GNS Vietnam 2025: What do guidelines say about preventing allergy and managing CMPA?

Juan Jose Díaz MartÍn, MD, PhD

Narrator

Doctor Juan Jose Díaz MartÍn is a professor of pediatrics at the School of Medicine, Oviedo University and consultant in the Pediatric Gastroenterology and Nutrition section of the Asturias Central University Hospital. He is a full member of the European Society of Pediatric Gastroenterology, Hepatology and Nutrition, and coordinator of the Gastrointestinal Allergy Working Group of the Spanish Society of Pediatric Gastroenterology, Hepatology and Nutrition.

Professor Díaz Martín is a member of the Spanish Society of Microbiota, Probiotics and Prebiotics, and president of the Scientific Executive Committee of Congresses of the Spanish Association of Pediatrics. He has authored over 125 papers in national and international scientific journals and book chapters and has been an invited speaker at numerous congresses and specialty meetings. Additionally, he has presented more than 200 communications at national and international conferences.

Please welcome Doctor Díaz Martín.

Doctor Juan Jose Díaz Martin

Good morning. Again, thank you for being back after this great lecture of Professor Berni Canani. We're going to talk about clinics, we're going to talk about clinical practice. Just a quick show of hands. How many of you have visited a cow’s milk allergy infant in the last three months?

Not one of you. I cannot believe it. So, there's no allergy in southeastern Asia? Oh, amazing. So, we're going to talk about allergy anyway. Cow’s milk allergy is a really prevalent condition. It's not only prevalent but its prevalence is increasing. In the last decades all over the world, with this data from Argentina, you can see here in the last decades that prevalence is increasing.

But not only is it increasing in prevalence, but it's increasing in severity. It's one of the main causes of anaphylaxis fatalities. The ingestion of milk in children but also in adults. So that means that allergy, if not correctly treated, could last for several years. And the first thing we have to do when we try to get a diagnosis from cow’s milk allergy is to suspect the suspect allergy.

We have to think about it, because if we don't think about it, we will never get the correct diagnosis. And this is a problem. And as you can see in this chart, there is a big delay in the diagnosis of allergy in countries like the UK. 24 weeks - an infant with symptoms of allergy before getting a correct diagnosis.

So, we must suspect it. And usually, we suspect too much, we think too much about allergy, and over-diagnosis is a much bigger problem than under-diagnosis. But both of them, under diagnosis and over diagnosis, are a problem. They are putting the children in bad conditions; we have problems associated both with under- and over-diagnosis.

The risk of acute reactions, the micronutrient deficiency, failure to thrive, low quality of life, the economic burden for families and for countries that are paying for the treatment and the use of unnecessary medication. We need to get a correct diagnosis of all our infants with cow’s milk allergy. And to get the correct diagnosis we need to follow the guidelines.

That's the objectives of this lecture - to follow the guidelines. We are lucky that in the last two to three years, we have plenty of data on this. Documents provided by scientific societies like the EAACI and ESPGHAN. EAACI is allergy-oriented, and ESPGHAN is gastroenterology-oriented. So, let's take a look.

And just before going through these guidelines, we have to learn the wording of these guidelines. When these guidelines say that there is a strong recommendation on any practice, they are talking about a thing that most people should be offered as an intervention. That's a strong recommendation. But sometimes they say, okay, we don't give a recommendation for or against.

And that doesn’t mean there is no use for that recommendation, it means that different choices could be appropriated for different people, and clinicians could help those people to make these decisions. Okay, so take a moment to consider this - strong recommendation and no recommendation, for or against - these are wordings that appear frequently in these guidelines.

First of all, when you get a child or get an infant in your practice, you might you have to make any other decisions, you have to conduct an interview, you have to take a physical exam, and you have to follow the symptoms. Remember that cow’s milk allergy symptoms are nonspecific. They are the same symptoms that could be present in another type of infant.

