Deciphering who index cases are in influenza outbreaks, and thinking about rashes in immunocompromised individuals

In this podcast we discuss household transmission of influenza with Dr Sarah Cox and Dr Julia Bennett. We also discuss rashes in immunocompromised individuals with Dr Sarah Clifford and Dr Naomi Bulteel.

Read the Influenza study here https://www.journalofinfection.com/article/S0163-4453(26)00073-3/fulltext

Cohen study in South Africa looking at household transmission https://www.thelancet.com/journals/langlo/article/PIIS2214-109X(21)00141-8/fulltext

The work their group has been doing on COVID was also recently published https://academic.oup.com/jpids/advance-article-abstract/doi/10.1093/jpids/piag061/8738471?redirectedFrom=fulltext&login=false

The article on rashes in immunocompromised people in CLIP: https://www.sciencedirect.com/science/article/pii/S259017022500113X

HIV and Leprosy review https://doi.org/10.1016/j.det.2010.08.016

Global Health Observatory https://www.who.int/data/gho

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 0:02

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.

0:15

And me, Dr. Michael Blank, and we're both infection trainees in the UK. Today, we have two fascinating papers we're going to be talking about. The first looks at household transmission of influenza and the transmission dynamics related to that. And then we'll look at difficult diagnoses of rashes in immunocompromised individuals. So first, the influenza paper

Michael 0:42

I'm very excited to be joined today by the authors of a recent paper in the Journal of Infection entitled Influenza Household Transmission and Genomic Diversity in the United States: A Prospective Cohort Study, 2022 to 2024. And I'm joined by Doctors Julia Bennett and Dr. Sarah Cox, who are both at the University of Washington. So welcome to the podcast

Sarah Cox 1:06

Thanks for having us

Michael 1:10

Let's get started talking a little bit about, uh, your research and, and the background to it. What was known about influenza transmission before your study?

Julia Bennett 1:22

Sure. So by saying that, um, influenza still causes quite a substantial burden of disease. So just here in the US, there are millions of flu illnesses and unfortunately tens of thousands of, of deaths from influenza every year. And influenza virus spreads from person to person, so this is primarily through respiratory droplets, people doing things like talking, sneezing, or coughing. And we do know that households are an important setting where the transmission of influenza occurs, and these types of household transmission studies offer us, um, a unique opportunity to study the dynamics of transmission Do you want me to expand more on, um, kind of like past studies or

Michael 2:12

yeah, tell us a little bit more about what research was already in the literature and, and what we already knew.

Julia Bennett 2:18

Yeah, sure. So, um Prior, influenza household transmission studies were mostly conducted before the COVID-19 pandemic, um, and there's one review, a study that included fifty-six studies, and they estimated, something called a secondary infection risk, which within the context of a household study is just the proportion of household contacts that subsequently become infected after one person brings the virus into the household. So in these past studies, there was a range of secondary infection risk between one and thirty-eight percent, although really the bulk of them were closer to five and twenty percent. Um, and we don't... we're not entirely surprised by that wide range in estimates because we know things like different of the virus circulating in different years, different study populations, different study designs can all impact, impact that estimate. But there were very few influenza household transmission studies conducted the COVID-19 pandemic, so we were interested in having some updated data on more recently circulating viruses and also as we kind of re-emerged from the disruption the pandemic caused to respiratory viruses. And there were also a few gaps that most prior studies hadn't addressed. So the first is that there's been very few studies that have been able to look at the ways, um, that asymptomatic individuals contribute to influenza transmission within household settings. And then second, uh, is genomics, which we were able to include in our study to help tease out exactly how transmission is occurring. there's only one other study I'm aware of for influenza that has used genomics in this way, and it just helps us understand, did the transmission actually occur in the household? So as an example, did your toddler get the flu at school and bring it home and pass it on to somebody else in the household? Or did multiple people in the household independently just get infected around the same time? So as an example, did your toddre-toddler get the flu at school and then around the same time that same week, you were also incidentally infected at the grocery store?

Michael 4:48

And what was known about asymptomatic transmission before your study?

Julia Bennett 4:54

We do know that asymptomatic transmission occurs. Um, there's one other household influenza study that was actually conducted in South Africa. This was led by Cheryl Cohen and her group, and, um, they did find that within households, transmission occurred more frequently when the index case, so the first person infected, was symptomatic than if they were asymptomatic. But they still did observe some asymptomatic transmission, so we, so we do know that it happens, but it seems to happen less frequently than transmission from a symptomatic individual

Michael 5:31

That brings us onto your study and, the questions it was trying to answer. And maybe, you know, we've already mentioned the COVID pandemic, but given the time duration that this study was conducted over, you could contextualize it a bit more in that timeframe

Sarah Cox 5:46

Yeah. So this, this study was actually done in the context of trying to evaluate COVID vaccine effectiveness, um, and like a larger study basically to study COVID vaccine effectiveness in children, um, and adults. And we specifically used the same cohort to be able to evaluate household transmission on lots of different pathogens. So in addition to flu, also looking at RSV and, uh, other viruses like HMPV. And, um, at this time, the community was very used to doing testing. It was often people looking to get tests, and that was something that was exciting about this study, is that people could do testing directly from their home, um, and get results. And so a lot of families were interested in participating just for that. And I think right at the beginning of the study, um, sometimes for sports or other things, families would need, um, a test result or to travel to certain countries, things like that. So it was kind of an easy way to get a test, um, by being part of the study. Um, so kind of that's what was going on. And I think in terms of virus circulation, we all know that when the COVID pandemic hit, a lot of other viruses like flu and RSV disappeared, right? Um, and then they started to come back, so this was kind of right around the time that, um, viruses were re-emerging, but, um, that the patterns were different than what we had seen in the past. And so we were particularly interested in looking at how household transmission may or may not have changed, um, from before the pandemic.

