Gerry Lee, MD: Hello, everyone, and welcome to another episode of Allergy Talk, a roundup of the latest in the field of allergy and immunology by the American College of Allergy, Asthma, and Immunology. For today's episode, we're going to review another issue of Allergy Watch, a bi-monthly publication which provides research summaries to college members from the major journals of allergy and immunology.

 And you can catch archive issues of Allergy Watch through college.acaai.org/publications/allergywatch.

And not to forget, we do have an ACAAI community on the Doc Matter app where we can have conversations of all the articles we discuss today. Well, hello again. My name is Gerry Lee. I'm an Associate Professor at Emory University. I'm an Assistant Editor of Allergy Watch. And once again, I'm joined by the Editor in Chief of Allergy Watch, Dr. Stan Fineman.

Stan Fineman, MD: Thanks, Jerry. And, hello, everybody. I'm the current Editor in Chief of Allergy Watch. I'm a past president of the college, and I'm on the clinical faculty at Emory.

Gerry Lee, MD: And for the third chair, once again, we are joined by the Associate Editor of Allergy Watch, Dr. Shyam Joshi. Shyam, welcome back to Allergy Talk.

Shaym Joshi, MD: Thank you so much for having me back. I'm an Associate Professor of Medicine and Pediatrics at Oregon Health and Science University and the Associate Editor of Allergy Watch. I look forward to our discussion today.

Gerry Lee, MD: Okay, well, Stan, I think decades after the original hygiene hypothesis, we have actually sort of proven it. So what did we learn about it?

Stan Fineman, MD: Well, the hygiene hypothesis, as y'all know, and everybody listening probably already knows that in 1989, Stration was the one who proposed it, and published it in the British Medical Journal; that having older siblings in the home, exposure to animals and things like that, can reduce your risk for developing allergies.

And, you know, over the years, we still call it a hygiene hypothesis. We've tried to prove it over and over. And, this study, also is trying to prove it and show that it's valid. So the study and title, is Gut Microbiota Maturity Mediates the Protective Effect of Siblings on Food Allergy.

It was published in JACI in September of 2023, and the lead author is Goa. And, it's an interesting study because it's basically a study cohort from a infant study group called the Barwon Infant Study Group in Australia. And they monitored these children from 2010 through 2013, so over a three year period. So they had a sampling of 1,074 infants. And what they did is they collected fecal samples in the infants, when they were one month of age, six months of age, and at one year of age, and then they did allergy testing at a year of age, both skin prick testing and for food challenges to see if the change in the microbiota really impacted their developing food allergy.

And then of course they looked at the number of siblings in the home as well to see if that had anything to do with their change in their fecal microbiota or the development of allergies. And, what they found was that they looked at fecal, 16S RNA sequence data and was collected during the time points that we mentioned.

And then they calculated these Z scores based on the 16SR, RNA sequence variants, and the higher scores of these variants indicated more mature gut microbiota. The data was also collected, they looked at the presence of pets or exposure to livestock in the household or whether or not the children were delivered by C-section or for vaginal delivery and also breastfeeding and how long they breastfed and at what age they started introducing solid food because we all know some of those factors may be variables as well.

Overall, the higher microbia by age, the Z score at one year of age was associated with a reduced risk of food allergy. So the effect was not driven by the specific taxa of the microorganisms, they have a whole sheet here showing the variety of different microbiota that they measured. And they felt that having a higher number of siblings was associated with a higher Z score at one year of age.

Also, having a dog at home was also associated with a higher Z score, so the microbiota by age Z score for one year, was mediated 63 percent of the protective effect of having more siblings, and 27 percent of the protective effect of having the dog. So, having more siblings was more protective than having a dog in the home. The study findings suggest that the mechanism by which having an older sibling protects against food allergy may be the advanced maturation of infant gut microbiota.

And Jerry, as you commented in your comments, the birth cohort demonstrates that infants with more siblings have a more mature gut microbiota. And a decreased risk for food allergy. And the study provides further evidence supporting the influential 1989 study by Strachan.

Gerry Lee, MD: All I have to say is, I just think it's just so funny that people are looking at this thing. Well, maybe someone else has done another study and more specific like this, but this recall to the original 1989 study, I thought was just so interesting to put into practice. And obviously, we're always interested in how we can prevent allergic disease.

And really, exposure to adverse microorganisms, not infection per se, but exposure to adverse microorganisms is education. We teach our kids a lot of things. And teaching them about bacteria, absolutely, is a good lesson learned. It, certainly, if we think about the risk versus benefit, we continue to see benefits of children exposed to diverse environments.

