Sara Dong & Arthur Jackson walk through a few recent papers they found interesting.

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Hi everyone.

Welcome to Febrile, a cultured podcast about all things infectious disease.

I am Sara Dong, a Med-Peds ID fellow and Arthur is back with me today for another Febrile Digest.

Hey Sara!

Thanks for having me again.

So we're going to do another literature review, like we did not too long ago and sort of like a clinical update of a couple of things that we found interesting and just wanted to share.

So I think I'll start us off.

I wanted to try, at least to do my best, to summarize what we know about these acute hepatitis cases that have been seen in children and have sort of gotten picked up in some of the news outlets, or if folks are on Twitter.

I will note that we're recording this on May 4th and it's going to get released in a week and a half or so from now, so there may be newer information since we record.

But the first report that was published was from the UK Health Security Agency from April 8.

And they put out a notice saying that they're investigating potential causes of an unusually high number of acute hepatitis cases of unknown etiology in children in Scotland, England, and Wales.

And then that was followed up, really the next week, on April 14th by, uh, another Rapid Communication.

This time from Eurosurveillance, and I'll put links to all these for anyone to look at.

Um, but this had a little bit more detail about the initial investigation for the first Scottish cases.

And around the time that they published in mid April, they had 13 cases from March and April.

The children were a median age of a little under four years old.

They all had vomiting, jaundice, and ALT numbers that were over 2000 and then their other workup had had been overall unrevealing.

Hepatitis A B, C, and E as well as COVID testing were negative.

And then there was a mixture of both negative and positive testing for Adenovirus.

So three of these children were evaluated for transplant and one actually received a successful liver transplant.

Uh, so at this point they were still hypothesizing infectious pathogen versus some sort of toxic exposure, but infection was already being favored due to some of these adenovirus tests that were positive.

Um, and then that was followed the next week by the WHO Multi- country Disease Outbreak News, uh, that summarized these initial clusters in Europe.

And at that point had compiled at least 169 cases, but a much broader, uh, age range than the prior two reports.

So anywhere from one month to 16 years old, but 10% of the patients required liver transplant, uh, which is a really high number.

And then adenovirus have been identified in a least 74 of the cases, which really prompted this to be one of the leading hypotheses.

And then to get us back, another recent report in MMWR from the end of April explained what they had seen in pediatric patients at the University of Alabama in Birmingham.

Had a similar story, severe acute hepatitis, otherwise immunocompetent children, a median age of two years old, and they had vomiting and diarrhea and ultimately signs of hepatic dysfunction.

It looked like the ALT, AST ranges were anywhere from 600 up to the 4000s, and they did find adenovirus viraemia based on PCR numbers without a clear alternate explanation for what was going on, such as other like Hepatitis A, B, and C or auto-immune causes, Wilson's, things like that.

And so it's interesting.

They did have information about the quantity of the viral load being anywhere from 1000 to 70,000 [copies/mL].

And this ended up being about nine children that were identified.

I think what was interesting though, is the liver biopsies don't actually show any specific viral inclusions, it sounds like, or clear immunohistochemical evidence of adenovirus, but again, children with acute liver failure and high high amounts of, I guess I should say, percentages of kids getting evaluated or ultimately transplanted.

So that was a whirlwind, but hopefully summarize, summarizes is kind of what we know so far and, and what the concern is, but I suspect we'll hopefully get more information in these coming weeks and months.

Yeah.

You did a great job there, putting all that together.

That's a lot of information.

I did talk really fast!.

Um, it's, I, I, I don't have a, kind of a, a real feeling as to where this is leading to, do you?

No and I think it's interesting because I mean, we know the adenovirus can make people quite sick and, or I guess I should say children and sort of immunocompromised hosts sick in certain circumstances, but it's unusual for them to have this profound liver failure.

And it's hard to know.

Maybe it's not adenovirus at all?

Exactly.

I've, I've, I've heard, I've heard arguments on all sides, Twitter, as you know, tells you one thing, then tells you the exact opposite in another thread.

