cohort. So there were people that went blotchy- rashy, quite significant rash, and the whole, our allergy specialist recommended that they took their cetirizine in the morning, and we also had a supply of short-acting and long-acting antihistamines in the clinic. there was another group, wasn't there? There was people deemed probably could receive it in the community, but they had their own personal fear of receiving- Mm a vaccine. So there was a tiny population of people that it actually wasn't

Amy 12:46

Mm-hmm.

Becky 12:50

we sort of did a half-half approach for those. That they came along, um, whilst we were seeing with the ones that we were considered more high risk, and they had their vaccine as well.

Amy 12:59

A safe space for people Yeah.

Becky 13:00

It was jolly. It had, like, lovely vaccine nurses. Tea and coffee was flowing in a infection control appropriate way.

Amy 13:07

Yeah. Nice. And so how many people did end up being referred, and what was the sort of breakdown of those?

Becky 13:16

So, there were over 700 people that were initially referred and triaged. and then 186 individuals at triage was accepted, and then people that, weren't accepted, a lot of the time our allergist would actually phone the patients as well and talk to them about reactions that they'd had in the past. and the GP would get a letter saying, "We've looked at everything. You're safe to get vaccine in the community." And then 186 people came to the clinic, and Apart from this cohort that Becky mentioned earlier where thought actually they pr- probably would be safe, but We sort of just brought, brought them in anyway. people kind of fell into three different groups. So the three different groups were that they might have an undiagnosed PEG allergy and which meant that they might have a reaction to the mRNA vaccine. so the majority of that cohort of people were people who had an unexplained allergy or anaphylaxis. And that was 67% of that first group, or 59 people. And then, the next group was people who'd had an allergy or anaphylaxis to multiple different classes of drugs because as we know, PEG is in a lot of different drugs, and so it might be that the reaction that they were having to all these different drugs was because of PEG. And then there were a few other people who were referred because they'd had an allergy to a cosmetic agent or some chemotherapy, the Depo injection, or macrogol, and macrogol actually is just PEG. And then the second group of people was people who were potentially gonna have an allergy to the AstraZeneca vaccine because they might

Amy 14:50

Mm-hmm.

Becky 14:51

reaction to polysorbate. So there were 88 people who might have an allergy to mRNA and then 35 might have an allergy to the, AstraZeneca vaccine, and the majority of those people were people who had a previous reaction to a vaccine. And then polysorbate is in a few other things, so it's in biologics, again, chemotherapy, and it's also in the Mantoux test. so there are a few people that were referred because they'd had a reaction to those things. And then the final group of people, which was, actually formed the biggest group of people in the end, it was 74 people, were people that had had a reaction to the first COVID vaccine second COVID vaccine, so people who'd already had a reaction.

Amy 15:35

And so did anyone have a reaction? Did you have to whip out the adrenaline at any point?

Becky 15:42

So there were 41 people who had a reaction, in total. the most common types of reaction that they had were tingling of their face or tongue or mouth, or some swelling, and some people had some skin reactions, and the majority of people had those kind of reactions. so with this was all in the parameters of something's happening, but ABC is okay and obs are stable, we're gonna keep going, and we're gonna reassure them, and we're gonna watch this. and none of those required, any further intervention. the three that required intervention, were essentially people that had known angioedema, and that is a different situation. So that's not an adrenaline responsive condition, boy, does it look impressive and quite alarming. Now, these people actually knew their condition, they knew this was probably gonna happen. And whether it happened because of the stress of the situation, the cold air coming out of their car into clinic, or the vaccine, was a little academic. The fact is, they had an enormous tongue, and I wasn't gonna send them home with their airway looking potentially compromised. And so we had an agreement with critical care that they would come and see anybody, and they came along. She has-- he, she has, an airway that

Amy 17:00

very reasonable. And so nobody had

Becky 17:01

If it got any

Amy 17:02

anaphylaxis throughout the

Becky 17:06

sats drop. point did their heart rate or blood pressure parameters, change, so they did not receive adrenaline, me intramuscularly. one personally chose to have adrenaline nebs, and that's something she personally chooses to do with advice of her own allergy specialist, and we weren't gonna upset that dynamic. Yeah. Nobody had

Amy 17:35

whole... That's to say your triage was incredible, really. That's amazing.

