DN Forum - January 2024

DAIRY NUTRITION FORUM

FORUM PUBLICATION FOR INDUSTRY & HEALTH PROFESSIONALS

Milk allergy - evaporating the myths, Dairy and Sleep condensing the facts from folklore to science Volume 16, Issue 1 | January 2024 Volume 13, Issue 2 | August 2021

Editorial Editorial

Traditionally, the management of food

Summary Points •

Food allergy involves an adverse

Summary immunologicalPoints response against

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a specific food protein, which is normally is this that specific Sleep is a harmless. modifiableItfactor immune response that makesto supports health, contributing food physiological allergy distinct from other both and psychological food hypersensitivities, such functions. Insufficient sleep isas a intolerances. Food allergy is broadly largely unrecognised public health classified as 1) IgE-mediated, 2) nonproblem globally.

The circadianorsystem IgE mediated (cell-mediated) 3) responds to many signals including mixed IgE-and cell-mediated. the light-dark cycle, food intake, Accurate diagnosis is key.

The drugs gold temperature, physical activity, standard for the diagnosis of a food and stress. allergy is a double blinded placebo controlled oral food challenge, Dietary components can act on but as this is resource heavy, an accurate neurotransmitters which influence clinical history with complimentary sleep, and likewise, sleep deprivation blood tests is the most common can influence metabolic hormones and approach. appetite. This relationship between CMPA rarely occurs in infants that food and the internal circadian clock are exclusively While it is is referred to as breastfed. chrononutrition. still one of the most common food Current indicates dairy allergiesresearch under the age of 3that years has positive effects Cow’s it only affects abouton 1%sleep. of children milk protein is rich tryptophan, under the age of 2in years and up to 90% ofiscases are resolved byserotonin 3-5 which a precursor for both years.

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• •

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•

For young children, unnecessary avoidance of common food allergens may be counterproductive and it is now advisedThese that the maternalplay and melatonin. hormones diet should notinbe restricted during important roles the regulation of pregnancy or breastfeeding, sleep.

Small amounts of melatonin as aoccur strategy for preventing the also naturally in cow’s milk. development of food allergy.

Fermented milk has been shown to The amount of cow’s milk protein significantly sleep efficiency. excreted in improve breastmilk is so small that Lactic acid bacteria present in any more than 99% of infants with fermented gammaCMPA aredairy likelyproduce to tolerate breastmilk aminobutyric acid, a neurotransmitter from a dairy-consuming mother. which associated with sleep.

Calcium Thus,isthere is a shift from moving these mothers to a dairywith free poor diet and inadequacy is associated continued breastfeeding is advised. sleep and therefore, the calcium The management in non-breastfed component of dairy may be another babies involves changing the infant factor which influences sleep. to extensively hydrolysed or amino acid-based formulas, with controlled The overall composition of milk also reintroduction. makes it a nutritious bed-time drink.

ItThe provides casein-rich milk ladder plays protein, a pivotalwhich role is encouraged as a pre-sleep intervention in safely reintroducing dairy foods strategy to increase muscle protein to achieve tolerance and resolution. synthesis overnight fordemonstrates both athletes Novel Irish research thatolder the management of IgEand people. mediated CMPA can be safely achieved in GP primary care, using the milk ladder.

allergy adopted a blanket approach Warm milk avoidance before going is a of absolute of to thebed food tradition that has been passed down allergen. However, over the last throughnew generations a practice decade, researchas has deepened to facilitate a restful night’s sleep. our understanding of the complex As with other bedtime routines, immune activity involved, and this has it may be the ritual itself that helps led to novel approaches to optimise to induce the anticipation of sleep. the management of food allergy.

Also, drinking milk before falling asleep could be associated with In this edition, explore memories the latest soothing, earlywe childhood scientific research in this area and that evoke calmness.

However, it is examine how exposure to potential also believed that naturally occurring components in milk support allergens at the rightcan time, and inthe process sleep. can facilitate an the rightof quantity, adaptive immune response.

In this edition of DN Forum, we introduce the science of sleep andpage explore on how On 4 ofthe thisresearch publication, we food interacts with sleep and the feature our updated ‘Common Dairy circadian system. We will focus Myths’ booklet. We hope you enjoy specifically on the scientific this edition and look forward to any evidence which examines the feedback orand comments you wish to role of milk dairy products. share: nutrition@ndc.ie We hope you enjoy this edition of DN Forum and look forward to any feedback or comments you wish to share: nutrition@ndc.ie

Dr Marianne Dr. MarianneWalsh Walsh Nutrition Manager The National Dairy Council (NDC) Council (NDC)

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DN Forum

Volume 16, Issue 1 | January 2024

An update on cow’s milk protein allergy INTRODUCTION A look back at the earliest suggestion of allergies, shows how these conditions impact individuals from all backgrounds and ethnicities.