And they, um, so as in I think anyone who claims to know for sure what's going to be the true outcome is ,eh, isn't to be taken too seriously.

Yeah, and I think it's just important for people to be aware so that if they have a case that doesn't quite have an explanation, that you figure out who's the right person to report it to like for us, you know, mechanisms of reporting it back to the CDC or whatever similar mechanism folks have local to them.

Yeah, it's great that the, um, this is one where COVID vaccine is not being highlighted as a, as a putative cause.

So I'm very glad to hear that.

Um, so will I go onto my next study?

So we were going to talk about the Landman, et al.

study.

It's a French multi-center trial that was published in Lancet HIV recently.

So they call it the QUATUOR trial, 59 sites in France.

They looked at four days on, three days off for HIV therapy.

This was really interesting.

They, um, they enrolled about 336 adults.

They, they had multiple baseline regimens.

They included protease inhibitor based regimens, and NNRTI, as well as integrase inhibitor regimens.

They looked at, um, a non-inferiority and they found non-inferiority, which was really interesting.

Um, obviously people when there is going to be a, this break in the mantra of "you must take your, your medicine every day", um, the concern then is, is it going to be in any concern for virological resistance?

They, they found that there was no signal of major virological resistance coming through in the intermittent arm compared to the, the, the arm that stayed on their therapy, um, 7 days, um, although they did find a numerically slightly higher amount in the intermittent arm.

So a larger study probably is needed to see whether that is something that, that comes through.

And this was a study that went on for 48 weeks, so like the equivalent of a year.

They followed their patients pretty much every three months.

And, um, and they, and they did a number of interesting kind of analyses including patient satisfaction, which has extremely high, um, acceptability extremely high.

Of course, the reason for doing this is to see whether or not you're, you're just wasting additional resources by giving it seven days in the week if you don't need to give it seven days of the week.

So the, they found there was an actual cost saving of 43%, which is huge if you're looking at that as a budgetary component.

They also looked at some of the other, um, potentially you might call them secondary markers, such as inflammatory markers.

The, they did not find any rise in things like ultra-sensitive CRP or the like.

And so that's reassuring to think that there isn't background inflammation that isn't being picked up at the, at the time of virological load measurement.

So it's a really interesting study.

And, um, it makes you think, is this going to change the way we practice in the future?

Obviously a lot of people are already switching to dual therapy rather than, um, triple therapy.

So this is a study looking at triple therapy in this intermittent regimen.

So could it be applied to dual therapy in the future?

And, uh, I suppose it's the question of how low can you go or or something along those lines?

It's it's not enough yet to change my practice.

But it is very interesting.

And, um, I, I think it looks like something that might end up changing practice as time goes on.

Yeah.

And it feels like a hard to remember schedule, but I think, even before us changing our practice, maybe it's just a good example or a way to sort of, for ourselves and to counsel our patients, that I don't know for those patients who are suppressed and they probably are missing doses here and there more than perhaps they tell us in clinic that maybe we can relax a little bit.

I, you know, I don't know if that's another way to think about it, particularly for patients who difficulty with adherence to the medication.

Yeah.

That's certainly another benefit of any rate.

Anyway, no question about it.

You can, you can lean on the data a little bit from that point of view.

Yeah.

So my next article is what I thought was a really cool study, uh, from Justesen and others in CID from earlier in April.

They combined population-based data about bacteremia and colorectal cancer and found a couple of bacterial species, primarily anaerobic gut bacteria, that were associated with an up to 20% colorectal cancer, or I'll probably say CRC, diagnosis risk within one year following their bacteremia.

So for context, I suspect many who are listening to Febrile know about the often tested link between colorectal cancer and Strep Bovis group bacteria, um particularly gallolyticus.

The relationship between cancer and Clostridium septicum bacteremia is also known, but the associations of other anaerobic bugs is, is a little less well known.

And so this was a population-based cohort study in about 2 million people where they had 45,000 bacteremia episodes with also 231,000 blood culture negative cases in Denmark.