Becky 17:41

Well, I think it makes you think about What is called anaphylaxis. The other thing that felt was beneficial about the clinic was there was a cohort of people that had always thought they were allergic to vaccines because they were told they had a reaction as a child to one of the childhood vaccinations, or one year had a reaction to a flu vaccine. And because we then went on and offered them this monitored vaccine clinic appointment and gave them another polysorbate 80 containing vaccine, and they were fine, opened up that maybe they weren't allergic to vaccines after all and could go on. Um, and so some came back and asked if they could have their first flu vaccine since this, just to check that that is safe going on. So we were beginning to chip away at other vaccine allergy already at the tail end, of lockdown and the pandemic. Yeah.

Amy 18:34

You've mentioned in the paper that, people with previous reactions to COVID-19 vaccines were more likely to have a reaction in clinic. And, and so why do we think that that might be?

Becky 18:47

it, it's, really, you then have to start thinking about why people are having a reaction to COVID vaccines, and is it because of PEG, is it something else that's going on? this idea of, um, something called an immune-mediated stress response, which is recognized by the WHO as, as a concept that happens, and it's essentially a stress-driven response that can occur as a result of having a vaccine and- can look a bit like anaphylaxis or allergy. so people can get skin changes, they can get tingling and feel like they're struggling to breathe. but it's not actually reaction driven by allergies, so there's no IgE response. more a stress-mediated response. And then there are some other theories as well about why people might be having reactions to the vaccines that again is unrelated to PEG. So, there are some theories about people having reactions to complement or complement-driven processes, that occur as a result of the mRNA vaccines. and this could potentially be a, cause of why people are reacting to the vaccines. I guess that's maybe why people who've had a reaction to an initial then have another reaction as well, rather than people who've a possible PEG allergy.

Amy 20:05

N-nationally or globally, was it found that people were more likely to have a reaction to COVID-19 vaccines than other vaccines I-is there something in that sort of stress response that was to do with that it was a pandemic and everybody was permanently slightly terrified,

Becky 20:25

I think there are some, there are

Amy 20:27

Hmm.

Becky 20:31

vaccines and have compared all the different types of vaccines. and COVID vaccines definitely wasn't one of the highest, like didn't have the greatest proportion of It was strange times, weren't it? And we were learning and giving information almost at the same time to people we were

Amy 20:50

Hmm.

Becky 20:50

after in the pandemic. but it was terrible timing that reactions happened so early, I think, It felt like the right thing be able to offer a clinic where you could just pause and go, "Should we just check if something really is happening here With all the parameters of safety in place. We then had to then challenge our own protocol because the guidelines changed of who should get Pfizer and who should get AstraZeneca vaccine. So we had this concept that, you know, if you had a unexplained allergy or unexplained anaphylaxis, that we should probably avoid PEG but then, the signal regarding VITS became apparent AstraZeneca. And so then I remember having this discussion with that were writing the protocol, which was quite an extraordinary discussion. It was like, if we have young people coming to clinic, what would be worse to give them? The thrombotic thrombocytopenia. Is Which, we have more understanding of now, but at the time, it was creating a lot of understandable concern, and actually, felt it was more straightforward to treat anaphylaxis, which is an extraordinary thing to say, but essentially we did have a pathway for what would happen if someone had an anaphylactic reaction. So then the cohort that we would have said, "you had a reaction to mRNA, as in you had a, you had a rash or something funny happened to you an hour after your first mRNA, or you had unexplained allergy." In our initial SOP, you would then go on and get AstraZeneca. But actually, if you were in the age group where that was no longer recommended by the JCVI, we, we actually re-challenged people who'd had an initial reaction with a second dose of an mRNA. Sometimes we had the opportunity to give a different construct, you know, maybe the Moderna rather than the Pfizer. Or in those with un- explained anaphylaxis, we were no longer avoiding PEG. We were offering them as well, and nothing happened. So actually we were, as is often the way, we were put in a situation where we really had to test this hypothesis, and it looked like PEG was even less likely to be a culprit. and there was, um, a really similar proportion of people had a reaction to the AstraZeneca vaccine as had a reaction to the PEG vaccine. Mm-hmm. There doesn't really seem to be, like, much to predict or explain who was gonna get vaccine reaction.

Amy 23:13

That's perfect. Thank you. And so you've mentioned that after people had their COVID vaccines, that people came back to have further vaccines with yourselves, or some people requested to. have you now extended the clinic?