Michael 7:19

So what did you do in your study?

Sarah Cox 7:22

Yeah. So specifically, we were interested in estimating the secondary risk of flu virus transmission within households. So basically, that's after one household member is infected with flu, who we call the index case, what proportion of household contacts, so other members in their household, subsequently became infected, um, like usually within the week or so after. So what we did, uh, for this study, which was called the Cascadia Study, is that we, uh, basically followed a large group of healthy families over time. So this was a community-based prospective observational cohort study of households in the US, basically starting in June of twenty twenty-two and then all the way through March of twenty twenty-four. Um, and we enrolled families that lived in the metropolitan Seattle region, um, and that part of the study was led by the University of Washington, and then also families that lived in the metropolitan region of Portland, Oregon, um, which, uh, and that part of the study was led by Kaiser Permanente Center for Health Research. And all this, uh, work was funded by the CDC. I can talk more about sample collection and, like, kind of how the different aspects of the study worked in practicality

Michael 8:37

yeah, that'd be great

Sarah Cox 8:39

Okay. Yeah, so participants, um, in the study collected nasal swabs at least weekly, which were tested for a res-- a panel of respiratory viruses, including flu viruses. And one unique aspect of the study was that specimens were done entirely remotely. So swab kits were delivered to participants' homes by a courier, and they would self-swab and then return the specimens mailed back, uh, to the laboratory every week. And what was fun about this is each family member got to pick an animal that represented them in their household. So each week they would get a box, and it would have their animal, whether it was an octopus or a bear or something else, and, um, that helped to make sure that different family members didn't accidentally mix up their swabs and, um... 'cause, yeah, we have barcodes, but I think still making sure that, uh, Johnny got his swab done with the octopus and Mary got her swab done with the bear, um, uh, helped keep everything straight. And it was also a really, like, fun way to engage young kids. I think in the consenting process, we learned how much picking the animal mattered to the kid. Um, and so that was kind of fun. And later in the study, they got stickers with their animals, which was fun too. Um, but yeah, so that's kind of sample collection. And then in terms of lab testing, we did, uh, weekly swabs, um, that were analyzed using multiplex RT-qPCR tests, um, designed specifically to detect flu and then also other viruses like SARS-CoV-2 and RSV. Um, and then these tests would give us a cycle threshold value, basically the number of PCR cycles needed to detect the virus, which indicates how much of the virus was present. And then based on that value, we would know whether the sample was positive or negative. Um, and basically lower CT values mean higher viral load. And then we also, on participants that were symptomatic or that were positive for one of the initial viruses tested, we did a w-- broader multiplex panel that, um, had more details. So, this gave, nuances like whether it was flu H1N1 or H3N2 or flu B, um, and then also other pathogens like rhinovirus, um, for example

Michael 11:02

Did you have problems getting the kids to have the swabs? Do you know if some of them resisted their parents or, or family members from doing it?

Sarah Cox 11:11

Yeah. So again, this is like after kind of the initial bit of the pandemic, so I think a lot of kids were used to doing swabs, um, i- in their households and in schools. That being said, doing this every single week for a year, like over a year or two years, um, was hard, and I think towards the end of the study, uh, some kids decided they didn't wanna keep doing this anymore. They didn't wanna swab every week. Um, but for the most part, it was pretty easy. I think kids were used to it. We had, um, like interactive videos and diagrams and things to explain how to do it, and then obviously really young children, um, weren't swabbing themselves. Their parents were swabbing for them. So yeah. I think another thing that's unique is these were tiny swabs, so they were really small. I don't know if it's in the supplement of our paper, but you can look online of, about the Rhinostick swabs we used, and basically they're like, uh, if... when you look at them compared to like a pencil or something, they're way smaller than lots of the swabs you see, and I think that also kind of reduced fears and discomfort

Michael 12:15

Right. I was wondering as I was reading a paper whether some of the kids might have had better tests than the adults because someone else was doing it to them. Uh, whereas maybe an adult would be getting a, worse test if they did it themself. But I guess it's difficult to know the answer to that question, isn't it?

Sarah Cox 12:34

Yeah

Michael 12:37

So and then y- you made some phylogenetic trees with your results, is that right?

