What type of formula is available for infants with milk allergy

CMPA affects about 7% of formula-fed babies but only about % of exclusively breast-fed babies, who also tend to own milder reactions. Exclusive breast-feeding may also protect babies from developing an allergy to cow’s milk protein after they are weaned[4].

There are a number of diverse proteins in cows milk: there are five protein components in each of the casein and whey fractions of milk. A kid can be allergic to one or more components within either group.

CMPA is more likely in children who own other atopic conditions such as asthma, eczema or hay fever, or if shut family members own those conditions.

The presence of atopic eczema is a predictor for sensitisation to common food allergens. The earlier the eczema starts and the more severe it is, the higher the risk of food allergy[5].

If there are other food allergies, it is more likely that CMPA will persist into later childhood.

Some work has been done looking at the development of food allergies and whether this can be prevented by feeding infants at risk with hydrolysed formula. However, the results own so far not been clear[6, 7].


Lactose intolerance[20]

Many people confuse lactose intolerance with CMPA.

Lactose intolerance is an inability to digest lactose, due to an inadequate production of the digestive enzyme lactase.

It is generally a condition of older childhood and adulthood. Worldwide it is extremely common, although it is less prevalent in northern European races. It is unusual for babies and young children to be intolerant of lactose, although they do fairly commonly develop a transient lactose intolerance following an episode of gastroenteritis.

People with a lactose intolerance can often consume products such as yoghurt and cheese in which the lactose has been altered and they may be capable to own little amounts of milk without symptoms.

What type of formula is available for infants with milk allergy

They can generally tolerate lactose-free milk.

Clinical Editor’s comments (October )
Dr Hayley Willacy recommends the recently released international Milk Allergy in primary care guideline[1]. The guideline includes updated recommendations on presentation and recognition of cow’s milk allergy (CMA); diagnosis; management of mild-to-moderate confirmed non-IgE-mediated CMA within primary care; suspected severe non-IgE-mediated CMA and referral. A number of additional resources own been developed alongside the guideline to support parents and carers, including an initial factsheet for parents; a home reintroduction protocol to confirm diagnosis; a milk ladder and milk ladder recipes.

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  • Extensively hydrolysed formulas

  • Osborn DA, Sinn J; Formulas containing hydrolysed protein for prevention of allergy and food intolerance in infants.

    Cochrane Database Syst Rev. Oct 18(4):CD

  • Vandenplas Y, De Greef E, Devreker T; Treatment of Cow's Milk Protein Allergy.

    What type of formula is available for infants with milk allergy

    Pediatr Gastroenterol Hepatol Nutr. Mar17(1) doi: /pghn Epub Mar

  • Other mammalian milks (camel, mare, ass, goat and ewe)

  • Vandenplas Y; Lactose intolerance. Asia Pac J Clin Nutr. Suppl 1:S doi: /apjcns

  • Boyle RJ, Ierodiakonou D, Khan T, et al; Hydrolysed formula and risk of allergic or autoimmune disease: systematic review and meta-analysis. BMJ. Mar i doi: /bmj.i

  • Partially hydrolysed cows milk-based (eg, Karicare SensiKare [Nutricia], NAN HA [Nestlé])

  • Yeung JP, Kloda LA, McDevitt J, et al; Oral immunotherapy for milk allergy.

    Cochrane Database Syst Rev. Nov CD doi: /CDpub2.

  • Formulas

  • Working group. It comprised 11 experts representing 4 paediatric societies: Sociedad Espaola de Gastroenterologa, Hepatologa y Nutricin Peditrica (Spanish Society of Paediatric Gastroenterology, Hepatology and Nutrition, SEGHNP), Asociacin Espaola de Pediatra de Atencin Primaria (Spanish Association of Primary Care Paediatrics, AEPAP), Sociedad Espaola de Pediatra Extrahospitalaria y Atencin Primaria (Spanish Society of Outpatient and Primary Care Paediatrics, SEPEAP) and Sociedad Espaola de Inmunologa Clnica, Alergologa y Asma Peditrica (Spanish Society of Paediatric Clinical Immunology, Allergology and Asthma, SEICAP). Once the group agreed on the aspects that needed to be considered in the areas of clinical manifestations, diagnosis, treatment, followup and prevention of non-IgE CMPA, the list was distributed for review based on personal experience.

  • Goats milk-based formula

  • Dupont C, Hol J, Nieuwenhuis EE; An extensively hydrolysed casein-based formula for infants with cows' milk protein allergy: tolerance/hypo-allergenicity and growth catch-up.

    Br J Nutr. Apr (7) doi: /SX. Epub Mar

  • Leonard SA, Nowak-Wegrzyn AH; Baked Milk and Egg Diets for Milk and Egg Allergy Management. Immunol Allergy Clin North Am. Feb36(1) doi: /

  • Pepti-Junior (Nutricia)

  • The Milk Ladder; MAP Guideline

  • Vandenplas Y, Koletzko S, Isolauri E, et al; Guidelines for the diagnosis and management of cow's milk protein allergy in infants. Arch Dis Kid. Oct92(10)

  • Cows milk protein allergy in children; NICE CKS, June (UK access only)

  • Bloom KA, Huang FR, Bencharitiwong R, et al; Effect of heat treatment on milk and egg proteins allergenicity. Pediatr Allergy Immunol. Dec25(8) doi: /pai Epub Dec

  • Lactose-free cows milk-based (eg, Karicare De-Lact, Digestelact [Nutricia], S LF [Wyeth])

  • Amino acid formulas

  • Agostoni C, Terracciano L, Varin E, et al; The Nutritional Worth of Protein-hydrolyzed Formulae.

    Crit Rev Food Sci Nutr. (1) doi: /

  • Rice milk

  • Hill DJ, Hosking CS; Food allergy and atopic dermatitis in infancy: an epidemiologic study. Pediatr Allergy Immunol. Oct15(5)

  • Liao SL, Lai SH, Yeh KW, et al; Exclusive breastfeeding is associated with reduced cow's milk sensitization in early childhood. Pediatr Allergy Immunol. Aug25(5) doi: /pai

  • Host A, Halken S; Cow's milk allergy: where own we come from and where are we going? Endocr Metab Immune Disord Drug Targets. Mar14(1)

  • Other preparations

  • Boyano-Martinez T, Garcia-Ara C, Pedrosa M, et al; Accidental allergic reactions in children allergic to cow's milk proteins.

    J Allergy Clin Immunol. Apr(4) doi: / Epub Feb

  • Neocate (SHS)

  • Other preparations

  • Alfaré (Nestlé)

  • Amino acid formulas

  • A2 milk (A2 Australia)

  • Soy formulas

  • Venter C, Brown T, Meyer R, et al; Better recognition, diagnosis and management of non-IgE-mediated cow's milk allergy in infancy: iMAP-an international interpretation of the MAP (Milk Allergy in Primary Care) guideline. Clin Transl Allergy.

    Aug doi: /sy. eCollection

  • Literature search. We conducted 2 searches in PubMed/MEDLINE (Appendix B, online supplemental material, Figure S1), submitting the resulting list of articles to every the authors, who each selected the articles that were relevant for addressing specific questions.

  • EleCare (Abbott)

  • Miraglia Del Giudice M, D'Auria E, Peroni D, et al; Flavor, relative palatability and components of cow's milk hydrolysed formulas and amino acid-based formula. Ital J Pediatr. Jun doi: /s

  • Oat milk

  • Cows milk-based (including anti-regurgitation)

  • Ludman S, Shah N, Fox AT; Managing cows' milk allergy in children.

    BMJ. Sep f doi: /bmj.f

  • Drafting of the document. After reviewing the selected articles, the authors expressed their results as statements, basic concepts and recommendations that were later put to a vote by the whole group. The entire document can be consulted in the webpages of each of the societies that participated in its development.

Various baby formulas — such as soy, extensively hydrolysed and amino acid-based formula — that can be used to treat cows milk protein allergy are available in Australia. An analysis of Australian formula-prescribing practices indicated that they did not appear to be in line with authoritative statements and position papers or the guidelines of the Australian Pharmaceutical Benefits Advisory Committee (PBAC).1

In , the Committee on Nutrition of the American Academy of Pediatrics stated that soy formula was a suitable option for treating infants with cows milk protein allergy.2 In April , the Committee on Nutrition of the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) recommended that soy protein formulas should not be used in infants with cows milk protein allergy during the first 6 months of life, because few infants had been studied, and the reported rate of adverse reactions to soy protein was higher in infants under 6 months of age.

This committee also recommended that, when soy formula is used to treat cows milk protein allergy in infants over 6 months of age, tolerance to soy formula be established by clinical challenge.3

The PBAC guidelines once restricted the use of extensively hydrolysed formula to infants with combined intolerance to cows milk protein and soy protein. It also restricted the use of amino acid formula to infants with combined intolerance to cows milk protein, soy protein and extensively hydrolysed formula. In November , the PBAC accepted the advice of its Nutritional Products Working Party to ease the restrictions: the requirement to protest intolerance to soy protein before treating infants with these products was removed.