My friend from college who grew up in upstate New York, used to say dirt don't hurt. I'm not sure. Oh, you know, immune deficient, maybe it's going to hurt. But most people who are immune competent, there's a lot of benefit to diverse microbial exposure. And this is just further evidence.

Shaym Joshi, MD: We see this pretty often in immigrants where they have no family history of allergies and they come over here and their child has severe eczema, has multiple food allergies, has asthma, has allergic rhinitis, and we kind of discuss that America's different. America has a different environment. I was just curious for Stan and Gerry, like, what do you tell these parents, especially the ones with really young ones, of how do you expose them to more stuff other than tell them to go play in the dirt? Do you have any specific tips on what they can do?

Stan Fineman, MD: I encourage them to play outside. I mean, that's the main thing. I mean, unfortunately, I think that's part of our problem is a lot of kids are homebound and they don't get outside and play. People ask me all the time, how come we're seeing so much more allergy than we did years ago?

And I talk about the hygiene hypothesis and I try to explain that our lifestyles have changed. We're certainly eating more processed type foods. Our microbiota has probably changed, but the fact that we are inside more, air conditioning, we probably use more antibiotics than we used to, more vaccines, kids don't get as sick. I mean, there's a whole variety of things. To answer your question, I just tell patients, let the kids play outside.

Gerry Lee, MD: I like reframing that intervention as education. So a lot of well meaning caregivers are doing these sorts of things for protective reasons. They want to protect their child, but at the same time, they want to educate their child. So I want to use positive language that we're really teaching our children to be active, healthy, independent, and exposed to a wide variety of experiences. And certainly we can educate their immune system and provide a wide variety of experiences. So I think that's just the key word I try to frame the conversation, that we're just trying to teach your children. Whether that has evidence or not, I'm not sure, but certainly, I, don't think there's significant harm either.

Babies are pretty tough. Most babies are pretty tough. Well, let's go to the next article. And I think this brings up a very important point about the reliability of skin testing in food allergy, because we do see patients right after reaction, and so the question is, is it the right time to skin test them?

So, Shaym, what did we find out?

Shaym Joshi, MD: Yeah, I think this is a super important topic. This article comes from Clinical and Experimental Allergy, which I think is one of the most underrated journals out there. It is just an absolute fantastic journal, coming out of England, and their articles are just tremendous, usually. So, it's one I definitely keep an eye on, on a month to month basis.

But this article is called, The Duration of Skin Prick Test Refractory Period Following Food Induced Allergic Reactions. And so what we know about this refractory period after a reaction is almost completely based off of previous studies in drug allergy and venom allergy. The thought is right after a reaction, you have this refractory period where the cutaneous mast cells are just not going to be as reactive.

And so you end up with this risk of false negatives. And the two studies this is really based off of is one was based off of perioperative drug testing and they found that only 60 percent of the patients had a positive skin test four days post reaction versus if you waited four to eight weeks, 88 percent had positive testing.

So 60 percent to 88 percent going from 4 days to 4 to 8 weeks afterwards, which is where that 4 to 6 weeks kind of comes from. The other study is in the venom world, and they found that 79 percent of patients had a positive skin prick or specific IgE testing one week after a systemic allergic reaction to venom.

And if you waited 4 to 6 weeks, that number approaches 100. So there does seem to be some form of refractory period immediately after a reaction. But the question is, and especially in these two studies that this is all based off of, what happens in between a few days and a month? A week or two or two later? Where are we with that? So this study tried to address that gap, but also specifically look at food allergies.

So this is a prospective study of 34 children in Canada that had allergies to either milk, egg, peanut, or hazelnut. And what they did is they took these patients and actually conducted a food challenge until they reacted, evaluated the severity of the reaction, so of these 34 kiddos, 79 percent of them had anaphylaxis.

Then what they did is they did skin prick testing 1 to 2 hours after the onset of symptoms, then they brought them back 1 to 2 weeks later, then they brought them back 30 to 40 days later. And they compared where the skin testing was in those three different time points. And so the results that they found was in those patients that, again, had a positive oral food challenge, when they did the testing one to two hours after the reaction, there was a 71 percent sensitivity. But when they brought them back at the one to two week mark, there was a 95 percent sensitivity. And at the 30 to 40 day mark, you're at 100 percent sensitivity. So the results or their discussion point was, yes, at one to two hours after the reaction, you are going to get some false negatives.