Sarah Cox 12:43

Yeah. So I think another unique aspect of our study is that we attempted whole genome sequencing on any of the specimens that were positive for flu and that had high enough viral load to help us get a deeper understanding of the transmission dynamics. Um, and so we used Nextstrain, which is a powerful open source platform to analyze the genomes and, um, place sequences in context with other known flu strains. Um, and so this part of the work was actually led by Dr. Amanda Casto. Um, and she... Yeah, she helped. I, I worked with her, but she mainly created those phylogenetic trees, um, which are basically like a family tree for viruses. And by seeing how viruses cluster on those trees, we can infer which viruses were closely related to one another. So yeah, I guess, for example, um, if viruses from two people in a household clustered, uh, closely together on a tree and differed only by a few genetic mutations, that would suggest that one likely infects the other in the household or what we call intra-household transmission. Um, but on the other hand, if two household members' viruses appear in totally different parts of the tree or belong to different genetic clades, like distinct lineage branches, that would flag that they probably caught flu from a different outside source

Michael 14:04

So what were your findings? What did, what

Sarah Cox 14:07

Yeah.

Michael 14:08

in the study?

Sarah Cox 14:10

Yeah, well, I think, high level, like big picture finding from the study is that over the two flu seasons, um, where we had weekly home testing and viral genome sequencing, we found that about one in 10 household contacts became infected, um, with transmission more likely when the first person infected had a high viral load. Um, and yeah, I think in terms of... We can go into more details about that, but in terms of high viral load, uh, that in the index case was strongly linked to more transmission. So, um, if the index initial sample had a cycle threshold value below the median, basically meaning they had a high viral load, the risk of household contact getting infected was about three times higher than if the index's viral load was lower, and this was a significant association. So the more virus the index shed, the more likely someone else in the household was to catch it, which I think fits the intuition that an individual who's shedding more virus is more contagious.

Michael 15:17

And how did that relate to asymptomatic versus symptomatic transmission?

Sarah Cox 15:22

Yeah. So, um, most of our index cases did have symptoms. I think it was just over 80%. And j- just comparing children and adults, children were less likely to be asymptomatic carriers than adults. So about 16% of pediatric index cases, um, were asymptomatic compared to, 28% of adult index cases were asymptomatic. And then in terms of onward spread, we observed probable household transmission more frequently in the index cases that were symptomatic versus those that were asymptomatic. And again, that was similar to what was seen in South Africa in that study Julia mentioned that was led by Cheryl Cohen. Um, but in our adjusted model, um, we also saw like, again, lower risk of household transmission for asymptomatic index cases, but this wasn't actually statistically significant, so it was like right on the cusp. So weak statistical evidence for it. But again, lots of studies have looked at this, and, of see different patterns and different things. I think it's hard to, hard to study

Michael 16:28

And did you find that there was a lower viral load in the asymptomatic group?

Sarah Cox 16:34

I can say viral load was similar between asymptomatic and symptomatic index cases, as well as vaccinated and unvaccinated index cases. So we really didn't see a big difference between those

Michael 16:48

And, was there a difference between intra-household transmission and transmission from outside the household?

Sarah Cox 16:56

Yeah. So we identified a few instances where two household members' viruses were kind of too different to have come from infecting one another. So we had a subset of 16 kind of index secondary pairs where we had sequence data, and, um, three out of the 16 pairs, so like just under 20%, had genetic data that was inconsistent with direct household transmission. So in those cases, the viruses were in different clades or kind of far apart on the phylogenetic tree, which I was talking about earlier, basically meaning that those secondary cases likely got infected from some outside contact around the same time, um, rather than the index case in the household. So kind of to put in practical terms with our limited available data, about 80% of the secondary cases within seven days truly looked like they were intra-household infections, whereas about 20% were probably due to outi- outside exposures happening in parallel. And, um, this tends to occur like, uh, ex, uh, things outside the household when community flu levels are high, so basically multiple household members might catch the virus independently in the same week from school or work, um, which can masquerade as household spread if you're only using timing data. So that was what was really unique about our study, is having the genomics. It was able to help us refine the picture a bit more. So more clusters were genuine within family transmission, but a notable minority were like false clusters or essentially what might be co-exposures or exposures from different people.

Michael 18:34

And did vaccination make much of a difference in your study?

Sarah Cox 18:38

So we had a highly vaccinated cohort of study participants. So I think when you think about the US or the world in general, like, uh, we had our participants, I think I wanna say over two, three-fourths of the study participants were annually vaccinated for flu, which is really high. So just take all of this like that in context with the study results. But yeah, I think most index cases were vaccinated, um, before their infection and among those, fifteen percent were asymptomatic versus twenty-nine percent of unvaccinated index cases who were symptomatic. And among household contacts, yeah, again, like seventy-six percent received annual flu vaccine before someone else in their household had, had flu. So lots of people had protection, and the coverage was similar across cases, index cases and household contacts, um, both with and without potential of secondary transmission. So we didn't see like major differences in terms of the transmission. I think another thing that's kind of interesting is we included flu vaccine, um, during the twenty-twenty-one to twenty-twenty-two respiratory virus season, so prior to the start of this study, in our risk factor analysis really as a proxy for health-conscious behaviors, um, to try to adjust for that. And we surprisingly found that this was significantly associated with an increased risk of secondary flu infection. Um, but we hypothesized that this association may just represent increased diligence in reporting symptoms and testing that led to increased likelihood of detecting any given flu infection in the household

Michael 20:19

Right. And the direction of causation there is very difficult to tease out, isn't it?