And, uh, they folded this up against a Danish Colorectal Cancer registry and found a couple different organisms, in addition to the Strep Bovis or Clostridium, uh, the ones that I was going to pull out are primarily Bacteroides species.

So Bacteroides ovatus and B.uniformis as well as some Fusobacterium.

And these patients were actually at similar risk for cancer as items like Strep bovis.

So this leads to that question of what risk level should really prompt a colorectal cancer workup?

Is there a time or a threshold when you would ask for that evaluation and cases of bloodstream infections with certain anaerobic gut bugs.

And then, you know, I think the followup question to that as whether it actually translates into improvement in their morbidity.

Uh, so the registry didn't have data on pre-malignant or adenoma lesions.

It's a little bit harder to translate in to thinking about timing for the benefit of their workup, but you do wonder if we'll be able to use information like this, or even more details like the subspecies, to help us decide whether that workup would be indicated.

But then, you know, I think the sort of flip side of this, as you do wonder a little bit, if you perhaps have lost that window of opportunity by the time they have bacteremia, and that's a, it's hard to tell from this type of study, but I think just a cool perspective on something that's ID related that you can think about if you were to see patients with, um, something like these Bacteroides bloodstream infections.

And so I suspect a lot of these patients probably were already in a range where it would be indicated to have their colorectal cancer screening, but just something to think about to potentially push for appropriate screening and, or perhaps earlier screening, if they have some sort of unique risk factors or the story doesn't quite add up.

It's interesting to see just the once again, the integration of big data with medicine.

So there is an obviously being able to study 2 million people that are get data in that, in that scenario.

So, so my next study is a New England Journal paper, and it's really just kind of referring or talking about the, the tebipenem, which is the new oral carbapenem.

So it's from Ekberg et al, New England Journal recently.

And, um, they looked at, they were doing a non-inferiority study looking at complicated UTIs or pyelonephritis in admitted patients.

And they randomized them to either ertapenem or this new drug, which is an oral drug called, uh, tebipenem pivoxil hydrobromide.

No surprise that it was proven to be non-inferior.

So I'm, I'm not, I'm not going to go to huge details about the methods and the likes.

So it was a study looking at this oral regimen of 600 milligrams, three times a day, versus ertapenem one gram once a day.

And they found that there was similar cure rates, no difference.

And it's just really interesting that there is now a new oral carbapenem, which is, uh, certainly the first time we've seen this.

Um, the question is, is this something that can be moved into other clinical areas, such as pneumonia, such as other, um, extended or highly resistant organisms?

I was interested to see them talking that in the U S, of all of the admitted patients with complicated UTI or pyelonephritis, they find the 20% of them were ESBL and 33% were fluoroquinolone resistance.

So, um, there really is a huge issue with, with antimicrobial resistance, which we all know about.

And obviously the solution might lie, I won't say obviously, the solution may lie in developing new antibiotics and it's good to see new antibiotics coming.

Obviously the concern is whether or not there will be, if you have greater ease of access to antibiotics, are you going to lead in time to, um, increased resistance rates?

Unless that's a concern.

Yeah.

And I saw that the company Spero Therapeutics, it sounds like maybe they're deferring working on tebipenem further and restructuring reportedly because the FDA was potentially not going to approve tebipenem.

Um, so it's interesting, like wherever you are on the spectrum of being terrified of oral carbapenems or being excited to have another option, that I think in many ways, it's always a little bit disappointing to see things that antibiotic wise get sort of worked up and, and brought forward.

But, um, the company's losing interest and not pursuing them, uh, which I think regardless of where you are on that spectrum can probably be a little bit disappointing for us in ID.

Yeah.

And then ID, it's important to note that when a new antibiotic comes on, we're the first people to say, please don't prescribe this unless it's really needed.

So, um, we definitely.

The idea.

It is somewhat terrifying.

The idea of a, an oral carbapenem that is licensed and, um, and available to anyone to prescribe.