But, there's no difference between their baseline skin testing and testing 1 to 2 weeks after the reaction. And there's no difference between baseline and 30 to 40 days after reaction. So when we get these kids in clinic and there is a concern of what food was it, we don't want the kids to keep avoiding foods because then we're increasing the risk of reaction, especially those patients that are high risk with moderate to severe eczema.

So really trying to be able to drill down and really figure out what the culprit food is does have some urgency to it. And the study really shows that you don't have to wait four to six weeks after the reaction to really do the testing. You can do it one to two weeks later and get really good results out of that, and if there is still high suspicion and it's negative, you can always repeat it four to six weeks later.

There were some limitations to the study. It was a pretty small study. They actually had a pretty high dropout rate, to get all the time points in, and they only tested for those four foods, milk, egg, peanut, and hazelnut. I wouldn't anticipate that being significantly different, but I would love to see more data on other foods as well.

So I thought it was really interesting study and something that probably will change the way I practice, and instead of delaying skin testing for four to six weeks, if we're a week or two out, I would probably go ahead and just go ahead and skin test these kids.

Gerry Lee, MD: I'm really glad that you presented this article. I mean, clearly, that's the rule or the common wisdom. And this study absolutely challenges that. When patients come in, yeah, they get referred from the ED and that parent wants their kid evaluated ASAP or that adult patient wants to know ASAP. It would be terrible just to turn them away, and say, just come back in a month. So I certainly am reassured with data like this, and obviously it allows us to have all the advantage of skin testing, answers right at the point of care, address it right there. That's what patients love about skin testing, and to offer that, you really provides a wonderful service for our patients.

So thanks for presenting this article. Stan, what are your thoughts?

Stan Fineman, MD: Well, for years, we've always told our patients, with venom, especially, we can't test you. You've got to come back in a month. And we would specifically look at the time and everything else. So, this is definitely a game changer. And I think that this is evidence based and I think this is the data we need to help our patients and answer the questions as soon as possible and help them deal with it.

Nobody likes to wait, four weeks before they find an answer to a medical problem.

Gerry Lee, MD: Oh, absolutely. I completely agree. Okay, well let's review one more. And this one was interesting in the latest issue of Allergy Watch. This was reviewed by Samantha Knox, and the title of the article is Clinical and Immunological Phenotypes of Selective IgM Deficiency in Children Results from a Multicenter Study.

And this was published in Pediatric Allergy and Immunology in 23. So selective IgM deficiency. I think I've seen this a couple times, at least I've been referred them, and my first thought when I got these referrals is like, what's that? I'm being very honest with you, that's not something that literally got drilled into me in fellowship.

But definitely as attending, I got a couple of these referrals. Now, just some history, Selective IgM Deficiency was described in 1967 in a child with meningococcal meningitis. So that's pretty serious, but it actually took years for it to actually codified as a inborn error of immunity.

That was 2017. So imagine the decades it took for us to finally coin this as a disorder. Now, the definition of the disorder is having an IgM that's decreased in isolation. So we're going to say, GNA is normal, and it's going to be under two standard deviations for the reference range, or decrease 10%, of the values obtained from healthy controls of the same age.

Also they include an absolute value of under 20 milligrams per deciliter for pediatric errors. And of course, we're going to make sure we've excluded like CVID or inborn errors of immunity. So that's really the definition they're going with. And so this is a study that came out of this Italian collaborative.

It's called the Italian Primary Immunodeficiency Network, or IPINET, and basically they are pulling together their clinical experience with this specific disorder because it's actually pretty, uncommon. So, they were able to collect, through this collaborative, 48 patients. First thing that was very interesting, significant male predominance, 83 percent of the cohort was male, so more common in males.

At least in this cohort, the average age was 8.9, though it was the full range of pediatrics from one year to 18.9 years of age. Their onset of symptoms was 4.9 years of age, but they had this average delay of diagnosis of 3.8 years. Now, in terms of manifestations, selective IgM deficiency in this cohort was 67 percent were as infectious problems; 31 percent bronchitis, 27 percent pharyngitis, 27 percent otitis. The next most common manifestation, about half of them had some sort of allergic manifestations. Atopic dermatitis in 27%, allergic rhinitis in 25%, asthma in 8%, and then a few with, like, cow's milk protein allergy or hives. And then there was just a handful of patients with autoimmune manifestations.

A couple had antithyroid antibodies, one had alopecia, one had psoriasis, and one had HSP. No one had malignancy. Now, in this cohort, about 8 percent had family history, and when they looked at the actual IgM level, the mean level was 33 mg per deciliter with a range of 5 to 52, and honestly, there wasn't a lot of consistent immunologic abnormalities when they looked at other measures.