Sarah Cox 20:23

Very.

Michael 20:24

they're having increased symptoms because they had the flu vaccine or is there a confounder there? Yeah

Sarah Cox 20:30

Yeah. And we're actually separately right now working on an analysis looking at flu vaccine effectiveness, like from this study cohort. So hopefully to come out in the literature soon.

Michael 20:44

You don't mention this in this, in the paper, but I was wondering whether there was much match between your circulating strains in Washington during that period and the vaccine strain.

Sarah Cox 20:56

I don't off the top of my head. Um, but I do know that both of the study seasons that were part of the Cascadia study, we were seeing way more flu A than flu B. Um, and then it was in the first study year, mostly H3N2, so 2022 to 2023 respiratory virus season. And then after that, kind of like up until after February of 2023, then it kind of shifted to H1N1.

Michael 21:22

I, I wonder if we could dwell a little bit on, on the finding that children were the most likely index cases. Um, are there some public health implications for this? Could you make all children wear masks, or close all schools, or, or do something to, to try and sort of break that, transmission?

Sarah Cox 21:43

Yeah, I think it's really hard. Flu is a virus that's been around for a very long time. Um, I think we saw what happened when you have, um, lots of NPIs, like non-pharmaceutical interventions, during something like the COVID pandemic. Flu disappears, right? But I don't think that's practical for everyday life, um, especially for kids. So yeah, I, I mean, in our study, we found that children are often the first person in the household to get flu. So most of our index cases were children with a median age of eleven years. Um, which kind of reinforces how important children are in spreading flu in communities and families., And whereas like for our secondary cases in the household, they were generally older. And so this pattern of a younger index case infecting an older contact suggests that kids bring the virus home and transmit it to siblings or parents. prevention and treatment efforts focused on children will likely have the greatest effect on interrupting transmission of flu in household settings. So this might be prioritizing vaccination or hygiene in kids. Even if you can't stop flu, um, you could potentially prevent cascade of transmission within the home

Michael 22:59

I wonder if we could talk a little bit about the limitations of your work and, uh, maybe consider sort of how it can be generalized to other places. Are there any major limitations in the results?

Julia Bennett 23:13

So in terms of generalizability, the Cascadia study where the data for this analysis came from didn't include infants, under the age of six months or adults over fifty. And so our results may not be generalizable to those groups, which is important because those are the populations that also are at the highest risk for severe disease outcomes from flu. So that's one thing. And then we also didn't capture flu transmission outside of households, of course. So there might be different patterns observed in other settings where we know flu transmission occurs, so schools, daycares, other congregate living settings like nursing facilities. And we do know as well that patterns of respiratory virus transmission vary across different populations globally. And so, we would expect to see some differences in different geographic settings as well.

Michael 24:20

I guess you could have a parent who is over the age of 50 who would be excluded from your study, despite being in the

Sarah Cox 24:28

Yeah.

Michael 24:28

Is that right?

Sarah Cox 24:29

Yeah, which did happen. I think a lot of families, especially in the Seattle area, have parents that are older. So yeah, there were definitely instances where that happened. I think not as frequently, but definitely in some multi-generational households where it would've been nice to include grandparents or other people in the house. It's always hard when you're... our initial research question was around COVID-BE in the certain populations, and we're kind of expanding to do other analyses within the cohort study data that we had. So yeah

Michael 25:01

I know in the UK at least, and I'm sure it's true in the US, there were quite a lot of outbreaks in care homes, or, residential homes where elderly people live. So I guess we don't know if there's a lot of asymptomatic transmission in that, environment based on your study?

Julia Bennett 25:18

Yeah, definitely an important setting for respiratory virus transmission in the US as well, where we don't know as much about how transmission is occurring

Michael 25:30

We did touch a little bit earlier about the difficulty with sampling kids. Do you know anything about the, false negative data on the sampling technique you used? Is it possible you were missing some flu cases?

Julia Bennett 25:51

Of course it's possible. This, method of remote at-home swabbing has been used previously by the, the study team, um, starting back around twenty eighteen, twenty nineteen. So there has been some validation work to show that this remote at-home collection, you can get just as good sample quality as you would from, someone taking a swab for you in person. So it does seem to be quite comparable as well as have high sensitivity and specificity. Sarah, I'm not sure if there's anything else you'd like to add.

Sarah Cox 26:26

Yeah, I think also in the supplement of the paper, there may be more details on this which you can refer to, or definitely links to other papers where they've d-done some of the validity testing

Michael 26:38

I guess any community study is gonna be about weighing up the benefit of being able to have very frequent testing as opposed to coming into a healthcare facility and the barriers that come with that. So there's no easy solution to the, to these research questions

Sarah Cox 26:57

And I think in an ideal world, like as a researcher, we would want swabs even more frequently than weekly, right? But I think it's the balance of what can you ask families to do, how often can you get people to do these samples versus, like, detecting s- early symptom onset in a family, right, versus the detection in their tests.