Early texts outline the death of a pharaoh from a bee sting after he developed symptoms in keeping with anaphylaxis1, the first description of hay fever symptoms was published and investigated in the late 1900’s2, 3, and more specific to the topic of milk allergy was an observation by Hippocrates that cow’s milk could cause urticaria, diarrhoea, vomiting and failure to thrive. However, it is only more recently, since the 1990’s that a global rise in food allergies has been documented4.

Food allergies can be broadly classified into three categories based on their pathophysiology. These include IgE-mediated, non-IgE mediated (cell-mediated) and mixed IgE-and cell-mediated food allergy conditions5,6, outlined in Figure 1. Food allergy and sensitisation happen when an abnormal immune response initially occurs towards otherwise innocuous food proteins7,8. This should not be confused with reactions or intolerances that are not immune mediated; these could include metabolic disorders, toxic contaminants, or pharmacologically active food components9.

The prevalence of different food allergies varies by age and is region specific. In Ireland, the three most common food allergies in those younger than 3 years are eggs, cow’s milk, and peanuts in order of prevalence10, whereas in those older than 3 years, the most common food allergies are peanuts, tree nuts, kiwi, fish, and pulses/legumes11.

In addition, neonatal skin barrier dysfunction predicts food allergy at 2 years of age, supporting the concept of transcutaneous allergen sensitisation, even in infants who do not have atopic dermatitis10. It is now understood that non-transcutaneous, early exposure may be beneficial and it is advised that the maternal diet should not be restricted during pregnancy or breastfeeding as a strategy for preventing the development of food allergy12.

Avoidance of specific foods, particularly those commonly associated with food allergy has become more common with the introduction of alternatives, greater food choice and an evolving food landscape.

This can be motivated by taste preferences, health, ethics, food fads, or even misinformation. However, for young children, unnecessary avoidance of the certain food types at the wrong time in their lives can have a significant impact on their growth and development, and increase their risk of developing food allergies, which may impact their quality of life well into adulthood. This publication will focus on the differences between IgE- mediated and non-IgE mediated cow’s milk protein allergy (CMPA), the latest management strategies, prognosis, and some novel research in the area.

PRESENTATION AND DIAGNOSIS OF CMPA When considering the presentation of suspected CMPA it is important to delineate between the true allergies and the intolerances, and then distinguish between IgE- and non-IgEmediated CMPA. The diagnosis of food allergy can be life changing, bringing significant changes to households, including a significant psychological impact for the child and the family. Our clinical practice has observed that some of these children develop an almost a fearlike response to certain food groups because of previous reactions IgE-Mediated: • Oral allergy syndrome • Urticaria/angioedema • Anaphylaxis

Francois Meyer1,2

Deborah Griffin1

Dr. Juan Trujillo1,2,3

Melissa Meyer4

1. Department of Paediatrics, Cork University Hospital, Cork, Ireland 2. Department of Paediatrics and Child Health, University College Cork, Cork, Ireland 3. Cork University Hospital, Irish Centre for Maternal and Child Health Research (INFANT), HRB Clinical Research Facility Cork (CRF-C), Cork, Ireland.

4. Department of Sociology and Criminology, University College Cork, Cork, Ireland

or symptoms experienced from eating the food protein. This can be particularly tiresome and stressful to the parents, although the success of new treatment strategies offers hope for positive outcomes.

IgE-mediated CMPA IgE-mediated food allergies usually have an onset of symptoms within minutes to 2 hours after food consumption/exposure. The skin, respiratory system, gastrointestinal and cardiovascular system may be affected but symptoms usually include an urticarial rash or even flushing or redness of the skin in the face or neck. More severe symptoms can include anaphylaxis13. CMPA rarely occurs in those infants that are exclusively breastfed, especially in those who have never had any dairy containing solids or formula milk. A recent paper

by Kelly et al. suggests that formula top-up feeding in the initial neonatal period predisposes these infants to the development of IgEmediated CMPA, especially for those infants who are subsequently exclusively breastfed14.

Diagnosis is usually made by a detailed allergic history or using the 15-minute EATERS history model15, with complimentary tests in the form of specific skin prick testing (SPT) and food protein specific serum IgE tests. The gold standard for the diagnosis of a food allergy is a double blinded placebo controlled oral food challenge, but this is a resource heavy undertaking and cannot be done for each child presenting with a possible allergy, hence an accurate clinical history is relied upon. IgE-mediated food allergies carry the risk of causing an anaphylactic reaction, which is a severe, multi-systemic allergic reaction and management requires adrenaline administration. The symptoms are highly variable16.