In , European proposals for treating cows milk protein allergy in formula-fed infants with extensively hydrolysed formula and amino acid formula were outlined in an algorithm.4

Consensus panel

In the light of these considerations, we constituted an Australian panel with representation from every states.

The panel was put together by the two lead authors (A S K and D J H) to represent practising paediatric clinicians. The panel was composed to include clinicians with expertise in paediatric allergy, gastroenterology, neonatology and general paediatrics.

There were two face-to-face meetings, in November  and June , and four telephone conferences.

What type of formula is available for infants with milk allergy

Meetings were co-chaired by A S K and D J H. Panel members (but not the co-chairs) were assigned individual tasks to review practice with regard to treatment as it related to specific clinical syndromes. After this material had been discussed by the panel, a position was reached. The number of panel members agreeing with the position (in view of the evidence presented) was recorded.

The panel considered the issues and reached a consensus on the indications for use of soy, extensively hydrolysed and amino acid formulas in the treatment of cows milk protein allergy under Australian conditions in general and paediatric practice.

As the selection of a formula depends on the syndrome to be treated, the panel has outlined the salient features of the diverse syndromes in breastfed and formula-fed infants. Selected references to the individual syndromes own been provided.

The spectrum of cows milk protein allergy

Cows milk protein allergy is defined as an immunologically mediated adverse reaction to cows milk protein. It affects about 2% of infants under 2 years of age.5 In this document, we use the term “allergy” in accordance with the World Allergy Organization’s definition (ie, allergy is a hypersensitivity reaction initiated by specific immunological mechanisms).6 Mechanisms may be IgE mediated or non-IgE mediated.

Cows milk protein allergy can also happen in exclusively breastfed infants.

Cows milk protein is often the first food protein ingested by formula-fed infants, and allergies present as a range of syndromes. A correct diagnosis is critical and will often depend on appropriate immunological and morphological investigations. In every cases, the diagnosis is confirmed by observing remission of the symptoms following removal of the protein. If the diagnosis remains uncertain, further confirmation should be obtained by observing relapse following challenge with cows milk protein. As some of the conditions may remit with time, rechallenge with cows milk protein after a period of avoidance is indicated in some cases.

A finish discussion of the diagnostic process and ongoing management4 falls exterior the scope of this guideline.

Consensus on the use of formulas

Three diverse types of formula (soy, extensively hydrolysed and amino acid) may be appropriate treatment in specific circumstances (Box 1). Some preparations are not recommended for treating cows milk protein allergy. The panel considers that there is no put for partially hydrolysed (known as HA) formulas nor other mammalian milks (such as goats milk)7 in treating cows milk protein allergy. The consensus recommendations for using baby formulas to treat allergy syndromes are shown in Box 2. Breastfeeding may be continued, and recommendations are provided for eliminating maternal intake of cows milk protein.

The panel believes the information provided is a guideline for most cases.

However, in severely affected infants or if the diagnosis is uncertain, it may be appropriate to start treatment with an extensively hydrolysed or amino acid-based formula which is not in accordance with this consensus.8 Such a case should be managed by a paediatrician with specific expertise in these disorders.

Cows milk protein allergy syndromes

The syndromes are classified as reactions which develop over minutes, hours or days. The recommendations include advice about the necessity for mothers to eliminate dietary intake of cows milk protein while breastfeeding. In some situations, failure to thrive affects the choice of formula. Recommendations provide for an alternative formula if treatment with the initial formula is not successful.

Immediate allergic reactions9

Cows milk protein allergy may manifest with erythema, angioedema, urticaria or vomiting.

Some infants may own contact urticaria where protein has touched the skin. Typically, there will be evidence of IgE sensitisation (positive skin prick test or an allergen-specific IgE antibody test [RAST] to cows milk). Symptoms develop within minutes of ingestion of little volumes of milk. Infants with cows milk protein allergy often own other food allergies, in specific to egg and peanut products.

Anaphylaxis is a severe immediate reaction with respiratory tract involvement and/or hypotension. Features of anaphylaxis may be hard to identify in infants. It may be suggested by coughing, wheezing, severe distress, floppiness or collapse.

Food protein-induced enterocolitis syndrome (FPIES)10

FPIES is an unusual disorder which generally presents with acute onset of repeated projectile vomiting, hypotonia, pallor and sometimes diarrhoea 1 to 3 hours after ingestion of cows milk protein.

FPIES may be mistaken for acute gastroenteritis, sepsis or intestinal obstruction, and multiple presentations before the diagnosis is established are not unusual. Typically, FPIES occurs at the first introduction of cows milk protein into the diet. It has not been reported in exclusively breastfed infants. FPIES may also be caused by other food proteins (eg, soy, wheat, rice and chicken). Despite the onset within hours of ingestion, the disorder is not IgE mediated.

Remission has generally occurred by the third year of life.

Atopic eczema11

Atopic eczema is a chronic, relapsing, pruritic inflammatory disease of the skin, generally associated with allergic sensitisation. Food allergy plays a role in some cases of eczema in children. It should particularly be considered in infants with moderate to severe eczema. It is generally associated with high levels of IgE antibodies to common foods (eg, milk, egg and peanut). Egg is the most frequently involved allergen, followed by cows milk protein. Although IgE antibodies own been implicated in most cases of cows milk protein-induced eczema, about 10% of cases are not IgE associated.

Gastrointestinal syndromes

Infants with cows milk protein allergy may present with vomiting, chronic diarrhoea, malabsorption and failure to thrive.

Most of the syndromes are not IgE associated and own other pathogenic immune mechanisms. Cows milk protein allergy is the most commonly identified food allergen sensitivity; however, in some cases, hypersensitivity to multiple food proteins is involved. Gastrointestinal biopsy may be required to define the disorder.

Gastro-oesophageal reflux disease (GORD)12

About 40% of infants referred for specialist management of GORD own allergy to cows milk protein. These allergic reactions are typically not IgE mediated. In these infants, intestinal biopsy commonly shows partial villous atrophy.

Allergic eosinophilic gastroenteritis13

Common features include weight loss and failure to thrive associated with postprandial vomiting, diarrhoea and, occasionally, blood loss.

In more severe cases, the infants may own iron deficiency anaemia and oedema due to hypoproteinaemia and protein-losing enteropathy.

Food protein-induced enteropathy14

Infants with allergic enteropathy due to cows milk protein may present with diarrhoea, failure to thrive, various degrees of vomiting and, sometimes, hypoproteinaemia and anaemia. Some cases own an associated soy allergy. The clinical signs of secondary lactose intolerance, including perianal excoriation from acidic stools, may be present.

Constipation15

Whether constipation is a clinical manifestation of cows milk protein allergy in infants and young children is controversial. Constipation is a common symptom in early childhood and, in some cases, resolves after removal of cows milk protein from the diet.

Cows milk protein-induced constipation is often associated with anal fissures and rectal eosinophilia.

Severe irritability (colic)16

The mechanisms of baby colic are poorly understood. Colic is not mediated by IgE, and the role of dietary factors is controversial. Persistent crying is a common problem that may affect about a third of young infants and gradually abates by 4 months of age without specific treatment in most cases. In infants with unremitting distress persisting beyond the typical colic period, an underlying organic cause may be more likely. Exclusion of cows milk protein helps in some cases, but these cannot be identified by allergy tests.

Food protein-induced proctocolitis17

Infants with allergic proctocolitis due to cows milk protein allergy generally present with mild diarrhoea and low-grade rectal bleeding.

If the baby is fully breastfed (breast milk colitis), symptoms may be caused by protein transferred via the breast milk. The bleeding is generally observed as stools containing mucus and flecks of blood rather than as candid rectal bleeding. Other systemic features (such as failure to thrive or anaemia) are generally absent, and the infants appear generally well. Rectal biopsies are not usual, but may be required to confirm the diagnosis in more severe or atypical cases.

Eosinophilic oesophagitis18

Eosinophilic oesophagitis is more often identified in older children than in infants, but may happen in both groups.

In infancy, typical symptoms are refusal of food, hard feeding, poor weight acquire and poor response to standard antireflux measures. Older children may present with dysphagia or episodes of impacted food bolus. Endoscopy is necessary to establish the diagnosis, which is based on eosinophilia of the upper and lower oesophagus. Eosinophil numbers are typically lower in infants with peptic reflux oesophagitis. Hypersensitivity to multiple foods may be seen in infants with eosinophilic oesophagitis. In older children and adults, aeroallergens may also be implicated.

Therapy may include hypoallergenic diets and swallowed steroid aerosol.

Other conditions associated with eosinophilic infiltration of the little and large bowel require specialist diagnosis and treatment, and may reply to elimination of cows milk protein.