Constipation, colic, runny nose - there are plenty of symptoms that could be related to allergy, and they're nonspecific. Can we get some time of diagnostic tests on these children? Let's look what the guidelines say. We can do specific IgE determinations, and if they are positive - by prick testing or even in blood - that doesn't mean that the child is allergic.

That means that there is a sensitization of the infant, but it doesn't enable a diagnosis of the disease. We can do patch testing, but it's not routinely recommended because it has very low reproducibility. I am a gastroenterologist, I like doing procedures. We can do endoscopy of these children, but it is nonspecific.

We can do IgG antibodies, but that's completely contraindicated. It's no use for IgG determination in the study of allergy, and other types of biomarkers like calprotectin, beta-defensin or cytokine determination are useful for research, but they are not useful for clinical practice. So, what we have for diagnosis, we have to do two things.

First of all is do what the guidelines call a ‘diagnostic elimination diet’ and then an ‘oral challenge’. So, the first thing we have to do is to take out cow milk proteins from the infant diet for 2 to 4 weeks. We have to see that symptoms disappear or improve. That's the first thing we have to know.

And of course, we are dealing with an infant that’s only food is milk. So, we have to provide a milk substitute. What are the suitable options that we can use for this type of diet? The guidelines, the ESPGHAN guidelines say that for this type of exclusion diet, extensively hydrolyzed formula is the first choice. And there are insufficient data to recommend between casein or whey.

We have, we can choose one or the other. If there is diarrhea or, severe malnutrition present, a lactose free formula is preferred. Amino acid-based formula should only be chosen for severe cases. Hydrolyzed rice formula could be also used as an alternative to extensively hydrolyzed formula, and soy formula should be only recommended if there is an economic problem or for cultural or palatability reasons.

Let's take a look at the picture. I want to show the first panel. An intact protein is what we get when we get when we give a child cow’s milk formula. This type of protein can be heated, and you get the partially hydrolyzed formula. Most children, more than half, 50% of the children with cow’s milk allergy, will react to a partially hydrolyzed formula.

So, it's not recommended. You cannot use a partially hydrolyzed formula for cow’s milk allergy treatment. Then these proteins can go through extensively hydrolyzation with enzymes, heat and so on. And you will get this type of formula, extensively hydrolyzed formula, where 95% of the peptides will be very small, below 1.5 kD.

95% of the allergic children will tolerate this type of formula, but still 5% of the children will react to this type of formula. There is, a small allergenicity still present, but these types of peptides will have an immunomodulatory effect. They will act on the immune system of the infant and might help them to tolerate afterwards. The only formula that will be tolerated by 100% of the cow’s milk allergy infants is amino acid-based formula.

There is no protein. Just the small blocks, the amino acids, that compounds the protein. This is tolerated by 100% of the children, no allergenicity, but no bioactive effects associated like in the extensively hydrolyzed formula. Okay, so if symptoms disappear, we're good. We're halfway there.

We didn't get the diagnosis, but if it doesn't improve, you must think that it might not be cow’s milk allergy. Remember that symptoms should improve - only in 5% of cases that children will, put the children on extensively hydrolyzed formula might not get well. 5% of the children will need to switch to another formula, but in most cases, it will not be a cow’s milk allergy.

So that's my first question. And remember this picture. This is something that you can see. Professor Canani just told us. You get a mama to your office, that is exclusively breastfeeding her infant. He's completely happy. He's growing well, he's gaining weight, but she shows you his diaper with blood in the stools. What will be your recommendation? To encourage to continue breastfeeding?

You say to the mom, ‘no, don't take cow's milk in your diet’ and you will visit the infant in one month. You say to the mom ‘your milk is not good, you have to stop breastfeeding’ and you change, you start the baby on extensively hydrolyzed formula. Or the same; ‘stop breastfeeding, but you will start a hydrolyzed rice formula’ or you can encourage breastfeeding, but you make no dietary restriction to the mom.

You say to the mom that she can continue on cow’s milk and follow up in one month? Please vote.