A true IgE-mediated CMPA is usually seen in children under the age of 1 year. It does not develop in childhood or adolescence17. While it is still one of the most common food allergies under the age of 3 years, it only affects about 1% of children under the age of 2 years10.

Mixed IgE-/Cell-Mediated: • Atopic dermatitis • Eosinophilic gastroenteropathies (e.g. eosinophilic esophagitis)

Figure 1 - Three categories of food allergies, defined by Waserman et al.7

Caoimhe Cronin1,2,3

Non-IgE-mediated (cell-mediated): • Food protein-induced entrocolitis • Allergic proctocolitis • Food protein-induced enteropathy • Coeliac disease/dermatitis herpetiformis • Heiner syndrome (pulmonary hemosiderosis) • Cow’s milk protein-induced Iron deficiency anemia

Milk allergy - evaporating the myths, condensing the facts

Non-IgE mediated CMPA Non-IgE mediated CMPA presents a constellation of different symptoms. This is because there are variations within non-IgE mediated CMPA. These are shown in figure 1, alongside other types of non-milk food allergies. They include food protein-induced enterocolitis syndrome (FPIES), food protein-induced allergic proctocolitis (FPIAP), food protein-induced enteropathy and cow’s milk protein induced iron deficiency anaemia.

The pathophysiology of FPIES is poorly understood and therefore makes definitive diagnosis quite difficult at times. Cow’s milk remains a major trigger, but other food allergens can be responsible.

Acute FPIES can occur at any age18. It is usually characterised by repetitive vomiting 1-4 hours after suspected food ingestions, and it is not unusual for medical personnel to suspect sepsis, severe acute gastroenteritis, or anaphylaxis at first, before considering FPIES. Despite its severity, symptoms usually subside within 24 hours when the allergen has been excluded. Chronic FPIES is usually only reported in infants under four months of age, following cows milk or soy formula18. One should suspect chronic FPIES when an infant has intermittent or progressive watery diarrhoea and progressive vomiting following ingestion of the suspected food19.

Food protein-induced allergic proctocolitis (FPIAP), which is another form of the non-IgE mediated food allergy, primarily affects the distal colon. It is characterised by inflammatory changes in this area within the colon, secondary to an immune-mediated reaction to the specific food protein. The most common triggers are cow’s milk, egg and soy protein20. The exact mechanisms are poorly understood, and further research is needed in this area. The diagnosis and management of FPIAP are intertwined as one eliminates the suspected food protein, and if there is symptom resolution this usually confirms the diagnosis.

Prevalence of FPIAP differs depending on the data source. According to American figures the prevalence varies widely from 0.16% in healthy infants to an estimated 64% of infants who present with blood in their stools21, 22. True prevalence is difficult to establish23. The typical age of onset is within the first two months of life but could present as early as day 6 of life.

MANAGEMENT AND PROGNOSIS Following initial assessment with an allergist, management of both IgE and non-IgE mediated CMPA includes educating the parents, referral to a dietitian for a nutritional assessment and a clear plan for alternatives to cow’s milk. Breastfeeding should be encouraged where possible19. In a recent paper by Munblit et al, they found that the amount of cow’s milk protein excreted in breastmilk is so small that more than 99% of infants with any CMPA are likely to tolerate breastmilk from a dairy-consuming mother, without having an allergic reaction. Thus, there is a shift from moving these mothers to a dairy free diet and continued breastfeeding is advised24. The management in non-breastfed babies involves excluding cow’s milk protein, thus starting the formula fed infant on extensively hydrolysed formula or in certain cases, amino acid-based formulas.

It is important to assess the feeding history; our clinic has observed a rise in the initiation of hydrolysed or extensively hydrolysed formulas for newborn babies, purely based on parental preference, or very quickly changing to these formulas at the first onset of any feeding difficulties. It is also important to ask if the infant was ever breastfed and which formulas, if any, have been used. For an infant who is already taking some solids it is important to check what foods have been offered.

Unfortunately, certain food allergies predispose the individual to an increased risk of other food allergies, and in the case of CMPA, it is important to take a history, and if needed, do further testing to exclude egg17 and peanut25 as well.

Reintroduction of the protein at the right time and in the correct form is important. The milk ladder, shown in figure 2, plays a pivotal role in this reintroduction26, 27. The milk ladder is a tool that has been used in IgE-and non-IgE-mediated CMPA to induce a state of tolerance to the milk protein. It works by exposing the body to a certain amount of milk protein that has either been cooked (low down on the ladder) and eventually uncooked or raw protein (at the top of the ladder)28,29.