1 Preparations available for treating cows milk protein allergy

Suitable

  • Soy formulas

  • Extensively hydrolysed formulas

    1. Pepti-Junior (Nutricia)

    2. Alfaré (Nestlé)

    3. Amino acid formulas

  • Amino acid formulas

    1. EleCare (Abbott)

    2. Neocate (SHS)

    Contraindicated or not recommended

  • Formulas

    1. Partially hydrolysed cows milk-based (eg, Karicare SensiKare [Nutricia], NAN HA [Nestlé])

    2. Goats milk-based formula

    3. Lactose-free cows milk-based (eg, Karicare De-Lact, Digestelact [Nutricia], S LF [Wyeth])

    4. Cows milk-based (including anti-regurgitation)

    5. Other preparations

  • Other preparations

    1. Oat milk

    2. Rice milk

    3. A2 milk (A2 Australia)

    4. Other mammalian milks (camel, mare, ass, goat and ewe)

    2 Formula feeding in syndromes associated with cows milk protein allergy*

    Syndrome

    Onset of reaction

    Maternal elimination of CMP if breastfeeding?

    Choice of formula


    NHMRC level of evidence‡

    Consensus panel agreement§

    First†

    Second (if first not tolerated)

    Third (if second not tolerated)


    Immediate reaction

    Immediate food allergy

    < 1 h

    Yes

    eHF (< 6 months)

    AAF

    II

    11/11

    Soy (> 6 months)

    eHF

    AAF


    Anaphylaxis

    < 1 h

    Yes

    AAF (followed by urgent consultation with paediatric allergist)

    IV

    11/11


    Food protein-induced enterocolitis syndrome

    1–3 h

    No

    eHF

    AAF

    IV

    10/11


    Delayed reaction


    Atopic eczema

    Hours to days

    Yes¶

    eHF (< 6 months or > 6 months with FTT)

    AAF

    IV

    11/11

    Soy (> 6 months, no FTT)

    eHF

    AAF


    Gastrointestinal syndromes, GORD, allergic eosinophilic gastroenteritis, food protein-induced enteropathy, constipation, severe irritability (colic)

    Hours to days

    Yes¶

    eHF (< 6 months or > 6 months with FTT)

    AAF

    I (severe irritability), III (GORD), IV (others)

    11/11

    Soy (> 6 months, no FTT)

    eHF

    AAF


    Food protein-induced proctocolitis

    11/11

    Formula-fed

    > 24 h

    eHF

    AAF

    IV

    Breastfed

    > 24 h

    Yes¶


    Eosinophilic oesophagitis in infants

    Days to weeks

    Yes

    AAF

    IV

    11/11


    Method for the development of the consensus document

    1. Literature search. We conducted 2 searches in PubMed/MEDLINE (Appendix B, online supplemental material, Figure S1), submitting the resulting list of articles to every the authors, who each selected the articles that were relevant for addressing specific questions.

    2. Working group. It comprised 11 experts representing 4 paediatric societies: Sociedad Espaola de Gastroenterologa, Hepatologa y Nutricin Peditrica (Spanish Society of Paediatric Gastroenterology, Hepatology and Nutrition, SEGHNP), Asociacin Espaola de Pediatra de Atencin Primaria (Spanish Association of Primary Care Paediatrics, AEPAP), Sociedad Espaola de Pediatra Extrahospitalaria y Atencin Primaria (Spanish Society of Outpatient and Primary Care Paediatrics, SEPEAP) and Sociedad Espaola de Inmunologa Clnica, Alergologa y Asma Peditrica (Spanish Society of Paediatric Clinical Immunology, Allergology and Asthma, SEICAP). Once the group agreed on the aspects that needed to be considered in the areas of clinical manifestations, diagnosis, treatment, followup and prevention of non-IgE CMPA, the list was distributed for review based on personal experience.

    3. Drafting of the document. After reviewing the selected articles, the authors expressed their results as statements, basic concepts and recommendations that were later put to a vote by the whole group. The entire document can be consulted in the webpages of each of the societies that participated in its development.

    Results and recommendations

    The term allergy refers exclusively to adverse reactions involving one or several immune mechanismsproven or highly suspectedand must be distinguished from reactions due to enzymatic, toxic or pharmacological mechanisms3,13 (Appendix B, online supplemental material, Figure S2). From a clinical standpoint, reactions mediated by IgE are characterised by the acute onset of a predominantly cutaneous or respiratory response associated to the presence of specific IgE antibodies. Reactions that are not mediated by IgE generally result from cellular immune responses, although in most cases the involvement of an immune mechanism cannot be proven.

    The only tools available for diagnosis of non-IgE CMPA are a detailed history and elimination of CMP from the diet followed by an oral challenge.1416 The first lays the foundation to suspect the presence of allergy, while the second is necessary to confirm the diagnosis.

    The delayed-onset symptoms are predominantly gastrointestinal, and they may present as any of these three syndromes: food protein-induced allergic proctocolitis, food protein-induced enteropathy and food protein induced enterocolitis syndrome (FPIES)17 (Appendix B, online supplemental material, Table S1). International consensus guidelines for the management of the latter own been published recently9 (Table 1). There are no specific diagnostic criteria for the other two, which must be diagnosed based on the clinical presentation (Table 2). Furthermore, non-IgE CMPA may mimic gastrointestinal disorders that are frequent in this age group, such as gastro-oesophageal reflux (GOR), baby colic and constipation.1721 The presence of a family history of atopy, involvement of several systems (gastrointestinal, cutaneous, respiratory manifestations) and absence of improvement with customary treatment suggests the presence of non-IgE CMPA in these patients.15,16,20,21

    When CMPA is suspected in a young kid based on the clinical history, CMP should be eliminated from the diet. Elimination leads to improvement and resolution of symptoms in a variable period of time, which may be of 1 to 5 days in acute forms (acute FPIES, vomiting), 12 weeks in cases of eczema or rectal bleeding, and up to 24 weeks in patients with constipation, diarrhoea and/or growth faltering.22 The CMP-free diet is to be maintained until symptoms resolve fully, and should not be prolonged past 6 weeks without confirmation of the diagnosis by means of an oral challenge. Not performing the challenge should only be considered in patients in whom repeated exposure is deemed too risky due to the severity of the initial reaction.

    In cases manifesting with proctocolitis, disorders such as GOR, constipation or colic, the symptoms resulting from reintroduction of CMP are generally mild and easily managed at the outpatient level, so the challenge can be performed at home under the supervision of a paediatrician (Table 3). If there is suspicion of an IgE mechanism (onset of symptoms within 2 hours of ingestion and/or development of cutaneous and respiratory symptoms associated with IgE-mediated reactions), severe atopic dermatitis, or moderate-to severe FPIES or enteropathy, reintroduction of CMP may involve a considerable risk, and should therefore be performed in the hospital (Appendix B, Table 4 and online supplemental material, Table S2) (Fig. 1).

    The oral challenge is interpreted based on clinical features, that is, the resurgence of symptoms, although these can take 1 to 2 weeks to develop (or 24 weeks in cases manifesting with altered intestinal function or eczema) or not be sufficiently pronounced in the initial days when the intake of CMP is lower. For this reason, observation in uncertain cases should be maintained for at least 4 weeks after reintroducing CMP in the diet. The Cow's Milk-related Symptom Score may be helpful in the evaluation of mild forms with symptoms similar to those of functional disorders.20,21

    The treatment of non-IgE-mediated CMP consists in the elimination of CMP from the diet. In exclusively-breasted infants, maintenance of breastfeeding must be prioritised, having the mom follow a CMP-free diet. Persistence of symptoms despite elimination from the maternal diet may be due to sensitisation to other foods (mainly soy and egg), whose exclusion should be considered, too. If the onset of symptoms is associated with the initiation of complementary feeding with formula or dairy products, exclusion of CMP from the mother's diet is not considered necessary.23,24

    Different formulas approved for treatment of infants with CMPA are currently available. Among these, extensively hydrolysed formulas (EHFs) based on casein and/or whey CMP are considered the first choice.211,25,26 istration of EHFs enriched with medium chain triglycerides should be considered in infants with growth faltering, including formulas containing lactose if lactose intolerance is not suspected. Although several studies published in recent years found a positive impact of formulas supplemented with probiotics in the development of tolerance,2729 further research is required to confirm this association.

    In children that refuse or cannot tolerate EHFs or families following a vegan diet, hydrolysed rice protein formulas own been proven efficacious and safe.211,30 The use of soy-based formulas is not recommended in infants aged less than 6 months.2 In severe cases with significant growth faltering or with rectal bleeding associated with haemodynamic instability, elemental formulas based on free amino acids are the first line of treatment.31

    There is a high probability that hydrolysed formulas and milks or formulas based on the milk of other mammals (sheep, goat, buffalo) will not be tolerated by children with CMPA.211 Plant-based drinks made with soy, rice, oat, quinoa, tiger nut or almond are of little nutritional worth and own low protein and energy contents, unlike plant-based baby formulas. These plant-based milks should never be given as a replacement for cow's milk, although they may be given as part of a varied diet to children aged more than 2 years.2,6,31

    We must remember that mothers and infants with a CMP-free diet are at risk of dietary vitamin D and calcium deficiency. It is recommended that mothers get supplementation for both. Infants will be given vitamin D, and calcium supplementation will be considered in case of insufficient dietary intake.15,32,33

    Frequently Asked Questions about Food Protein-Induced Enterocolitis Syndrome (FPIES)

    What are Some Common FPIES Triggers?