Becky 23:29

It was only a handful of people who actually came back for the, a second vaccine. 17 people, because they'd had a reaction, or m- maybe again felt a bit nervous about getting a vaccine in the community, came back to the clinic again. So there was a small cohort that we thought it was appropriate to keep offering and the monitored service, too. But as I alluded to earlier, it did open up conversations of, "Oh, I thought I was allergic to the flu vaccine. Mm. Could I maybe..." And so whilst we were in that phase where we were still aware there may be some people in the community... And I-- if I could say as an aside, there was a very vulnerable, isolated, tiny proportion of the community that hadn't come out their houses, of them started to come to clinic, all, like, with two or three masks on, you know, this was their first time out. It was a very big event for them. And, and you realized, hang on, there are some people that haven't even put their hand up yet. whilst

Amy 24:26

Mm-hmm.

Becky 24:26

running that, and we had maybe two or three clinic slots, we were like, "We could let that person come and see if they're allergic to flu vaccine." And, and so it opened up the concept that maybe when the pandemic is... I d- I'm almost like, you know, can't even say it. When it's over, then, maybe this should just be a vaccine allergy clinic.

Amy 24:47

And so now it is a vaccine allergy clinic?

Becky 24:50

it is

Amy 24:51

And how often do you run that?

Becky 24:53

I've got to the point where I am gathering cases

Amy 24:57

fit it in a bit more pragmatically.

Becky 24:59

Mm. Mm.

Amy 25:00

Wonderful. covered that either of you would like to touch on or that you'd like to sort of double down on and a key point that you'd like people to take away?

Becky 25:12

I think that skin testing is not an essential thing is definitely a key point, and as I mentioned earlier, all the evidence now says that you shouldn't skin test, when you're assessing people who've got a potential vaccine allergy. Yeah. I think there were lots of things in our favor that enabled us to set this clinic up, and I know that starting a new service in the NHS is difficult. but there was, there was this combination of experience Of, an area in the hospital we could offer it, and then a, an obvious need, and it was quite a finite need, and I think that's allowed us to start this clinic. And I think having done it, I mean, it was, it, it was an amazing experience but, quite challenging at times. and think now it just makes me even more interested in the immune response and all the different ways it manifests in the patients that we look after, and it, it sort of makes me feel that my dream would be to run this clinic, like, with an allergist there sort of speculating what they think is going on. Now, obviously the supply of allergy specialists is, gonna match that, but, I hope I haven't, um, overstepped the mark by discussing that, if there are any allergists listening. And was reassuring that nobody, nobody required IM adrenaline. That doesn't mean that no one does. Like, I'm not disputing that there w- there is anaphylaxis to vaccines, of course. And got very interested in the yellow cards and all that data. And that was a big reason why it blew up at the beginning. Because anyone who'd had a previous allergy to vaccines was excluded from those initial trials- Yeah weren't they? Yeah, that's a brilliant point. Yeah. And that's reminded me why I g- another reason why I got into it. Because we sort of felt like we'd, we'd vaccinated a lot of people, but of course we had excluded those- Yeah that cohort. Yeah.

Amy 26:59

Thank you both very much. That was really interesting. I just think that I just feel really lucky to be part of the infection community. I just feel like there's some really just impressive people, and I do think that patients are always at the center of that, and I just think, yeah, well done, 'cause I think it's a really good example of, of that. It's just nice to hear about people doing their jobs well.

Becky 27:23

Oh, yes. This is-- I, I went to someone's inaugural lecture, and I just thought, this applies to me, but it probably applies to quite a lot of colleagues. I approach things with an almost deranged level of skepticism. I think, um, people do, don't they? but I think a lot of our ID, papers recently have challenged stuff that's been set in stone, hasn't it? So it feels quite alive at the moment. There's quite a lot of opportunity.

Amy 27:47

Good.

Becky 27:48

You, Amy. We've never done anything like this before.

Amy 27:51

Well, you were both great, so thank you for doing it so graciously.

Becky 27:55

Thank

27:57

We've now been running this podcast for over six months and we are very keen to hear your feedback. You can do this by emailing Journal podcast@britishinfection.org, which is also, in the show notes. Or you can leave a comment, below the show notes. We'd love to hear from you and we're always looking to improve our podcast.