Michael 27:16

We could talk a little bit about, what has come out of the study and what, what other research it's gonna lead to or already has led to maybe. You already mentioned some COVID work that's been done as well. Um, I wonder if you could share some of that with us

Sarah Cox 27:32

Yeah. So I think one of the first big papers that came out of this CASCADIA study was around COVID vaccine effectiveness, in children. And there's been a number of other household transmission papers. So I led an RSV household transmission paper that's, um, run very similarly, so it's kind of interesting to compare what's happening. I know we have a paper under review on SARS-CoV-2 household transmission. Um, so again, just nice 'cause it's all within the same population, kind of looking at differences across these different pathogens, what we may see. Um, there's also been some work on correlates of protection for RSV and SARS-CoV-2. There'll be work on some viral interference, like I alluded to before. There'll also be a flu VE paper, hopefully. So lots of interesting questions. I think this data set is super rich, and we'll continue to use it over the years to come. We did collect some serologic data, so we have blood samples, and I think we're working with other groups to test those. In the future, we could incorporate that into some of the analyses to better understand what's happening

Michael 28:39

Great. Well, we look forward to seeing some of those results. I'm sure they'll be interesting reading, and, uh, who knows whether they'll be different to flu.

Sarah Cox 28:48

Thanks for having us

28:51

And now we turn to rashes in immunocompromised individuals

Michael 28:58

I'm delighted to be joined today by Dr. Sarah Clifford and Dr. Naomi Boutil, who, are the authors of a paper in the Clinical Infectious Practice Journal, entitled Rash in an Immunocompromised Patient Born in the Philippines. Welcome to the podcast

Sarah 29:15

Thank you for having us

Naomi Bulteel 29:16

Hi

Michael 29:18

And we were just talking, before we started recording about how challenging these cases are to, to diagnose rashes in immunocompromised patients. So it's very, very difficult. So I'm excited to be talking about your case

Sarah 29:33

Yeah, it's a really interesting case, and it was certainly very, difficult to diagnose at the time.

Michael 29:39

I wonder whether, you could summarize the key points of the case

Naomi Bulteel 29:44

Uh, well, I could probably start 'cause he was someone that I was looking after, um, Sarah, who, donated her expertise and interest in dermatology, um, can fill in any of the gaps. So this was a gentleman who's, been diagnosed as living with HIV about eighteen months before this presentation with the rash, I believe. Has had a number of missed opportunities to make an earlier diagnosis. So he'd been seen with herpes opth- zoster ophthalmicus, um, weight loss and blood dyscrasias, but wasn't offered HIV testing and subsequently presented with quite profound weight loss and respiratory symptoms, at which point an HIV test was done, and he was diagnosed at quite a late stage of infection. and Part of his initial presentation, he was found to have disseminated Mycobacterium avium complex, so blood cultures positive, as was sputum cultures, and he'd been getting treatment for that. So he'd ha-had a bit of a torrid time of it. In fact, he'd had complications from rifabutin. He'd developed uveitis secondary to that. Um, he'd been started on antiretroviral therapy together with the anti-mycobacterial chemotherapy, and had had a, a reasonable, response to that, um, with a CD4 cell count of, over a hundred at this point that his anti-mycobacterial chemotherapy was stopped, and that was a year after his initial presentation and diagnosis. And I actually had just started back in Edinburgh and taken over the care of this gentleman from one of my previous colleagues, and I was asked to see him urgently in clinic because he was complaining of a worsening rash. And it transpired that this rash had developed about a month before the discontinuation of his anti-myto-mycobacterial chemotherapy. when he'd initially been seen by one of the registrars in clinic, it was really quite nonspecific, sort of almost like a maculopapular rash. They'd tried some emollients and didn't think very much of it, but discharged him with advice. And he'd got in touch to say that the rash had got a lot worse. and when I saw him, certainly the rash had become, a lot more florid than had been described by the registrar who'd initially seen him, more nodular changes compared to what previously desc- been described as kind of maculopapular. and it was a bit unclear to me what the cause of the rash was at that stage was, as you've highlighted, the difficulties in, um, often making these diagnoses, particularly in individuals immunocompromise. So we'd spoken with our dermatology colleagues at that stage, um, as is their want, recommended some steroid cream, worsening advice and a review to see if that settled things, which it didn't. And things kind of developed from there.

Sarah 32:24

I think as, Naomi says, it was-- there was an extremely broad differential at that point. And so we can go through. I then got involved when Naomi, admitted him to hospital, and we were still very unsure about what the possible diagnoses were started to work him up. We had a skin biopsy that was done by dermatology, that showed that he had acid-fast bacilli that hadn't grown. And because of the Mycobacterium avium, I think it was very reasonable that we were considering whether, you know, he was having recurrence of a, like a continuous form of Mycobacterium avium, um, or, you know, given how severely immunocompromised he was. Remind me, Naomi, it was his ha- CD4 count was maybe 10 or it was extremely low, wasn't it?