    The most common FPIES triggers are traditional first foods, such as dairy and soy.

    What type of formula is available for infants with milk allergy

    Other common triggers are rice, oat, barley, green beans, peas, sweet potatoes, squash, chicken and turkey. A reaction to one common food does not mean that every of the common foods will be an issue, but patients are often advised to proceed with caution with those foods. Note that while the above foods are the most prevalent, they are not exclusive triggers. Any food has the potential to trigger an FPIES reaction. Even trace amounts can cause a reaction.

    How is FPIES Diagnosed?

    FPIES is hard to diagnose, unless the reaction has happened more than once, as it is diagnosed by symptom presentation.

    Typically, foods that trigger FPIES reactions are negative with standard skin and blood allergy tests (SPT, RAST) because they glance for IgE-mediated responses. However, as stated before, FPIES is not IgE-mediated.

    Atopy patch testing (APT) is being studied for its effectiveness in diagnosing FPIES, as well as predicting if the problem food is no longer a trigger. Thus, the outcome of APT may determine if the kid is a potential candidate for an oral food challenge (OFC). APT involves placing the trigger food in a metal cap, which is left on the skin for 48 hours.

    The skin is then watched for symptoms in the following days after removal. Please consult your child’s doctor to discuss if APT is indicated in your situation.

    How Do You Care for a Kid With FPIES?

    Treatment varies, depending on the patient and his/her specific reactions. Often, infants who own reacted to both dairy and soy formulas will be placed on hypoallergenic or elemental formula. Some children do well breastfeeding. Other children who own fewer triggers may just strictly avoid the offending food(s).

    New foods are generally introduced extremely slowly, one food at a time, for an extended period of time per food.

    Some doctors recommend trialing a single food for up to three weeks before introducing another.

    Because it’s a rare, but serious condition, in the event of an emergency, it is vital to get the correct treatment. Some doctors provide their patients with a letter containing a brief description of FPIES and its proper treatment. In the event of a reaction, this letter can be taken to the ER with the child.

    Does FPIES Require Epinephrine?

    Not generally, because epinephrine reverses IgE-mediated symptoms, and FPIES is not IgE-mediated. Based on the patient’s history, some doctors might prescribe epinephrine to reverse specific symptoms of shock (e.g., low blood pressure).

    However, this is only prescribed in specific cases.

    How Do You Treat an FPIES Reaction?

    Always follow your doctor’s emergency plan pertaining to your specific situation. Rapid dehydration and shock are medical emergencies. If your kid is experiencing symptoms of FPIES or shock, immediately contact your local emergency services (). If you are uncertain if your kid is in need of emergency services, contact or your physician for guidance. The most critical treatment during an FPIES reaction is intravenous (IV) fluids, because of the risk and prevalence of dehydration. Children experiencing more severe symptoms may also need steroids and in-hospital monitoring.

    Mild reactions may be capable to be treated at home with oral electrolyte re-hydration (e.g., Pedialyte®).

    What Does FPIES Stand For?

    FPIES is Food Protein-Induced Enterocolitis Syndrome. It is commonly pronounced «F-Pies», as in «apple pies», though some physicians may refer to it as FIES (pronounced «fees», considering food-protein as one word). Enterocolitis is inflammation involving both the little intestine and the colon (large intestine).

    How Do I know If My Kid Has Outgrown FPIES?

    Together with your child’s doctor, you should determine if/when it is likely that your kid may own outgrown any triggers. Obviously, determining if a kid has outgrown a trigger is something that needs to be evaluated on a food-by-food basis.

    As stated earlier, APT testing may be an option to assess oral challenge readiness. Another factor for you and your doctor to consider is if your kid would physically be capable to handle a possible failed challenge.

    When the time comes to orally challenge an FPIES trigger, most doctors familiar with FPIES will desire to schedule an in-office food challenge. Some doctors (especially those not practicing in a hospital clinic setting) may select to challenge in the hospital, with an IV already in put, in case of emergency. Each doctor may own his or her own protocol, but an FPIES trigger is something you should definitely NOT challenge without discussing thoroughly with your doctor.

    Be aware that if a kid passes the in-office portion of the challenge, it does not mean this food is automatically guaranteed «safe.» If a child’s delay in reaction is fairly short, a kid may fail an FPIES food challenge while still at the office/hospital.

    For those with longer reaction times, it may not be until later that day that symptoms manifest. Some may react up to three days later. Delay times may vary by food as well. If a kid has FPIES to multiple foods, one food may trigger symptoms within four hours; a diverse food may not trigger symptoms until six or eight hours after ingestion.

    Is FPIES A Lifelong Condition?

    Typically, no. Numerous children outgrow FPIES by about age three.

    Note, however, that the time varies per individual and the offending food, so statistics are a guide, but not an absolute. In one study, % of children with FPIES reactions to barley had outgrown and were tolerating barley by age three. However, only 40% of those with FPIES to rice, and 60% to dairy tolerated it by the same age.

    What is Shock and What are the Symptoms?

    Shock is a life-threatening condition. Shock may develop as the result of sudden illness, injury, or bleeding. When the body cannot get enough blood to the vital organs, it goes into shock.

    Signs of shock include:
    Weakness, dizziness, and fainting.
    Cool, pale, clammy skin.
    Weak, quick pulse.
    Shallow, quick breathing.
    Low blood pressure.
    Extreme thirst, nausea, or vomiting.
    Confusion or anxiety.

    What Does IgE vs Cell Mediated Mean?

    IgE stands for Immunoglobulin E.

    It is a type of antibody, formed to protect the body from infection, that functions in allergic reactions. IgE-mediated reactions are considered immediate hypersensitivity immune system reactions, while cell mediated reactions are considered delayed hypersensitivity. Antibodies are not involved in cell mediated reactions. For the purpose of understanding FPIES, you can disregard every you know about IgE-mediated reactions.

    When Do FPIES Reactions Occur?

    FPIES reactions often show up in the first weeks or months of life, or at an older age for the exclusively breastfed kid. Reactions generally happen upon introducing first solid foods, such as baby cereals or formulas, which are typically made with dairy or soy.

    (Infant formulas are considered solids for FPIES purposes.) While a kid may own allergies and intolerances to food proteins they are exposed to through breastmilk, FPIES reactions generally don’t happen from breastmilk, regardless of the mother’s diet. An FPIES reaction typically takes put when the kid has directly ingested the trigger food(s).

    What is a Typical FPIES Reaction?

    As with every things, each kid is diverse, and the range, severity and duration of symptoms may vary from reaction to reaction. Unlike traditional IgE-mediated allergies, FPIES reactions do not manifest with itching, hives, swelling, coughing or wheezing, etc.

    Symptoms typically only involve the gastrointestinal system, and other body organs are not involved. FPIES reactions almost always start with delayed onset vomiting (usually two hours after ingestion, sometimes as tardy as eight hours after). Symptoms can range from mild (an increase in reflux and several days of runny stools) to life threatening (shock). In severe cases, after repeatedly vomiting, children often start vomiting bile. Commonly, diarrhea follows and can final up to several days.

    In the worst reactions (about 20% of the time), the kid has such severe vomiting and diarrhea that s/he rapidly becomes seriously dehydrated and may go into shock.

    What is FPIES?

    FPIES is a non-IgE mediated immune reaction in the gastrointestinal system to one or more specific foods, commonly characterized by profuse vomiting and diarrhea. FPIES is presumed to be cell mediated. Poor growth may happen with continual ingestion. Upon removing the problem food(s), every FPIES symptoms subside. (Note: Having FPIES does not preclude one from having other allergies/intolerances with the food.) The most common FPIES triggers are cow’s milk (dairy) and soy.

    However, any food can cause an FPIES reaction, even those not commonly considered allergens, such as rice, oat and barley.

    A kid with FPIES may experience what appears to be a severe stomach bug, but the «bug» only starts a couple hours after the offending food is given. Numerous FPIES parents own rushed their children to the ER, limp from extreme, repeated projectile vomiting, only to be told, «It’s the stomach flu.» However, the next time they feed their children the same solids, the dramatic symptoms return.

    How is FPIES Diverse From MSPI, MSPIES, MPIES, Etc.?

    MPIES (milk-protein induced enterocolitis syndrome) is FPIES to cow’s milk only.

    MSPIES (milk- and soy-protein induced enterocolitis syndrome) is FPIES to milk and soy. Some doctors do create these subdivisions, while others declare that milk and soy are simply the two most common FPIES triggers and give the diagnosis of «FPIES to milk and/or soy.»