Michael 28:22

I am very excited to, be speaking with Professor David Haki, who is the author of, a recent paper in the Journal of Infection entitled Early Diagnosis and Treatment of Leptospirosis Optimizing Clinical Outcomes. Welcome to the podcast.

David 28:42

Thanks. Glad to be on.

Michael 28:46

I thought we could, start by talking a bit about how you got involved in research in Leptospirosis, and, what is it that makes you interested in it?

David 28:58

Thanks for the question, Michael. We're excited about our publication and Journal of Infection. I wanna make sure that credit is given, to all the authors, including, professor Najaro and, uh, por who were really, very important part of the article and the writing of it, the creation of it, the conception of it. Uh, they see hundreds in cases of lept osis there, in their network, in Bangkok and, and Thailand. And, have a tremendous amount of experience with this very subject, which is trying to get the diagnosis earlier, trying to get patients treated earlier and optimiz, improving clinical outcomes. I think it was really a team effort. But, to answer your question, what really pulled me into Lepto sclerosis research was that it is a really neglected tropical disease. There's a huge clinical need globally, and far, little, far too little attention was given to it. So when you see a disease that's causing severe illness and death, uh, it's concentrated in marginalized communities. It's underdiagnosed, it's underfunded. is where I felt like I could make the biggest impact. And so that's why I was interested in lepto Osis in the first place. been working in this field for almost 40 years. So. It was really a question of, you know, where's the biggest need? It wasn't really an academic decision, it was a values decision and really pleased with, where things have, have come over this very long period of time. Uh, as we've been advancing the research, improving diagnostics and care for patients, both human and animal. So it's ultimately, it's a sort of a health equity issue.

Michael 30:51

In that context, I wonder if you could tell us a little bit more about the extent. Of the problem of leptospirosis and maybe where, where is it? And how is the geographic distribution related to, to climate?

David 31:04

I mean, this is really a global problem. The biggest impact is in the tropical areas of the world. The, paper talks about, documentation that there have been, more than a million severe cases annually and, and something like 60,000 deaths a year. even more than that, uh, we measure di disease adjusted, life years. and that got, brings us up to something like 3 million, 2.9 million. Disease adjusted life years, which is a burden that is actually greater than far better known illnesses like Dengue fever. geographically it tends to cluster in south and southeast Asia with, substantial burden in Caribbean, parts of Africa, Latin America, uh, climate is a major driver and in the article we talk about how. Increasing extreme weather events with a heavy rainfall and flooding monsoons, hurricanes to, uh, cause a dispersal of the organisms and from soil into the water and how climate change is increasing, will likely increase the number of cases and the impact on both humans and animals.

Michael 32:21

And I, I guess that, ties into what you were saying before about it, it being, a disease that affects those that are worse off.

David 32:29

Correct. Yes, exactly.

Michael 32:32

It's not in this paper, but I read, you wrote somewhere else in the literature about different severity of disease depending on, um, which island patients came on, I think reunion and Myat. I wonder if you could say a little bit about that, in this context.

David 32:51

So, yes, it's fascinating. Absolutely fascinating. And it goes back to the lifecycle of the organism. It's a, it's considered. Zoonosis, which means that it's particularly transmitted from reservoir host animals to humans. And what's fascinating about the Rayon Mayotte uh, case is that what we learned from a study that was done there is that it's not just about the patients, it's about the ecology. where people live. So in Rayon, a much greater proportion of severe disease was linked to a particular leptospira species called Leptospira interrogations. Which causes more serious infection, and it's a more virulent species of leptospira. Whereas on Mayo, the infections were largely caused by other less virulent species because of the ecology, on the two different islands was so different. so the severity rates in the human patients was also lower on mayo. So differences in the reservoir hosts the type of species that are infecting those reservoir hosts. Uh, the exposure patterns, the population risks, uh, all add up to very different clinical pictures on those two islands. So that's another reason I, I'm fascinated by Leptos is that you don't just look at the human side of things, you. You also get to think about the microbiology, the pathogen, the environment, the epidemiology. All these shape to humans for severe disease.

Michael 34:31

That brings us quite nicely into discussing how we get to a diagnosis of human disease. And why is it so challenging? I mean, you, you talk about this quite a lot in your paper. Why do we get to diagnosis so late?