The first answer was right one year ago. That's science. That's medical science. It changes. Right? You were right. One year ago. You were right. And now you're wrong. Okay? That's why you come to this, meetings.

And you have to read the guidelines. The updated guidelines. That is what ESPGHAN says, you might be against this recommendation. In a previous guideline, that's all you know, if you suspect allergic proctocolitis, it was mandatory to remove cow’s milk proteins from the mom's diet. That's what you said.

Okay. But in these guidelines, the recommendation is if the child, the infant is exclusively breastfed and the symptoms are mild, you wait and see for one month. That's difficult, I know. The mom shows you there's blood in the diaper and you say ‘okay, let's wait for a month’. They always say, ‘you're crazy’ and they will move to another pediatrician!

I know it's difficult, but that's what the guidelines say. Okay, we can get the discussion on this. I completely agree, we can discuss. You want to know what the guidelines say? Remember the young man knows the rules, the old man knows the exceptions. Remember that. Anyway, this is what the guidelines say.

Remember that when symptoms disappear, we are only halfway there. We didn't make the diagnosis. To get the diagnosis, you should reintroduce the cow’s milk, because if not, you are halfway. You're not getting the diagnosis. First symptoms improve, then you should challenge. You should reintroduce the cow’s milk to the diet. Again, this is the same. You only have to avoid this challenge in severe cases.

Of course, if you have a severe FPIES or you get a child with anaphylaxis, please don't challenge these children, because you're putting them into a risk, right? And as I told you before, if symptoms do not improve too much, you might consider to switch. Let's say you started the child on extensively hydrolyzed formula, it didn’t improve so much, you can switch to a hydrolyzed rice formula or to an amino acid-based formula.

Okay? Remember that’s an option okay. Let's see what the guidelines say regarding long term treatment. You should put this child on a formula, you get the diagnosis, you should treat correctly. The GALEN guidelines say that the first choice is extensively hydrolyzed formula.

Second, choice amino acid-based formula. And there are considerations. They say that there is no recommendation for or against hydrolyzed rice formula. There's a recommendation against soy in infants younger than six months of age. And regarding probiotic supplemented formula, they say there's no recommendation for or against okay. Remember what I told you in the first slide. This doesn't mean that they are non-useful.

You should discuss this option with the families. Tiny differences in ESPGHAN guidelines. First choice is AAF, casein or whey hydrolyzed rice formula - at the same step as a first choice. Only in severe cases or in partial response can you use an amino acid-based formula and there are several considerations. Firstly, soy formula is used only for cultural reasons or palatability.

And regarding probiotic supplement formula, ESPGHAN says they don't have enough evidence to make a recommendation. The latest guidelines, the EAACI guidelines, the first choice is EHF, hydrolyzed whey formula. Second choice is elemental formula. Third choice; soy formula. And a strong consideration - you can either use, at the same level - extensively hydrolyzed formula without probiotics, but if you choose one with probiotics, it should contain LGG.

LGG supplemented formula is at the same level as other extensively hydrolyzed formula. It is the first guideline to say this recommendation. Regarding amino acid-based formulas as first choice, we have published this recommendation. Remember, it should be reserved for severe cases; if there is a nutritional impairment, anaphylaxis, severe FPIES, a severe eosinophilic esophagitis or, severe atopic dermatitis. You can choose, you can go first on amino acid-based formula.

How long should we put this infant on a diet? The recommendation is the more severe, the longer. For example, proctocolitis, maybe 3 to 6 months could be enough. If you get the FPIES, maybe you will need 18 to 2 years before you challenges these children, you check the tolerance. The general recommendation is, as a general rule, six months or 12 months of life, whatever it reaches first, for example, you get the diagnosis. At three months old, you can challenge at nine months. If you get the diagnosis in a seven-month-old, you make the challenge at 12 months of life, okay, six months of exclusion diet or 12 months of age. Whatever you reach first. What are not suitable options for treatment? Any of these are not indicated.