    MSPI is milk and soy protein intolerance. Symptoms are those of allergic colitis and can include colic, vomiting, diarrhea and blood in stools. These reactions are not as severe or immediate as an FPIES reaction.

    References

    Fogg MI, Brown-Whitehorn TA, Pawlowski NA, Spergel JM.

    (). Atopy Patch Test for the Diagnosis of Food Protein-Induced Enterocolitis Syndrome. Pediatric Allergy and Immunology – Retrieved on December 31, from

    Burks, AW. (). Don’t Feed Her That! Diagnosing and Managing Pediatric Food Allergy. Pediatric Basics. Gerber Products Company: Retrieved on December 31, from

    Moore, D. Food Protein-Induced Enterocolitis Syndrome. (, April 11). Retrieved on December 31, from

    Sicherer, SH. (). Food Protein-Induced Enterocolitis Syndrome: Case Presentations and Management Lessons. Journal of Allergy and Clinical Immunology Vol.

    , Retrieved on December 31, from

    Nowak-Wegrzyn, A., Sampson, HA, Wood, RA, Sicherer, SH. MD, Robert A. Wood, MD and Scott H. Sicherer, MD. (). Food Protein-Induced Enterocolitis Syndrome Caused by Solid Food Proteins. Pediatrics. Vol. 4: Retrieved on December 31, from #T1.

    Nocerino, A., Guandalini, S. (, April 11). Protein Intolerance. Retrieved on December 31, from WebMD Medical Reference from Healthwise. (, May 31). Shock, Topic Overview. Retrieved on December 31, from

    American Academy of Allergy, Asthma and Immunology. (). Tips to Remember: What is an Allergic Reaction? Retrieved on December 31, from

    Sicherer, SH.

    (). Understanding and Managing Your Child’s Food Allergies. A Johns Hopkins Press Health Book.

    Medical Review February

    Various baby formulas — such as soy, extensively hydrolysed and amino acid-based formula — that can be used to treat cows milk protein allergy are available in Australia. An analysis of Australian formula-prescribing practices indicated that they did not appear to be in line with authoritative statements and position papers or the guidelines of the Australian Pharmaceutical Benefits Advisory Committee (PBAC).1

    In , the Committee on Nutrition of the American Academy of Pediatrics stated that soy formula was a suitable option for treating infants with cows milk protein allergy.2 In April , the Committee on Nutrition of the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) recommended that soy protein formulas should not be used in infants with cows milk protein allergy during the first 6 months of life, because few infants had been studied, and the reported rate of adverse reactions to soy protein was higher in infants under 6 months of age.

    This committee also recommended that, when soy formula is used to treat cows milk protein allergy in infants over 6 months of age, tolerance to soy formula be established by clinical challenge.3

    The PBAC guidelines once restricted the use of extensively hydrolysed formula to infants with combined intolerance to cows milk protein and soy protein. It also restricted the use of amino acid formula to infants with combined intolerance to cows milk protein, soy protein and extensively hydrolysed formula. In November , the PBAC accepted the advice of its Nutritional Products Working Party to ease the restrictions: the requirement to protest intolerance to soy protein before treating infants with these products was removed.

    In , European proposals for treating cows milk protein allergy in formula-fed infants with extensively hydrolysed formula and amino acid formula were outlined in an algorithm.4

    Consensus panel

    In the light of these considerations, we constituted an Australian panel with representation from every states.

    The panel was put together by the two lead authors (A S K and D J H) to represent practising paediatric clinicians. The panel was composed to include clinicians with expertise in paediatric allergy, gastroenterology, neonatology and general paediatrics.

    There were two face-to-face meetings, in November  and June , and four telephone conferences. Meetings were co-chaired by A S K and D J H. Panel members (but not the co-chairs) were assigned individual tasks to review practice with regard to treatment as it related to specific clinical syndromes. After this material had been discussed by the panel, a position was reached. The number of panel members agreeing with the position (in view of the evidence presented) was recorded.

    The panel considered the issues and reached a consensus on the indications for use of soy, extensively hydrolysed and amino acid formulas in the treatment of cows milk protein allergy under Australian conditions in general and paediatric practice.

    As the selection of a formula depends on the syndrome to be treated, the panel has outlined the salient features of the diverse syndromes in breastfed and formula-fed infants. Selected references to the individual syndromes own been provided.

    The spectrum of cows milk protein allergy

    Cows milk protein allergy is defined as an immunologically mediated adverse reaction to cows milk protein. It affects about 2% of infants under 2 years of age.5 In this document, we use the term “allergy” in accordance with the World Allergy Organization’s definition (ie, allergy is a hypersensitivity reaction initiated by specific immunological mechanisms).6 Mechanisms may be IgE mediated or non-IgE mediated.

    Cows milk protein allergy can also happen in exclusively breastfed infants.

    Cows milk protein is often the first food protein ingested by formula-fed infants, and allergies present as a range of syndromes. A correct diagnosis is critical and will often depend on appropriate immunological and morphological investigations. In every cases, the diagnosis is confirmed by observing remission of the symptoms following removal of the protein.

    If the diagnosis remains uncertain, further confirmation should be obtained by observing relapse following challenge with cows milk protein. As some of the conditions may remit with time, rechallenge with cows milk protein after a period of avoidance is indicated in some cases. A finish discussion of the diagnostic process and ongoing management4 falls exterior the scope of this guideline.

    Consensus on the use of formulas

    Three diverse types of formula (soy, extensively hydrolysed and amino acid) may be appropriate treatment in specific circumstances (Box 1).

    Some preparations are not recommended for treating cows milk protein allergy. The panel considers that there is no put for partially hydrolysed (known as HA) formulas nor other mammalian milks (such as goats milk)7 in treating cows milk protein allergy. The consensus recommendations for using baby formulas to treat allergy syndromes are shown in Box 2. Breastfeeding may be continued, and recommendations are provided for eliminating maternal intake of cows milk protein.

    The panel believes the information provided is a guideline for most cases.

    However, in severely affected infants or if the diagnosis is uncertain, it may be appropriate to start treatment with an extensively hydrolysed or amino acid-based formula which is not in accordance with this consensus.8 Such a case should be managed by a paediatrician with specific expertise in these disorders.

    Cows milk protein allergy syndromes

    The syndromes are classified as reactions which develop over minutes, hours or days. The recommendations include advice about the necessity for mothers to eliminate dietary intake of cows milk protein while breastfeeding. In some situations, failure to thrive affects the choice of formula. Recommendations provide for an alternative formula if treatment with the initial formula is not successful.

    Immediate allergic reactions9

    Cows milk protein allergy may manifest with erythema, angioedema, urticaria or vomiting.

    Some infants may own contact urticaria where protein has touched the skin. Typically, there will be evidence of IgE sensitisation (positive skin prick test or an allergen-specific IgE antibody test [RAST] to cows milk). Symptoms develop within minutes of ingestion of little volumes of milk. Infants with cows milk protein allergy often own other food allergies, in specific to egg and peanut products.

    Anaphylaxis is a severe immediate reaction with respiratory tract involvement and/or hypotension.

    Features of anaphylaxis may be hard to identify in infants. It may be suggested by coughing, wheezing, severe distress, floppiness or collapse.

    Food protein-induced enterocolitis syndrome (FPIES)10

    FPIES is an unusual disorder which generally presents with acute onset of repeated projectile vomiting, hypotonia, pallor and sometimes diarrhoea 1 to 3 hours after ingestion of cows milk protein. FPIES may be mistaken for acute gastroenteritis, sepsis or intestinal obstruction, and multiple presentations before the diagnosis is established are not unusual. Typically, FPIES occurs at the first introduction of cows milk protein into the diet.

    It has not been reported in exclusively breastfed infants. FPIES may also be caused by other food proteins (eg, soy, wheat, rice and chicken). Despite the onset within hours of ingestion, the disorder is not IgE mediated. Remission has generally occurred by the third year of life.

    Atopic eczema11

    Atopic eczema is a chronic, relapsing, pruritic inflammatory disease of the skin, generally associated with allergic sensitisation. Food allergy plays a role in some cases of eczema in children. It should particularly be considered in infants with moderate to severe eczema. It is generally associated with high levels of IgE antibodies to common foods (eg, milk, egg and peanut).

    Egg is the most frequently involved allergen, followed by cows milk protein. Although IgE antibodies own been implicated in most cases of cows milk protein-induced eczema, about 10% of cases are not IgE associated.

    Gastrointestinal syndromes

    Infants with cows milk protein allergy may present with vomiting, chronic diarrhoea, malabsorption and failure to thrive. Most of the syndromes are not IgE associated and own other pathogenic immune mechanisms. Cows milk protein allergy is the most commonly identified food allergen sensitivity; however, in some cases, hypersensitivity to multiple food proteins is involved.

    Gastrointestinal biopsy may be required to define the disorder.

    Gastro-oesophageal reflux disease (GORD)12

    About 40% of infants referred for specialist management of GORD own allergy to cows milk protein. These allergic reactions are typically not IgE mediated. In these infants, intestinal biopsy commonly shows partial villous atrophy.