David 34:47

Another fascinating question. So yes, leptos is really difficult to diagnose in its earliest stages. the. After an incubation period, patients begin to have symptoms, but those sym early symptoms are. Undifferentiated. We use that term to say that it, it's, you have fever, you have some aches and pains, you have some headache, but it looks a lot like many other tropical febrile illnesses, as I mentioned dengue earlier, but malaria, influenza, all of these illnesses sort of look the same in their earliest stages. And so it's difficult for clinicians to, differentiate between these different possible causes, all of which have very different treatments by the way. And so, uh, in those early stages, the organism is, is already disseminating, it is, evolved to minimize the host response, minimize the symptoms in its earliest stages. It is trying to find its way, um, to the kidney of a reservoir host. That is why it is multiplying in the bloodstream. And so in those early stages, we know that bacteria can achieve actually amazingly high levels in the blood even though the patient may not be particularly sick. Some patients have even higher levels and they're at risk for more severe outcomes. Um, the longer it takes to make that diagnosis and start antibiotics and other types of supportive care, the less effective those treatments will be in preventing bad outcomes like kidney failure, pulmonary hemorrhage, even death. That early window of time when the bacteria in the bloodstream is the, window of time when we can really change the trajectory of the patient's outcome. So, that's why we wrote this paper to, to focus on this question. You know, how do we make an early diagnosis and initiate treatment at its stage when we, when treatment really makes a difference. A number of criteria have been developed. And the first one was developed by a, a guy named Soly Fein. the criteria he developed for diagnosis was really pioneering. I was fortunate to get to know Soly, really an incredible leader in our field. Um, and he was being very careful about the components of the scoring system, but that resulted in them being a bit complex. And less sensitive in the early stages. So in our paper we cover a number of newer, more streamlined scoring systems like the T LEPTO score and the department or OPD score, which are more practical for early diagnosis, triage, and timely treatment decisions by frontline physicians.

Michael 37:46

And. Thinking about severity, um, it might be worth touching on immune evasion here. So, leptos Sclerosis is very successful at evading the innate immunity. Is that part of the reason why detection is so difficult?

David 38:04

Absolutely. Yes. You, you've really touched on a key issue a really major subject of ongoing medical research. The organism, as I alluded to earlier, is, is highly adapted a mammalian host in ways that minimize triggering this innate immune response. So after exposure,. It can reach highly bloodstream concentrations before finally triggering a meaningful immune response. And it has adapted a number of absolutely fascinating ways to the in recognition by the innate immune system. So clinically you've got patients walking in, to your clinic, to your emergency department, uh, with tens of thousands of lept depar in their bloodstream. But, despite that it's difficult to. Know that this is a case of lepto Osis. Um, patients may not have formed antibodies yet, so serological tests don't work. They have limited inflammatory responses. So what we know is that, that once the immune system finally recognizes that this invader is present, it can have a over response. Um. Where there's a tremendous inflammatory response organ injury. And so, in a way it's sort of paradoxical that that host response that finally detects the infection is also what contributes to severe disease.

Michael 39:35

And that leads us on quite nicely to diagnosis because of course you already mentioned serological tests. Um, I wonder if we could talk a little bit more about the different testing strategies for leptospirosis.

David 39:49

Yeah. So in in our paper we talk about, the timing of when certain tests are appropriate. Serological tests have been. The sort of the mainstay of diagnostic testing for many years. And in fact there are very nice sort of lateral flow tests that can be used for serological testing, those tests tend to turn positive a little bit later in infection. So in the early stages, which is the emphasis of the paper, molecular amplification strategies are really best. And that they are able to detect the DNA and the bloodstream, the, the lepto spiral, DNA, even before antibodies appear. So those serological tests can miss the early disease. And so, um, in our, in our paper, we describe some work that's going on now to develop, uh, PCR and other. Even, you know, near to care bedside techniques that can do molecular amplification, using CRISPR technology so that, these can be deployed right there at the point of care and allow frontline clinicians to use these molecular tests in their sort of diagnostic. Armamentarium.

Michael 41:11

Are they, are they in routine practice yet? The the CRISPR techniques.