They are contraindicated in the treatment of cow’s milk allergy. Partially hydrolyzed formula, goat's milk formulas, or milk from other mammals like goat or sheep. The similarity of the proteins is close to 95%. So, you have really high risk of getting a severe reaction. And of course, the so-called vegetable “milks” - oat milk, rice milk, almond milk – they are not milks.

You cannot get milk from an almond. They are vegetable beverages. And they are suitable for older children, but you cannot feed an infant with this type of formula because you will get a high risk of undernutrition, a high risk of rickets - a high risk of several diseases. So please avoid these types of drinks.

Let's move into prevention and I will try to connect with what Professor Canani says. There are several factors that are implicated in the development of cow’s milk allergy.

But remember that we are dealing with a problem. We're not dealing with all types of allergies; we are dealing about cow’s milk allergy. The infant will receive milk in the first moment of life. And if mom decides not to breastfeed, this infant will receive cow’s milk in the first day of life. So, we have a little tiny space to initiate prevention.

Guidelines also talk about this issue. We have two important guidelines, the EAACI guidelines in 2021 and the ESPGHAN guidelines in 2024. So, is it primary prevention of cow’s milk allergy possible? Prevention is trying to avoid the appearance of the of the allergy. And maybe we get allergy in the first week of life. We have very, very short a window of time to, to get this prevention.

What do guidelines say? We can do biotics; prebiotics, probiotics, synbiotics in gestation or during pregnancy and in the first days, first weeks of life. We can also use vitamin D and fish oil during lactation and during pregnancy. The guidelines say that there is no recommendation for or against these nutritional supplements in the prevention of cow’s milk allergy.

Regarding breastfeeding, breastfeeding should be offered always because it offers multiple benefits. But regarding cow’s milk allergy prevention, you can get from a 3% decrease to a 2% increase.

So, you cannot recommend breastfeeding thinking on cow’s milk allergy prevention. You should recommend breastfeeding because of its multiple benefits. But regarding cow’s milk allergy prevention, you cannot recommend that. The timing of cow’s milk introduction is a matter of debate. EAACI guidelines, published in 2021, recommended to avoid supplementing infants with cow’s milk formula in breastfed infants in the first week of life (to avoid any type of milk in the first week of life), ESPGHAN says it's unclear that this recommendation could be made.

It's unclear to avoid this consumption of cow’s milk-based formula during early life reduces the risk of CMA. So, it's a matter of debate. We can get into this in the discussion afterwards. What is clear, and these are data from an important meta-analysis from Boyle, is that the use of partially hydrolyzed formula has no place in cow’s milk allergy prevention.

Even if it's closer to get an increased risk of allergy, you can see it is non-significant. That one is in the confidence interval. But it's closer to get an increased risk if you are using partially hydrolyzed formula to try to prevent cow’s milk allergy in an infant.

So, there's no use for partially hydrolyzed formula in CMA prevention. So, what can we do? Because all the things I told you about cow’s milk allergy prevention, it's really, low grade of recommendation. Well, connecting to what Professor Canani just said, maybe we should consider a more integrated approach, and we should start in pregnancy. We should start in pregnancy trying to get our moms with a healthy diet, with a mediterranean diet, or with a Vietnamese diet.

But, with natural foods - olive oil, fermented foods, trying to avoid obesity. Remember that if mom is obese before pregnancy, her microbiome will be dysbiotic and she will transmit this dysbiosis to her infant. So, remember about that. That's my last slide. These are my take home messages. To ensure an accurate diagnosis of cow’s milk allergy, it is essential to follow a diagnostic elimination diet of the appropriate duration, followed by a controlled reintroduction of cow’s milk proteins. Extensively hydrolyzed formula and hydrolyzed rice formula are the first therapeutic options recommended in current guidelines.

The only recommended probiotic in the guidelines is LGG. There is currently insufficient evidence to make strong recommendations for or against specific interventions to prevent cow’s milk allergy. And I leave you with this thought. Wisdom is knowing the right path to take, and integrity is taking it. Thank you so much.