    Allergic eosinophilic gastroenteritis13

    Common features include weight loss and failure to thrive associated with postprandial vomiting, diarrhoea and, occasionally, blood loss. In more severe cases, the infants may own iron deficiency anaemia and oedema due to hypoproteinaemia and protein-losing enteropathy.

    Food protein-induced enteropathy14

    Infants with allergic enteropathy due to cows milk protein may present with diarrhoea, failure to thrive, various degrees of vomiting and, sometimes, hypoproteinaemia and anaemia.

    Some cases own an associated soy allergy. The clinical signs of secondary lactose intolerance, including perianal excoriation from acidic stools, may be present.

    Constipation15

    Whether constipation is a clinical manifestation of cows milk protein allergy in infants and young children is controversial. Constipation is a common symptom in early childhood and, in some cases, resolves after removal of cows milk protein from the diet. Cows milk protein-induced constipation is often associated with anal fissures and rectal eosinophilia.

    Severe irritability (colic)16

    The mechanisms of baby colic are poorly understood. Colic is not mediated by IgE, and the role of dietary factors is controversial.

    Persistent crying is a common problem that may affect about a third of young infants and gradually abates by 4 months of age without specific treatment in most cases. In infants with unremitting distress persisting beyond the typical colic period, an underlying organic cause may be more likely. Exclusion of cows milk protein helps in some cases, but these cannot be identified by allergy tests.

    Food protein-induced proctocolitis17

    Infants with allergic proctocolitis due to cows milk protein allergy generally present with mild diarrhoea and low-grade rectal bleeding.

    If the baby is fully breastfed (breast milk colitis), symptoms may be caused by protein transferred via the breast milk. The bleeding is generally observed as stools containing mucus and flecks of blood rather than as candid rectal bleeding. Other systemic features (such as failure to thrive or anaemia) are generally absent, and the infants appear generally well. Rectal biopsies are not usual, but may be required to confirm the diagnosis in more severe or atypical cases.

    Eosinophilic oesophagitis18

    Eosinophilic oesophagitis is more often identified in older children than in infants, but may happen in both groups.

    In infancy, typical symptoms are refusal of food, hard feeding, poor weight acquire and poor response to standard antireflux measures. Older children may present with dysphagia or episodes of impacted food bolus. Endoscopy is necessary to establish the diagnosis, which is based on eosinophilia of the upper and lower oesophagus. Eosinophil numbers are typically lower in infants with peptic reflux oesophagitis. Hypersensitivity to multiple foods may be seen in infants with eosinophilic oesophagitis.

    In older children and adults, aeroallergens may also be implicated. Therapy may include hypoallergenic diets and swallowed steroid aerosol.

    Other conditions associated with eosinophilic infiltration of the little and large bowel require specialist diagnosis and treatment, and may reply to elimination of cows milk protein.

    1 Preparations available for treating cows milk protein allergy

    Suitable

  • Soy formulas

  • Extensively hydrolysed formulas

    1. Pepti-Junior (Nutricia)

    2. Alfaré (Nestlé)

    3. Amino acid formulas

  • Amino acid formulas

    1. EleCare (Abbott)

    2. Neocate (SHS)

    Contraindicated or not recommended

  • Formulas

    1. Partially hydrolysed cows milk-based (eg, Karicare SensiKare [Nutricia], NAN HA [Nestlé])

    2. Goats milk-based formula

    3. Lactose-free cows milk-based (eg, Karicare De-Lact, Digestelact [Nutricia], S LF [Wyeth])

    4. Cows milk-based (including anti-regurgitation)

    5. Other preparations

  • Other preparations

    1. Oat milk

    2. Rice milk

    3. A2 milk (A2 Australia)

    4. Other mammalian milks (camel, mare, ass, goat and ewe)

    2 Formula feeding in syndromes associated with cows milk protein allergy*

    Syndrome

    Onset of reaction

    Maternal elimination of CMP if breastfeeding?

    Choice of formula


    NHMRC level of evidence‡

    Consensus panel agreement§

    First†

    Second (if first not tolerated)

    Third (if second not tolerated)


    Immediate reaction

    Immediate food allergy

    < 1 h

    Yes

    eHF (< 6 months)

    AAF

    II

    11/11

    Soy (> 6 months)

    eHF

    AAF


    Anaphylaxis

    < 1 h

    Yes

    AAF (followed by urgent consultation with paediatric allergist)

    IV

    11/11


    Food protein-induced enterocolitis syndrome

    1–3 h

    No

    eHF

    AAF

    IV

    10/11


    Delayed reaction


    Atopic eczema

    Hours to days

    Yes¶

    eHF (< 6 months or > 6 months with FTT)

    AAF

    IV

    11/11

    Soy (> 6 months, no FTT)

    eHF

    AAF


    Gastrointestinal syndromes, GORD, allergic eosinophilic gastroenteritis, food protein-induced enteropathy, constipation, severe irritability (colic)

    Hours to days

    Yes¶

    eHF (< 6 months or > 6 months with FTT)

    AAF

    I (severe irritability), III (GORD), IV (others)

    11/11

    Soy (> 6 months, no FTT)

    eHF

    AAF


    Food protein-induced proctocolitis

    11/11

    Formula-fed

    > 24 h

    eHF

    AAF

    IV

    Breastfed

    > 24 h

    Yes¶


    Eosinophilic oesophagitis in infants

    Days to weeks

    Yes

    AAF

    IV

    11/11


    Method for the development of the consensus document

    1. Literature search. We conducted 2 searches in PubMed/MEDLINE (Appendix B, online supplemental material, Figure S1), submitting the resulting list of articles to every the authors, who each selected the articles that were relevant for addressing specific questions.

    2. Working group. It comprised 11 experts representing 4 paediatric societies: Sociedad Espaola de Gastroenterologa, Hepatologa y Nutricin Peditrica (Spanish Society of Paediatric Gastroenterology, Hepatology and Nutrition, SEGHNP), Asociacin Espaola de Pediatra de Atencin Primaria (Spanish Association of Primary Care Paediatrics, AEPAP), Sociedad Espaola de Pediatra Extrahospitalaria y Atencin Primaria (Spanish Society of Outpatient and Primary Care Paediatrics, SEPEAP) and Sociedad Espaola de Inmunologa Clnica, Alergologa y Asma Peditrica (Spanish Society of Paediatric Clinical Immunology, Allergology and Asthma, SEICAP). Once the group agreed on the aspects that needed to be considered in the areas of clinical manifestations, diagnosis, treatment, followup and prevention of non-IgE CMPA, the list was distributed for review based on personal experience.

    3. Drafting of the document. After reviewing the selected articles, the authors expressed their results as statements, basic concepts and recommendations that were later put to a vote by the whole group. The entire document can be consulted in the webpages of each of the societies that participated in its development.

    Results and recommendations

    The term allergy refers exclusively to adverse reactions involving one or several immune mechanismsproven or highly suspectedand must be distinguished from reactions due to enzymatic, toxic or pharmacological mechanisms3,13 (Appendix B, online supplemental material, Figure S2). From a clinical standpoint, reactions mediated by IgE are characterised by the acute onset of a predominantly cutaneous or respiratory response associated to the presence of specific IgE antibodies. Reactions that are not mediated by IgE generally result from cellular immune responses, although in most cases the involvement of an immune mechanism cannot be proven.

    The only tools available for diagnosis of non-IgE CMPA are a detailed history and elimination of CMP from the diet followed by an oral challenge.1416 The first lays the foundation to suspect the presence of allergy, while the second is necessary to confirm the diagnosis.

    The delayed-onset symptoms are predominantly gastrointestinal, and they may present as any of these three syndromes: food protein-induced allergic proctocolitis, food protein-induced enteropathy and food protein induced enterocolitis syndrome (FPIES)17 (Appendix B, online supplemental material, Table S1). International consensus guidelines for the management of the latter own been published recently9 (Table 1). There are no specific diagnostic criteria for the other two, which must be diagnosed based on the clinical presentation (Table 2). Furthermore, non-IgE CMPA may mimic gastrointestinal disorders that are frequent in this age group, such as gastro-oesophageal reflux (GOR), baby colic and constipation.1721 The presence of a family history of atopy, involvement of several systems (gastrointestinal, cutaneous, respiratory manifestations) and absence of improvement with customary treatment suggests the presence of non-IgE CMPA in these patients.15,16,20,21

    When CMPA is suspected in a young kid based on the clinical history, CMP should be eliminated from the diet. Elimination leads to improvement and resolution of symptoms in a variable period of time, which may be of 1 to 5 days in acute forms (acute FPIES, vomiting), 12 weeks in cases of eczema or rectal bleeding, and up to 24 weeks in patients with constipation, diarrhoea and/or growth faltering.22 The CMP-free diet is to be maintained until symptoms resolve fully, and should not be prolonged past 6 weeks without confirmation of the diagnosis by means of an oral challenge. Not performing the challenge should only be considered in patients in whom repeated exposure is deemed too risky due to the severity of the initial reaction.