David 41:16

so that's where the neglected tropical disease, part of this whole story comes in, which is that there needs to be more investment, in these technologies so that they can be. Made inexpensively, and investments made by healthcare systems, by countries that have a high burden of lepto posis. So that. These tests can be made available there. It's really still in the research phase, Michael. Um, but it's very promising we're excited about the potential. But we also talk about other kinds of approaches, for example. Um, looking at the host response from a proteomic or transcriptomic perspective, and at this point it's now pretty easy to distinguish. Viral infections from bacterial infections, and even within different classes of bacterial infections like lepto, osis versus let's say, uh, sepsis a, from a bacterial like staph or e coli, should be possible to use proteomics or transcriptomics or faster point of care decisions. So, although this is a bit futuristic, uh, we think that,, in the not too distant future, you could, uh, put a blood sample from a patient into one of these platforms be able to distinguish. Let's say dengue from influenza, from lepto sclerosis, from staph infections and have an answer, even though you don't have a clue what kind of infection the patient actually has. The proteomic transcriptomic broad pathogen panel type of tests don't require somebody to yes, what the disease is in advance.

Michael 43:14

And that would make a big difference to early diagnosis as well, I imagine.

David 43:20

That's right. It is a universal principle that any infectious disease is better treated early than late. So yes, it, it would impact lepto, it would impact other kinds of infections as well.

Michael 43:32

And maybe less futuristic. You mentioned some rapid tests including lip L 32.

David 43:38

So the standard PCR test for looking for lepto spiral, DNA in the blood. Involves a test for lip L 32. It's a, gene that's present in the DNA of all the pathogenic leptospira. And it's widely used to detect lepto sparrow, DNA. In blood samples really in many places. And there are kits that can be ordered commercially, for lip L 32 PCR, the current tests are relatively fast, but still require a laboratory to do those tests. And so they aren't truly point of care.

Michael 44:26

You anticipate some, some point of care tests in in the near future.

David 44:33

At some point in the not too distant future, let's put it that way, we think that there will be point of care tests that are molecular for lepto. And so earlier I had mentioned the CRISPR based amplification test. That has a lateral flow readout. What is being developed and, and something we mentioned in the paper is, is to use a molecular amplification test again for lip L 32, but in this case, a, uh, a point of care. Type of system that has a lateral flow readout where you look for a line on a strip turning positive. And so it's a, very, uh, innovative way of bringing the advantages of, of direct pathogen detection, molecular amplification to the bedside. It's pretty sensitive and, it would revolutionize early diagnosis of lepto sclerosis because again, it can be, you can actually start with a, a blood sample or a urine sample and then run that test right at the point of care.

Michael 45:44

Do you think that the timing of the treatment, we have sort of alluded to this question, but do you think the timing of the treatment will always affect the outcomes?

David 45:54

Absolutely. Yeah. So, we reviewed a number of interesting studies, most of them a bit historical, uh, where patients were. Treated with, antibiotics or in some cases, randomized to non-treatment, no antibiotic. And what we found was that timing is everything. So if you have a, a cohort of patients who already have failure, they already have jaundice, uh, and other complications, antibiotics wouldn't be expected to have much impact. And that's in fact what they found. if you got antibiotics to those patients in early lepto sclerosis, again, going back to the whole point of this article, within the first few days of symptoms and before patients had significant. Impacts on their, their organ systems, like the kidney, then you always see, an impact. Um, when you're looking at a population or a cohort of patients, you, you definitely will see improvements in terms of, shortening the length of fever. And shortening the length of hospital stay. Um, those kinds of markers have been demonstrated in a number of studies.

Michael 47:11

And you mentioned doxycycline a bit earlier, is that always the treatment of choice?

David 47:17

So, yeah, in mild to moderate disease, um, pretty widely used. Obviously, we like to avoid that in children, because of its, you know, impacts on teeth and bones and so forth. But, yes, doxycycline is one of my favorite antibiotics. It's actually quite safe. It does have some risks associated with sun exposure. It can, photos cause photosensitivity, so you tell people to stay indoors while they're taking doxycycline. And, it can up, it has some gastrointestinal, irritation that can happen if you take it on an empty stomach. But it's really effective for lepto and, actually works relatively quickly to kill the organism and, widely used for this diagnosis. So terms of other kinds of treatments, uh, what we're learning is that in some settings. Beta-lactam antibiotics were typically used for more severe cases, so penicillin, ceftriaxone, things like that, um, are very effective. But,, in certain populations, and we don't really understand how widespread this is in certain populations, there can be what's called a jish Herxheimer reaction patients can, for the first couple of hours after treatment, can have a bit of a severe, uh, more severe. Symptoms. And it's also reflected in some laboratory tests. So there's a growing interest in azithromycin, for IV intravenous care. The sort of jury is not out yet on whether or not we're really gonna make that recommendation, but it's more what's the best treatment in terms of patient outcomes.