Yeah, well, speaking of stewardship, that was a great transition.

My next article it's a little bit of a combo of transplant ID and antimicrobial stewardship.

And I think many of us an ID are very acutely aware of the challenges that come with trying to balance our broad approach to transplant, or you could even say immunocompromised hosts in general and wanting to be good stewards or "stewies".

And so there was a paper by, uh, Dr.

So and others called Bring It On-- Top Five Anti-microbial Stewardship Challenges in Transplant ID and Practical Strategies to Address Them.

And this was in Anti-microbial Stewardship and Health Epi.

And so I thought this was a really cool, sort of like a summary paper.

And they took five examples of challenges that we see a lot and provided some strategies on how to approach the question and your multidisciplinary team.

And so the five that they selected were -- asymptomatic bacteriuria in renal transplant recipients, febrile neutropenia in hematopoietic stem cell transplant, antifungal prophylaxis in liver and lung transplant recipients, LVAD infections, and then C diff infection.

So I'm not gonna read those, but, uh, if it's a pretty quick read and there's a really great table one that actually summarizes everything altogether.

Um, so I'd recommend people check it out.

Yeah, I think it sounds really, really important and really difficult to, uh, to properly get a handle on.

So another one I was going to talk about is the OFID publication by Hillenbrand et al, about Candida and the eyes.

So I thought this is quite interesting for a few reasons.

There's always been the arguments raging between infectious diseases and ophthalmology as to whether or not it is indicated to get a, an ocular exam on every patient who has a candidemia.

As an ID doctor, I've always gone with the, with the line that yes, it is important and it is needed.

Um, I liked in their discussion, they kind of brought up the two questions saying, well, the, what you need is these two questions to be answered.

Is the incidence high enough of ocular complications of candidemia and then a really important one, will a change in management happen if there are ocular complications of candidemia.

And this is the second point is the one that has really been called into focus recently because the, um, since 2014, um, or sorry since 2016, the IDSA has been saying, um, that the primary treatment for candidemia should be echinocandins.

Echinocandins don't have ocular penetration.

So you can imagine that, um, that you can intuitively imagine that the, the, eye will be more vulnerable if you're treating with a non azole non-amphotericin regimen, um, in a, in a systemic candidal infection.

So this was a study.

It was a large retrospective review where they looked at 2014 until 2020, they identified 226 cases of candidemia and, um, and they found about a 23% overall ocular complications associated with the candidemia, of which 25% they felt were truly due to the candidemia or were candida specific.

What they found, which is more interesting, was that as time progressed, so pre 2016, it was around about 18%, and 2019, it was about 40%, 2020 of small numbers, it was about 60%.

So, so really and truly, they were feeling that they were seeing a, a greater increase in ocular complications with time.

So basically, it is suggesting that with the advent of echinocandins, um, you really do need to be more concerned about getting an ophthalmological review, the reason being that if you identify, um, an ocular problem associated with candidemia, you will need to change your regimen to either an azole based regimen or an amphotericin-based regimen to, to treat out the course.

I feel like this is a great summary of the questions really come up when, when you're faced with this in patients that are in the hospital and ever since the change in the ophthalmology guidelines suggesting against routine exams, I think it's a good, good excuse for all of us to take a look at what we, what we know and understand about endophthalmitis and thinking about this.

The, uh, one of the other points that they made was they were saying, well, if only a minority of them were Candida specific where these just background eye changes and they said they didn't really feel they were because those background eye changes worsened with times that they felt that they were Candida associated or worsened by the candidemia or something, but they, they, they, they really did feel it was clinically significant.

Yeah.

Yeah.

Well, my next one is another tie in back to actually a, a Febrile episode.

So I selected a paper from Dr.

Fitzpatrick and a couple others also from CID that looked at the information that we understand about the impact of maternal hyper immune globulin and valacyclovir on outcomes of CMV infection and pregnancy.

And so this is a review from some authors in Australia who basically summarize what we know about using these two therapies to prevent vertical transmission or to potentially reduce a sequelae of neonatal CMV infection.