    In cases manifesting with proctocolitis, disorders such as GOR, constipation or colic, the symptoms resulting from reintroduction of CMP are generally mild and easily managed at the outpatient level, so the challenge can be performed at home under the supervision of a paediatrician (Table 3). If there is suspicion of an IgE mechanism (onset of symptoms within 2 hours of ingestion and/or development of cutaneous and respiratory symptoms associated with IgE-mediated reactions), severe atopic dermatitis, or moderate-to severe FPIES or enteropathy, reintroduction of CMP may involve a considerable risk, and should therefore be performed in the hospital (Appendix B, Table 4 and online supplemental material, Table S2) (Fig. 1).

    The oral challenge is interpreted based on clinical features, that is, the resurgence of symptoms, although these can take 1 to 2 weeks to develop (or 24 weeks in cases manifesting with altered intestinal function or eczema) or not be sufficiently pronounced in the initial days when the intake of CMP is lower. For this reason, observation in uncertain cases should be maintained for at least 4 weeks after reintroducing CMP in the diet. The Cow's Milk-related Symptom Score may be helpful in the evaluation of mild forms with symptoms similar to those of functional disorders.20,21

    The treatment of non-IgE-mediated CMP consists in the elimination of CMP from the diet. In exclusively-breasted infants, maintenance of breastfeeding must be prioritised, having the mom follow a CMP-free diet. Persistence of symptoms despite elimination from the maternal diet may be due to sensitisation to other foods (mainly soy and egg), whose exclusion should be considered, too. If the onset of symptoms is associated with the initiation of complementary feeding with formula or dairy products, exclusion of CMP from the mother's diet is not considered necessary.23,24

    Different formulas approved for treatment of infants with CMPA are currently available. Among these, extensively hydrolysed formulas (EHFs) based on casein and/or whey CMP are considered the first choice.211,25,26 istration of EHFs enriched with medium chain triglycerides should be considered in infants with growth faltering, including formulas containing lactose if lactose intolerance is not suspected. Although several studies published in recent years found a positive impact of formulas supplemented with probiotics in the development of tolerance,2729 further research is required to confirm this association.

    In children that refuse or cannot tolerate EHFs or families following a vegan diet, hydrolysed rice protein formulas own been proven efficacious and safe.211,30 The use of soy-based formulas is not recommended in infants aged less than 6 months.2 In severe cases with significant growth faltering or with rectal bleeding associated with haemodynamic instability, elemental formulas based on free amino acids are the first line of treatment.31

    There is a high probability that hydrolysed formulas and milks or formulas based on the milk of other mammals (sheep, goat, buffalo) will not be tolerated by children with CMPA.211 Plant-based drinks made with soy, rice, oat, quinoa, tiger nut or almond are of little nutritional worth and own low protein and energy contents, unlike plant-based baby formulas. These plant-based milks should never be given as a replacement for cow's milk, although they may be given as part of a varied diet to children aged more than 2 years.2,6,31

    We must remember that mothers and infants with a CMP-free diet are at risk of dietary vitamin D and calcium deficiency. It is recommended that mothers get supplementation for both. Infants will be given vitamin D, and calcium supplementation will be considered in case of insufficient dietary intake.15,32,33

    Frequently Asked Questions about Food Protein-Induced Enterocolitis Syndrome (FPIES)

    What are Some Common FPIES Triggers?

    The most common FPIES triggers are traditional first foods, such as dairy and soy.

    Other common triggers are rice, oat, barley, green beans, peas, sweet potatoes, squash, chicken and turkey. A reaction to one common food does not mean that every of the common foods will be an issue, but patients are often advised to proceed with caution with those foods. Note that while the above foods are the most prevalent, they are not exclusive triggers. Any food has the potential to trigger an FPIES reaction. Even trace amounts can cause a reaction.

    How is FPIES Diagnosed?

    FPIES is hard to diagnose, unless the reaction has happened more than once, as it is diagnosed by symptom presentation.

    Typically, foods that trigger FPIES reactions are negative with standard skin and blood allergy tests (SPT, RAST) because they glance for IgE-mediated responses. However, as stated before, FPIES is not IgE-mediated.

    Atopy patch testing (APT) is being studied for its effectiveness in diagnosing FPIES, as well as predicting if the problem food is no longer a trigger. Thus, the outcome of APT may determine if the kid is a potential candidate for an oral food challenge (OFC).

    APT involves placing the trigger food in a metal cap, which is left on the skin for 48 hours. The skin is then watched for symptoms in the following days after removal. Please consult your child’s doctor to discuss if APT is indicated in your situation.

    How Do You Care for a Kid With FPIES?

    Treatment varies, depending on the patient and his/her specific reactions. Often, infants who own reacted to both dairy and soy formulas will be placed on hypoallergenic or elemental formula.

    Some children do well breastfeeding. Other children who own fewer triggers may just strictly avoid the offending food(s).

    New foods are generally introduced extremely slowly, one food at a time, for an extended period of time per food. Some doctors recommend trialing a single food for up to three weeks before introducing another.

    Because it’s a rare, but serious condition, in the event of an emergency, it is vital to get the correct treatment.

    Some doctors provide their patients with a letter containing a brief description of FPIES and its proper treatment. In the event of a reaction, this letter can be taken to the ER with the child.

    Does FPIES Require Epinephrine?

    Not generally, because epinephrine reverses IgE-mediated symptoms, and FPIES is not IgE-mediated. Based on the patient’s history, some doctors might prescribe epinephrine to reverse specific symptoms of shock (e.g., low blood pressure). However, this is only prescribed in specific cases.

    How Do You Treat an FPIES Reaction?

    Always follow your doctor’s emergency plan pertaining to your specific situation.

    Rapid dehydration and shock are medical emergencies. If your kid is experiencing symptoms of FPIES or shock, immediately contact your local emergency services (). If you are uncertain if your kid is in need of emergency services, contact or your physician for guidance. The most critical treatment during an FPIES reaction is intravenous (IV) fluids, because of the risk and prevalence of dehydration. Children experiencing more severe symptoms may also need steroids and in-hospital monitoring. Mild reactions may be capable to be treated at home with oral electrolyte re-hydration (e.g., Pedialyte®).

    What Does FPIES Stand For?

    FPIES is Food Protein-Induced Enterocolitis Syndrome.

    It is commonly pronounced «F-Pies», as in «apple pies», though some physicians may refer to it as FIES (pronounced «fees», considering food-protein as one word). Enterocolitis is inflammation involving both the little intestine and the colon (large intestine).

    How Do I know If My Kid Has Outgrown FPIES?

    Together with your child’s doctor, you should determine if/when it is likely that your kid may own outgrown any triggers. Obviously, determining if a kid has outgrown a trigger is something that needs to be evaluated on a food-by-food basis. As stated earlier, APT testing may be an option to assess oral challenge readiness.

    Another factor for you and your doctor to consider is if your kid would physically be capable to handle a possible failed challenge.

    When the time comes to orally challenge an FPIES trigger, most doctors familiar with FPIES will desire to schedule an in-office food challenge. Some doctors (especially those not practicing in a hospital clinic setting) may select to challenge in the hospital, with an IV already in put, in case of emergency.

    Each doctor may own his or her own protocol, but an FPIES trigger is something you should definitely NOT challenge without discussing thoroughly with your doctor.

    Be aware that if a kid passes the in-office portion of the challenge, it does not mean this food is automatically guaranteed «safe.» If a child’s delay in reaction is fairly short, a kid may fail an FPIES food challenge while still at the office/hospital.

    For those with longer reaction times, it may not be until later that day that symptoms manifest. Some may react up to three days later. Delay times may vary by food as well. If a kid has FPIES to multiple foods, one food may trigger symptoms within four hours; a diverse food may not trigger symptoms until six or eight hours after ingestion.

    Is FPIES A Lifelong Condition?

    Typically, no. Numerous children outgrow FPIES by about age three. Note, however, that the time varies per individual and the offending food, so statistics are a guide, but not an absolute.

    In one study, % of children with FPIES reactions to barley had outgrown and were tolerating barley by age three. However, only 40% of those with FPIES to rice, and 60% to dairy tolerated it by the same age.

    What is Shock and What are the Symptoms?

    Shock is a life-threatening condition. Shock may develop as the result of sudden illness, injury, or bleeding. When the body cannot get enough blood to the vital organs, it goes into shock.

    Signs of shock include:
    Weakness, dizziness, and fainting.
    Cool, pale, clammy skin.
    Weak, quick pulse.
    Shallow, quick breathing.
    Low blood pressure.
    Extreme thirst, nausea, or vomiting.
    Confusion or anxiety.

    What Does IgE vs Cell Mediated Mean?

    IgE stands for Immunoglobulin E.