Michael 49:02

And just to go back to the antibiotics, doxycycline and azithromycin are both antibiotics that tackle the intracellular component of infections. So is there something in that? Is that why it's avoiding the JH reaction?

David 49:19

Thank you for that lovely question. So what we think is going on. Is that, as folks who understand the mechanism of action of antibiotics? No. you give a beta lactam antibiotic, you're actually causing the organism to lice. And when, when the bacteria sort of breaks open and, and, and essentially explodes releasing. Um, it's, it's in components. It, then those components then can be recognized by the innate immune response and trigger this more severe host response as a result of the antibiotic therapy. It typically happens again in the more severe cases and in when treatment is late. Um, and only in, apparently only in certain population groups. So it, it's not a universal problem and we're not really saying you shouldn't use penicillin at this point, but we're asking people to be sure to monitor the patient's response, and. You see whether or not the, the additional supportive care is gonna be needed in the first few hours after that antibiotic therapy is initiated. Azithromycin has the advantage as, as does doxycycline, that it, it doesn't cause that lysis of the bacteria and release of its, bacterial components that, uh, may worsen the innate immune response, which again, as I mentioned earlier, is really why patients get so sick.

Michael 50:49

Interesting. And I'm sure as time goes on, we're gonna see more evidence emerging about the best possible antibiotic for this disease.

David 50:57

That's right. There's a lot of interest in knowing antibiotic to give to, you know, the right pa, the right antibiotic for the right patient at the right time. There we go. To summarize it.

Michael 51:11

That's every ID doctor's dream. Just thinking a bit more wider, um, beyond the individual patient or individual clinician, uh, there's a, there's quite an interest. Section in, in your paper, talking about systems, not just the individual's practice. And I wonder if you could say a little bit more about this.

David 51:35

Yes, exactly. So what, what, uh, we've learned from the experience in Thailand is that, uh, you can't just rely on individual clinicians to, educated about every possible disease, including leptos, um, and to, to always be thinking about it in when they see a febrile patient. So systems are being developed, uh, there in Thailand and elsewhere to help make early diagnosis easier. So that means, um, an integrated sort of system in which. we think, uh, about lepto sclerosis in the sort of one health context. health means that we're linking human disease, animal disease, environmental data to help us recognize early when there's been an outbreak. And so if an outbreak has occurred, wouldn't it be great if, uh, the physicians who are there on the front line get a text message? says, there's an outbreak of lepto in your area. Uh, consider lepto when you're seeing patients with these particular, presenting symptoms. And so that, that allows them to deploy these point of care diagnostics that we're talking about earlier. Effectively, it's sort of an integrated surveillance. Community education, obviously really important. not only the physicians, but also the patients. that if there's a, if there's a lepto outbreak in their area, that they should go in and, and seek care in a timely way and not wait until they get really, really sick. So, it's not just outreach to the physicians, it's also outreach to the patients. We think that, this is a way to improve outcomes for patients by making them aware that,, they may be at risk if they're in a particular area. There's been flooding, there's been heavy rainfall, and they have risk factors that might, make them more susceptible to leptos. So better outcomes come from coordinated public health and infrastructure, not just smart doctors,

Michael 53:52

It's interesting. It's quite sobering to think about our role within a much wider system.

David 53:58

correct.

Michael 54:01

And then and finally, I wonder if you could share with us what you are most excited about in the area of leptospirosis research.

David 54:11

I love that question because there is a lot of excitement in the area now, uh, as we're continuing to, uh, try to make the connection between what we're learning in the, in the research field. Uh, essentially at the bench, the research bench and the laboratory, were trying to translate discoveries. To the bedside and, where it really matters. low cost, easy to use. Diagnostics available in, on the front lines. And that's what's most gratifying about working in this field now is seeing how discoveries move into tools that are sort of real world and, potentially commercially available in the, not, in the not too distant future. So. Better point of care diagnostics, earlier detection, earlier diagnosis, uh, faster, treatment algorithms. So. It's exciting to see these changes come.

Michael 55:17

Great. And we look forward to seeing them, uh, I'm sure in a very short period of time. Thank you Professor Haki for coming on this podcast and sharing with us some fascinating insights into leptospirosis.

David 55:33

It was my pleasure, Michael. Thank you.