Naomi Bulteel 33:09

When he initially present- presented or at that

Sarah 33:12

At that stage, it was

Naomi Bulteel 33:15

So it had dropped to-- I mean, that's a good point to highlight. So he had had a CD4 cell count of over a hundred at the point that they'd stopped the anti-mycobacterial chemotherapy, but he actually hadn't had consistent immune restoration. So one of the things that we were considering at the point, and I think led to some of the diagnostic uncertainty, was the actual fact we'd stopped his anti-mycobacterial chemotherapy before we'd seen the sustained CD4 response. And as you'll know, classically, we tend to offer secondary prophylaxis until someone's had a CD4 cell count over a hundred for at least six months. So that was one of the anxieties was whether or not we'd stopped his chemotherapy too early. Um, so I think it wasn't so low, Sarah, when he presented that next time, but it was still below a hundred at that stage 'cause he'd only had the one over a hundred, and then when he re-presented with the wor-worsening rash, it had

Sarah 34:03

I guess with that picture, so I then went to examine him, and the rash had got substantially worse even then when he'd been seen, in clinic, and he had started to have fevers, he was looking quite unwell. And when I examined him, some of the larger lesions, did have reduced sensation. And with the acid-fast bacilli and the granulomatous changes on the pathology, and the history of being in the Philippines, we thought that we should definitely... And now him having systemic symptoms, we thought that we probably needed to urgently rule out leprosy, and all the other cultures had kind of already been sent off and were coming back negative, which really did help the diagnosis 'cause, know, things had already been sent off and were in progress and weren't growing, and we weren't getting any at that stage. So it led us more to thinking, actually, this could really be leprosy.

Michael 35:02

I'm struck as we're talking about this about ju- just how awful it must have been for this person. I mean, not only the long journey, uh, of treatment and complications, but, to, to have to deal with the, the complications then of leprosy. It, it must have been psychologically quite challenging for this person

Sarah 35:22

Yeah, he was certainly worried about it. Um, for me, actually, I was struck with how, I don't know if he'd actually heard of leprosy before, think that actually protected him to a certain degree, he obviously, in a lot of countries and cultures, there is a lot of stigma, and still a lot of stigma associated with it, to the point at which in Brazil it's not okay to call it leprosy, you have to call it Hansen's. Actually for him, I think he was protected by the fact that where, when h- where he'd grown up in the Philippines, there wasn't high number of cases and there wasn't such stigma associated with it. So I think when we gave him the diagnosis, it was more kind of the diagnosis that you would give to someone with any sort of mycobacterial infection. He was like, "Oh, that sounds, concerning." And he was worried about the duration of treatment and was it gonna get better, less so I felt, um, that he was suffering from the associated stigma of the disease

Naomi Bulteel 36:24

Yeah, I would completely agree 'cause that was something

Sarah 36:26

Worried about, yeah

Naomi Bulteel 36:27

we were conscious of when we were breaking the diagnosis and making sure he had support with that. But certainly, he didn't behave as if he considered it very stigmatized. I think his partner was sort of more aware at the time that we were giving the diagnosis,

Sarah 36:40

Yeah

Naomi Bulteel 36:40

But he's-- marvelous actually. He's coped really well with, what's been a really complicated course of treatment. Um,

Sarah 36:47

Yeah

Naomi Bulteel 36:48

but yeah, thankfully not too

Sarah 36:49

Yeah

Michael 36:52

And just in terms of how the diagnosis was made, i-in the end, what was the definitive test that, that confirmed that this was leprosy?

Naomi Bulteel 36:59

As Sarah had said, he'd had a biopsy done, um, prior to the, the subsequent presentation with sort of the fevers, the back pain, and the new numbness over the lesions. But it hadn't been specifically sent for, molecular testing. So we knew that there were acid-fast bacilli, but when he represented and, thankfully saw Sarah, who put it all together, and we arranged for the sample that had been tested locally, to be sent down to Great Ormond Street,

Sarah 37:25

PCR, And that isn't routine. I have to say we've had a few cases in our unit recently, and actually all of them have had, PCR molecular testing done, which has confirmed the diagnosis. But I think the guidelines routinely say that it's not offered. But I'd have to say our experience locally is that, they do tend to get the molecular testing obviously leprosy is not gonna grow but our pathologists are getting much more experience with it now. And so definitely since that case, I've had a couple of cases that have been flagged by the pathologist that actually this looks like leprosy because that would be usually how that would come up. The pathologist would see the granuloma and see that it was following the nerve fibers and see the acid fast bacilli and, and raise it as a concern. but it's obviously, extremely rare in the UK, and that was certainly our first case locally. And so there wasn't that kind of same experience

Naomi Bulteel 38:22

Yeah. He did then go on to have slit skin smears. One of the, national leprosy advisors came up to Scotland, but they were negative, in fact, although there was a concern about the, the test itself. So yeah, it was lucky that they did agree to do the molecular testing on the biopsy

38:37

And he developed a type two reaction. Is that right?

Sarah 38:41

He presented with a type two reaction. So I think when we diagnosed it, he was having a type two reaction. He had developed a lot more nodules. They were very erythematous. He had a high fever. so yeah, uh, he presented that

Michael 39:00

And are, are there groups which are more at risk of a type two reaction?

Sarah 39:05

Certainly not, with HIV, the coinfection. In fact, the most studies show that it's more likely to be a type 1 reaction and most-- and he had lepromatous leprosy, or borderline lepromatous. And he's very unusual. Well, there's been some varying data, but the largest case study in Brazil showed that they normally have paucibacillary and normally present with a type 1 reaction. So he's a quite a unique case

Michael 39:32

And is there a difference between the treatment for a type 1 versus a type 2 reaction?