You know, this is an area that we're still trying to understand.

There's definitely various observational studies that support the use of valacyclovir, if you can time it right in pregnancy, which is a challenge in and of itself.

And it's interesting because what we know about the use of CMV hyper immunoglobulin, uh, it wasn't supported as a preventative strategy in the two available randomized controlled trials that we have.

But, uh, there are several observational studies that were in contrast to that.

I actually posted this previously from the Febrile account when I saw it because it timed really well with our ongoing case-based episodes.

So hopefully folks are listening to those.

We're doing this Curious Congenital Conundrum series.

The episode for CMV from Drs.

Hermione Lyall and Nuria Sanchez Clemente.

It's number 37.

Dr.

Lyall does a really nice job summarizing these tools and thinking about the evidence for them in the context of this example case that we did, uh, for the episode.

So I think if people listened to the episode to think about CMV in pregnancy and newborns, and then also read this paper, it's a really great synergy and they'd work, work together.

And hopefully the Consult Notes and the website as well.

I think I've linked to all the majority of the papers that would be relevant, but it was just had good timing.

Yeah it sounds really good.

Uh, my last paper is the, um, is an editorial.

I just thought it was interesting and topical and, um, it was written by a written in the BMJ.

They don't give a name of an author.

So I wonder, is that the editor in chief or is it the, the board of editors have written as a group, but the it's talking about infectious diseases and war and their, their interrelatedness.

And, um, it's, it's specifically mentioning the Ukrainian war.

So, um, just to highlight some of the points that they make, they talk about the destroyed infrastructure from a health infrastructure, also from a transport infrastructure in terms of being able to get to and from hospitals, um, in terms of resource redirection to the war effort, rather than to, to healthcare.

They of course look at vaccine preventable diseases, especially measles outbreaks and polio outbreaks, they mentioned.

They talk about people on antiretrovirals and the insurance and disruption to their supply chain, TB, overcrowding, COVID and, uh, and the overcrowding happening both in the sights of the war, but also in, in refugee camps, um, where the displaced people have had to move.

They do reference wars in Afghanistan, Yemen, uh, Burma, but they, they do focus a lot on this Ukraine war.

And they're very brave in their final paragraph where they talk about how yes, it will be great if Ukraine can, can get out of this without the same destruction we're seeing everywhere else in the same association.

But in one way, they said, if that does happen, it will probably be an indictment of the West's approach to white wars versus non-white wars and wars in places where, where this color of people's skin is not, uh, Caucasian or white skin.

I thought it was very brave and very appropriate that they would, that they would call out and bring it into the, into the mainstream.

Yeah.

This piece made me think of how a lot of the, uh, Febrile guests who've come on the show, you know, we ask about, can you share a piece of culture or something that you think you'd recommend for the listeners and multiple people have brought suggestions for books or, or items that emphasize this connection between ID and history or world events or war.

And I think a lot of these are brought up in the context of reflecting on our journey with COVID, but I, I think the idea of creating an awareness of our past to learn, um, to learn from is important in various scenarios, and that includes conflict and war.

You know, I think the main message.

I totally agree with that our response to and decisions about both these world events, as well as our patients and infections, they don't exist in some sort of isolation from one another that they are fundamentally tied to one another.

Yeah.

And it's would say, um, it's amazing to see the same awful outcomes happening again and again and again and again.

So, um, it's, it's really important.

To be aware of it, but not just to be aware of it, but to try to use that knowledge, to change the outcome, hopefully.

Yeah.

Well, we did it, Arthur!

We got in right under 30 minutes.

We have like a minute left.

I so nice to have you back.

And uh, we'll keep, keep bringing these episodes and hopefully, you know, folks have suggestions for things that we should talk about.

They can always send it to us.

Absolutely!

Thank you so much for having me on again.

It's a real honor.

Thank you.

Thank you all for listening.

Like our other episodes, I'll put links to all the articles in our consult notes.