For example, only one patient had a total T cell count which was decreased, though there was 14 patients with decreased CD4 cells, 8 patients had decreased B cells, we only had 3 patients with decreased myogen stimulation, and then we had 10 patients with decreased switch memory B cells, so that was 20%, that was a little bit more common.

And only a few of the patients, now again, only 17 patients had pre and post titers, only a few of them had decreased responses to vaccines. Now, they also didn't have a lot of them to do long term follow up. Of the 16 patients, they did have long term follow up information. Only two of them had any other additional abnormalities.

For example, two of them eventually developed decreased IgA. So again, you always wonder in childhood, are you sort of heading towards CVID? Are you on your journey? We're not sure. They didn't have enough follow up to determine that. But, taken together, I think this just shows you that we can recognize this as a specific condition that has a NIH designation, has a IUIS designation, that we know what to monitor for, that we should be thinking about, not only ruling out other inborn errors of immunity, but bringing it to attention, the potential for respiratory infections and allergic manifestations.

And then, of course, monitor ranges. They really emphasize that even though it's not common, there can be decrease of other isotypes in the future. Clearly, this is an uncommon condition. Like I said, I've only seen this twice in my career. But each time it really did challenge me a little bit just because it's so uncommon. That natural history as well as what to tell the patient about prognosis is not fully defined, but I think this provides additional information in the sense that, we should recognize this as a disorder that deserves particular attention, workup, and continuing monitoring. And, Dr. Knox, who reviewed this article, also supported that. Really, again, with patients with isolated low IgM, we really should be looking at additional immunologic abnormalities just to make sure this is not the tip of the iceberg of something else.

Stan Fineman, MD: Jerry, I thought this was interesting because we see a delay in the diagnosis in most of the patients we have with immune deficiencies. Especially the humoral immune deficiencies, and, I probably missed this, in practice, I wouldn't be surprised.

I mean, I guess it just means you really need to keep checking your specific quantitative immunoglobulins completely. I mean, can't tell you how many times I've had referrals from somebody who just got an IgG level and, they said, well, looks like it's okay.

But, I think more now we're seeing more the quantitative immunoglobulins with the three different components. But, I did have a question about treatment, but, glad that you brought this up because I think it's something that it's probably under our radar screen.

Shaym Joshi, MD: I wonder if this is actually more common than we give it credit for. So because the manifestations, doesn't seem as severe as CVID or some of these other humoral immune deficiencies, we're probably missing a lot of these patients, and I'm not aware, and Gerry, you may be able to correct me, is, are there any population based evaluations of this condition on its own?

Because I'm wondering if there are a lot of people walking around asymptomatic, and this is just not a lab that's drawn frequently.

Gerry Lee, MD: I'm not aware of that, but I agree. I think, our antenna is always up for the things that we know. So we are always looking at the G, we're always looking at the A, but the M, we're like, okay, well, I'm not going to say that I'm, specifically looking at the M. I'm looking with M plus something else, right?

So I think this article is bringing our attention that we should be looking at the M specific as well. But you're right. Obviously, this is a very selected population. Broad based studies where we can characterize it in an unbiased fashion could probably maybe increase the magnitude of how this condition could be more common.

And again, some of these things we're seeing in healthier people too, recurrent, quote unquote, bronchitis or cough and allergic conditions. And so that association is something that, yeah, and we should just keep in our radar and just recognize that it potentially has some association with increased risk of infection.

Okay. Well, that was another three amazing articles that I think I learned a lot from. I learn a lot every time I listen to this podcast, and if you also are enjoying this collective learning experience, please rate our podcast on iTunes and give us any feedback. Suggestions for articles or other corrections you'd like to make.

 If you want to teach us something, you just email us at allergytalk one word@acaai.org Anyways. appreciate everyone's time, thank you for listening, and we'll catch you on the next episode. Have a good day.

 The ACAAI is presenting this podcast for educational purposes only.

It is not medical advice or intended to replace the judgment of a licensed physician. The college is not responsible for any claims related to the procedures, professionals, products, or methods discussed in the podcast, and it does not approve or endorse any products, professionals, services, or methods that might be referenced.

Today's speakers have the following disclosures. Drs. Lee and Fineman have nothing to disclose. Dr. Joshi has been an advisor for Genentech, Sanofi, Regeneron, Novartis, and Takeda, as a consultant in his executive role in Nectar Allergy.