Sarah 39:36

Not really. You'd use steroids largely. maybe in a type 2 you might go for thalidomide a bit sooner sometimes.

Michael 39:44

And do you think your case was more complex than, than some in the literature?

Naomi Bulteel 39:50

I mean, there's not a huge amount of, literature out there on co-infection with HIV and leprosy. As Sarah says, some of the biggest case theories seem to come from But there's not any suggestion that leprosy occurs more commonly in people living with HIV, which is, I think, why it wasn't on the initial differential, and that's something we can maybe talk about, that sort of diagnostic uncertainty. And then where there is the literature, as Sarah says, most people tend to present with a type one reaction. Um, and it is seen as an IRIS phenomenon, but usually within six months of starting antiretrovirals. So for our gentleman to present,, over a year into treatment with a type two reaction is quite unusual. And we've had some discussion about why that might be. One of the possibilities that we wonder about might have, affected the course of his presentation is the fact that he was receiving antibiotics that did have some activity against leprosy as part of his MAC treatment. Um, and then also the fact that, although he'd been started on antiretrovirals more than six months previously, he hadn't actually had particularly good immune reconstitution as well. So whether or not that affected it. But yeah, certainly quite a complex presentation and not one that's well described in the literature.

Sarah 40:56

only thing that has been commented on in literature that we are seeing is, people presenting with this immune reconstitution type syndrome after starting antiretroviral therapy in areas where there's, um, leprosy and HIV, that is starting to be the first kind of presentation. They usually get picked up once they've been started on antiretroviral therapy

Naomi Bulteel 41:21

Yeah, I was interested. I was reading a article on the cutaneous manifestations of, um, HIV, and within that it talked about kind of unmasking of leprosy, in the context of iris, which I thought was really

Sarah 41:34

Yeah

Michael 41:36

And y- you mentioned you've had some subsequent leprosy cases. I, I wonder whether this case has made you reflect on your own practice, and whether you would do things differently if this case came round again?

Naomi Bulteel 41:48

Sarah diagnoses everyone with leprosy now. It's certainly higher up our differential.

Sarah 41:54

it at most MDTs, yes. Yes, think of it a lot more, and it's given an... as a department much more experience. have to say, personally, I'm much more comfortable using thalidomide now. I have had a few patients on it, and it's worked really well. So that's my reflection on the case. I, um, feel much more comfortable using it, whereas initially, you know, nobody has experience in our area, of using thalidomide, apart from in hematology. Um, so be my reflection on it. I was wondering also, since that there's been some discussions about testing for rifampicin resistance, and you can do molecular testing for rifampicin resistance, and I wonder retrospectively if maybe we would have considered that. I don't know if actually it was available at the time, but I think it certainly is available now.

Naomi Bulteel 42:46

Yeah, I would agree. I think it's definitely something we consider more. We've talked about, the complexity of, diagnosing rashes in people living with HIV, particularly that with those with advanced HIV. And certainly, I think my focus at the time of seeing him was probably a bit too much on the fact that he had advanced HIV. So thinking about those opportunistic infections that we see more frequently in people living with HIV, thinking about the previous AIDS-defining diagnoses he'd had. The fact that we hadn't, classically continued any secondary prophylaxis for that was on the back of my mind. of the additional, non-infectious inflammatory, um, rashes and dermatoses that you can see in people living with HIV, drug reactions. It was kind of around that, and then not enough focus on the fact that he was from the Philippines, he'd had recent exposure there. So certainly for me, I think it's been really helpful sure that, you're not focusing in too narrowly and making sure that you're considering the same sort of epidemiological considerations that you would in, in others presenting with a rash. Sarah has been doing really good work with our dermatology team locally about making sure that when we're doing biopsies, we are making sure that we're getting samples for molecular testing as well. 'Cause oftentimes if we're not thinking about it, it requires trying to get those samples that have been formal and fixed and, um, extract molecular material from those which can be challenging or people having to go back for another biopsy, which obviously isn't the most patient-centered. So that's been really helpful for the pathway discussions locally. and then I would totally agree. I think retrospect, I would have considered thalidomide earlier, 'cause it was very difficult to wean this gentleman off steroids, um, and he had a few relapses of the reaction requiring uptitration of his steroids, and did re-- develop adrenal suppression, towards the end of his treatment. So I'm thankful to say the adrenals have recovered, and he's now off steroids. But, um, I do think we should have co-- thought about thalidomide earlier. There was that, I guess, anxiety about not being something that we're that familiar with the use of locally. Um, at one point, I think we were told that we might need to have him on low-molecular-weight heparin or sort of prophylaxis when he was on thalidomide. So it sounded like it was gonna be a bit more complicated, but certainly with the amount of, um, of the duration that he spent on steroids, I think it would have been something we should have considered earlier.

Michael 44:58

And we've touched on this a little bit, but, the diagnostic uncertainty,, of this case, is for a number of reasons. We've already talked about availability bias if you don't see the cases very often. But also HIV itself creates that diagnostic uncertainty, doesn't it?