Previous research has shown that the usage of the milk ladder is an effective and safe way for the management of IgE-mediated CMPA,

www.ndc.ie | www.fhi.ie

with the goal to achieve tolerance30. As use of the milk ladder is not yet widely practiced, the effectiveness of using the Irish Food Allergy Network (IFAN) iMAP milk ladder, was recently explored in Ireland and the UK31, 32. The research indicated that high levels of maternal anxiety are associated with poorer progress31 but overall, cow’s milk can be successfully and safely reintroduced in a cautious low-dose exclusively home-based programme32.

THE MILK LADDER STEP

12 infant formula (powder) Sterilised milk/infant 11 formula (tetra packs) 10 Cheese Pasteurised milk/

STEP

STEP

9

Use hard cheese such as Cheddar

AMOUNT 1 pot yoghurt (125ml)

Yoghurt

STEP

8

Milk chocolate (milk chocolate buttons)

STEP

7

PURCHASED ½ mini pizza 1 mini pizza

Pizza

STEP

6

MAP

AMOUNT 100 mls 200 mls

AMOUNT 25g cheese

STEP

GUIDELINE

AMOUNT 100 mls 200 mls

Lasagne

STEP

5

Shepherds Pie

STEP

Scotch pancakes

4

AMOUNT 10g chocolate Milk chocolate buttons (½ bag or 35g) Choose a pizza that does not contain milk in the base

HOME-MADE ½ pizza 1 pizza

PURCHASED Lasagne (200g)

HOME-MADE 1 child’s portion

PURCHASED Shepherds Pie (200g)

HOME-MADE 1 child’s portion

PURCHASED 1 scotch pancake 3 scotch pancakes

HOME-MADE ½ scotch pancake 2 scotch pancakes

Use Scotch pancakes containing milk protein rather than whey powder

NOTE THAT SCOTCH PANCAKES CONTAIN LESS MILK THAN MUFFINS BUT THEY ARE BAKED FOR A MUCH SHORTER TIME

STEP

3

Mini muffins/ PURCHASED ½ muffin/cake (15g) cup cakes 1 muffin (30g)

STEP

2

Garibaldi PURCHASED HOME-MADE 1 biscuit biscuits/ ½ biscuit 2 biscuits Digestives 1 biscuit

STEP

Malted milk biscuits

1

PURCHASED 1 biscuit 2 biscuits

HOME-MADE ½ muffin 1 muffin

HOME-MADE ¼ biscuit ½ biscuit

Choose biscuits that contain milk

Use malted milk biscuits that contain milk powder rather than whey powder

Figure 2 - The Milk Ladder used by the Irish Food Allergy Network.35 While most children (between 69-83%) seem to tolerate baked cow’s milk there is still a risk of anaphylaxis in those with IgE-mediated allergy, and although small, the risk is still there26,33. In clinical practice all children who are still on a food ladder by the age of 3 years, need to carry adrenaline auto-injectors, and their family and care givers should be trained in their administration. Further research has shown that the introduction of baked cow’s milk, significantly increases oral tolerance rates to the raw form of the protein27.

Resolution of IgE-mediated CMPA can be expected in 75-90% of cases before the age of 5 years28. For non-IgE-mediated CMPA, FPIES requires complete avoidance until planned reintroduction via an oral food challenge after 12-24 months of avoidance. Prognosis is good, with most cases resolving by 3-5 years18. For FPIAP, about 20% of breastfed infants have spontaneous resolution, while nearly all infants become tolerant by between 1-3 years of age21.

LOOKING TO THE FUTURE: NOVEL IRISH RESEARCH A recent study conducted at University College Cork and Cork University Hospital, compared the outcome and safety of the milk reintroduction in IgE-mediated individuals in a primary care setting (GP led) compared to a tertiary care setting (specialist led)34. The findings correlate with those from a tertiary care environment. This demonstrates that the management of IgE-mediated CMPA can be safely achieved using the milk ladder in primary care.

This study is very encouraging as it shows potential to decreases the demand for intense follow-up in a tertiary care environment, it is important that these children are still referred to a specialist initially and that the needed education and training is given to families, but very reassuring that an IgE-mediated food allergy can confidently and safely be managed at home with ongoing guidance from dietitians and other medical professionals.

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Volume2 16, Issue 1 | January 2024 Volume 4 Volume 13, 13, Issue Issue 2 || August August 2021 2021 4

DN Forum

CONCLUSION

CMPA has the potential to have a major bio-psycho-social impact on the individual and their families, but new research offers hope for References obtaining tolerance and improved management in CMPA. Taking a good clinical history remains a key step in identifying the causative allergen.

The next step is to determine whether the reaction is IgE or non-IgE mediated in nature. IgE-mediated allergies usually need further testing, with avoidance of the suspected allergen. For most CMPA, the food protein can be reintroduced safely using the Milk Ladder. FPIES requires 1.

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