Sarah 45:14

100%, and it could, you could list y- 20 possible diagnoses for the cause of this rash, and all are feasible, and all could be occurring at the same time. You know, it's really complicated when patients are immunocompromised. I think that combination of time, seeing how it progresses, sending the pathology and then making sure, um, as Naomi says, making sure you've got fresh v- and fixed tissue that can go So fresh tissue can go for molecular diagnostics, i- is just essential really.

Naomi Bulteel 45:48

I think there was probably a bit of confirmation bias as well in retrospect with the fact that, I was a little bit worried about, the MAC treatment and whether or not we discontinued that a bit too early. And then having a biopsy which came back showing AAFBs kind of led, that led to that confirmation bias. But just an open mind. Re-remembering Hickam's dictum.

Michael 46:13

One of my takeaways was just how little I know about the epidemiology of leprosy, and, I wonder whether we could touch a little bit about the specific case i-in the Philippines, and, a reminder about the epidemiology of leprosy

Sarah 46:25

Yeah. The Global Health Observatory, there's an interactive global desktop for the WHO, is, is basically my go-to for all things like this, and If you typed in, leprosy, it w- gives you for every country the prevalence and incidence of leprosy in that country. And so for the Philippines, it's, 29 cases per million, so it's not loads, and that's versus Brazil, which is about 129 per million. bear with me. That's probably not exact numbers, but that's roughly what we're looking at. And India. So India and Brazil are probably the countries that have the most cases worldwide. I probably shouldn't say 'cause we've had so few cases. I won't say where our cases of leprosy have been from, but, um, India and Brazil are certainly the most common, and the Philippines is less common, but it is present there

Michael 47:22

We'll put a link in the show notes so people can have a look for themself. I wonder if, finally we could maybe step back a bit and talk about the, more general approach to diagnosing rashes in patients living with HIV. Do you have a structure or an algorithm that you tend to use?

Sarah 47:41

I think I just always go with the clinical assessment and the biopsy findings and making sure that you don't narrow things down too much, like Naomi was saying. That it, you know, you always get a surprise. You always can look at the rash and think, "Oh, this looks exactly like this." And it just-- they present so differently when people are immunocompromised. I think you have to just keep a very open mind. And, then if you're, if you do have a bias towards a certain diagnosis and your results aren't supporting that, you have to, you know, think again and do another biopsy and more diagnostics. think I would just take into, you know, what the person's epidemiology is, so where they were born, and their exposures, as you always do in ID, and make a list of kind of the top ten that you think you def-- you know, are the most likely, and then correlate that with your culture and path and clinically. And we do have an MDT locally, which is really helpful, where there's a dermatologist and, um, pathologist, and we-- and I've taken a couple of cases to it. And that's a really nice, um, kind of group, um, because I obviously think much more about the infectious causes and don't have so much experience with non-infectious causes. So it... I find that really helpful f- to see it from the dermatologist perspective, um, that I'm not missing something non-infectious but important. And then there's also MDTs, like national MDTs, that are really helpful if you're not sure, or if you think that it could be, say, leishmaniasis. There's a leishmaniasis MDT,, if you think that diagnostically it looks like that you're not certain, um, and the tests aren't supporting it, you could always, look to see what MDTs are nationally to get more advice from specialists

Naomi Bulteel 49:31

Yeah, I would agree. I think the-- specifically to assessment of rash in people living with HIV, I think the immune status is obviously something that we need to take into consideration. So, both the current CD4 cell count, but if you've got the nadir CD4 cell count as well, that can sometimes increase the of various opportunistic infections or malignancies if they've had a very low nadir CD4 cell count. Um, things like previous AIDS defining conditions, previous malignancies, all of those things might factor into, what your likeliest differentials might be. But just as this case shows, you do need to think outside of the box 'cause the rash may be something that is not necessarily seen more frequently in people living with HIV. We're seeing inflammatory dermatoses. Um, with that dysregulated immune response, we also see, um, a lot of drug reactions. More so in, uh, people living with advanced, HIV who are starting medications. But, um, so there's just a,, whole range of differentials that you need to consider, which is why I think what Sarah's saying, you know, phone a friend, make sure you've got, um, a number of people around the table, um, and getting off sufficient tissue and sending it to the right

Sarah 50:37

Yeah.

Michael 50:38

Thank you for sharing your insights with us about this case and the broader challenges of diagnosis in patients living with HIV.

Naomi Bulteel 50:47

I was just gonna end on, what is the most important note that the individual in question is now doing really well off both the steroids and all anti-mycobacterial chemotherapy and just doing really well on antiretrovirals with, a good immune reconstitution. So

Sarah 51:00

Yeah

Naomi Bulteel 51:00

that's the most important thing, so I'm pleased to be able to report

Sarah 51:03

Definitely

Michael 51:04

Great. Th- thank you for that update. I know that you, you submit these papers and then they end up being published years after the submission, so it's good to have that update. Well, thank you both very much for coming on the podcast and sharing your insights with us

Sarah 51:18

Thank you. Thanks for inviting us.

Naomi Bulteel 51:20

Thanks

Sarah 51:20

Cheers.