    It is a type of antibody, formed to protect the body from infection, that functions in allergic reactions. IgE-mediated reactions are considered immediate hypersensitivity immune system reactions, while cell mediated reactions are considered delayed hypersensitivity. Antibodies are not involved in cell mediated reactions. For the purpose of understanding FPIES, you can disregard every you know about IgE-mediated reactions.

    When Do FPIES Reactions Occur?

    FPIES reactions often show up in the first weeks or months of life, or at an older age for the exclusively breastfed kid.

    Reactions generally happen upon introducing first solid foods, such as baby cereals or formulas, which are typically made with dairy or soy. (Infant formulas are considered solids for FPIES purposes.) While a kid may own allergies and intolerances to food proteins they are exposed to through breastmilk, FPIES reactions generally don’t happen from breastmilk, regardless of the mother’s diet. An FPIES reaction typically takes put when the kid has directly ingested the trigger food(s).

    What is a Typical FPIES Reaction?

    As with every things, each kid is diverse, and the range, severity and duration of symptoms may vary from reaction to reaction.

    Unlike traditional IgE-mediated allergies, FPIES reactions do not manifest with itching, hives, swelling, coughing or wheezing, etc. Symptoms typically only involve the gastrointestinal system, and other body organs are not involved. FPIES reactions almost always start with delayed onset vomiting (usually two hours after ingestion, sometimes as tardy as eight hours after). Symptoms can range from mild (an increase in reflux and several days of runny stools) to life threatening (shock). In severe cases, after repeatedly vomiting, children often start vomiting bile.

    Commonly, diarrhea follows and can final up to several days. In the worst reactions (about 20% of the time), the kid has such severe vomiting and diarrhea that s/he rapidly becomes seriously dehydrated and may go into shock.

    What is FPIES?

    FPIES is a non-IgE mediated immune reaction in the gastrointestinal system to one or more specific foods, commonly characterized by profuse vomiting and diarrhea. FPIES is presumed to be cell mediated. Poor growth may happen with continual ingestion. Upon removing the problem food(s), every FPIES symptoms subside. (Note: Having FPIES does not preclude one from having other allergies/intolerances with the food.) The most common FPIES triggers are cow’s milk (dairy) and soy.

    However, any food can cause an FPIES reaction, even those not commonly considered allergens, such as rice, oat and barley.

    A kid with FPIES may experience what appears to be a severe stomach bug, but the «bug» only starts a couple hours after the offending food is given. Numerous FPIES parents own rushed their children to the ER, limp from extreme, repeated projectile vomiting, only to be told, «It’s the stomach flu.» However, the next time they feed their children the same solids, the dramatic symptoms return.

    How is FPIES Diverse From MSPI, MSPIES, MPIES, Etc.?

    MPIES (milk-protein induced enterocolitis syndrome) is FPIES to cow’s milk only.

    MSPIES (milk- and soy-protein induced enterocolitis syndrome) is FPIES to milk and soy. Some doctors do create these subdivisions, while others declare that milk and soy are simply the two most common FPIES triggers and give the diagnosis of «FPIES to milk and/or soy.»

    MSPI is milk and soy protein intolerance. Symptoms are those of allergic colitis and can include colic, vomiting, diarrhea and blood in stools. These reactions are not as severe or immediate as an FPIES reaction.

    References

    Fogg MI, Brown-Whitehorn TA, Pawlowski NA, Spergel JM.

    (). Atopy Patch Test for the Diagnosis of Food Protein-Induced Enterocolitis Syndrome. Pediatric Allergy and Immunology – Retrieved on December 31, from

    Burks, AW.

    What type of formula is available for infants with milk allergy

    (). Don’t Feed Her That! Diagnosing and Managing Pediatric Food Allergy. Pediatric Basics. Gerber Products Company: Retrieved on December 31, from

    Moore, D. Food Protein-Induced Enterocolitis Syndrome. (, April 11). Retrieved on December 31, from

    Sicherer, SH. (). Food Protein-Induced Enterocolitis Syndrome: Case Presentations and Management Lessons. Journal of Allergy and Clinical Immunology Vol. , Retrieved on December 31, from

    Nowak-Wegrzyn, A., Sampson, HA, Wood, RA, Sicherer, SH. MD, Robert A. Wood, MD and Scott H. Sicherer, MD. (). Food Protein-Induced Enterocolitis Syndrome Caused by Solid Food Proteins.

    Pediatrics. Vol. 4: Retrieved on December 31, from #T1.

    Nocerino, A., Guandalini, S. (, April 11). Protein Intolerance. Retrieved on December 31, from WebMD Medical Reference from Healthwise. (, May 31). Shock, Topic Overview. Retrieved on December 31, from

    American Academy of Allergy, Asthma and Immunology. (). Tips to Remember: What is an Allergic Reaction? Retrieved on December 31, from

    Sicherer, SH. (). Understanding and Managing Your Child’s Food Allergies.

    What type of formula is available for infants with milk allergy

    A Johns Hopkins Press Health Book.

    Medical Review February


    Diagnosis[8]

    Allergic reactions can be immunoglobulin E (IgE)-mediated reactions or non-IgE-mediated reactions. Cow’s milk proteins can cause reactions of either type or both together, which can make them hard to diagnose.

    IgE-mediated reactions

    IgE-mediated reactions trigger histamine release and happen within two hours of milk being consumed.

    They include skin reactions such as itching, erythema, urticaria and acute angio-oedema, most commonly of the face. There can be abdominal symptoms such as colicky pain, nausea, vomiting and diarrhoea. Respiratory symptoms can be upper or lower respiratory tract: nasal itching, sneezing, rhinorrhoea, congestion, cough, chest tightness or wheeze.

    It is extremely rare for cow’s milk to trigger an anaphylactic reaction. Antihistamines can be used to treat the symptoms.

    Allergic reactions may be more severe in people with asthma, particularly if the asthma is poorly controlled[9].

    This type of allergy can be diagnosed with a skin prick test or a blood test (specific IgE, previously known as RAST). If this type of allergy is suspected, refer the kid to a paediatrician who will arrange for the test to be done in hospital.

    Non-IgE-mediated reactions

    Non-IgE-mediated reactions happen hours or days after consuming milk.

    Skin reactions such as atopic eczema are common, as well as itching and erythema. Abdominal symptoms include colicky pain (including infantile colic), reflux, blood or mucus in stools, constipation or diarrhoea. There may be lower respiratory tract symptoms such as cough, wheeze, breathlessness or chest kid may be pale and tired, and growth may be faltering.

    The best way to establish if cow’s milk is causing these symptoms is to exclude it from the diet. There should be an improvement in symptoms within two weeks.


    Differential diagnosis

    With such a wide range of symptoms that can be caused by CMPA, the differential diagnosis is extensive, and includes other food allergies, non-food allergies such as pollen, animal dander, other gastrointestinal disorders, pancreatic insufficiency such as in cystic fibrosis, and infections — eg urinary tract infection.


    Management [10]

    Alternative milks

    Soya formulas own been prescribed in the past for CMPA but soya is also a common allergen, so this is no longer routinely advised.

    About % of children allergic to cow’s milk will also react to soya. Soya milk also contains isoflavones which own a feeble oestrogenic activity.

    Other milks, such as pea, oat or coconut, may be used after the age of 2 years, depending on the child’s nutritional status and any other allergies they may own. A brand fortified with calcium should be used if available. Rice milk is not recommended for children aged under years.

    If the symptoms of CMPA persist into older childhood or beyond then patients need to continue to avoid milk and milk products.

    The proteins in goat’s milk and other mammal milks which may be available are almost identical to those found in cow’s milk, so those are not suitable substitutes. It is significant to maintain an adequate calcium intake. Children who are avoiding cow’s milk for allergy reasons should be referred to a paediatric dietician for specialist advice.

    Challenge test

    The prognosis of CMPA is excellent with a remission rate of approximately % at 1 year, % at 2 years and % at 3 years[15].Children can own a challenge test every months to see if they are capable to tolerate milk.

    It may take several days for the reaction to show, particularly for non-IgE allergy.

    The challenge test can be carried out in stages, according to the ‘Milk Ladder’[16]. This is a hierarchy of milk-containing foods, beginning with those least likely to cause a reaction and gradually moving towards being capable to drink a glass of milk. In baked form, such as muffins, cakes or malted milk biscuits, cow’s milk is less allergenic and may be tolerated sooner than unbaked milk. There is some evidence that including cooked milk in the diet may hasten the resolution of allergy to non-cooked milk[17, 18].

    If the kid has had IgE type reactions, particularly if they own been severe, then a challenge test should be carried out under shut supervision.

    Allergen avoidance

    The management of CMPA generally consists of avoidance of the allergen.

    If CMPA is the cause of the symptoms then they should resolve within two weeks of stopping cow’s milk.

    If the kid is formula-fed, they can be given extensively hydrolysed milk formula such as Nutramigen®, Aptamil Pepti® or Pepti Junior®. These are based on cow’s milk but the proteins are broken below into smaller peptides that are less likely to trigger an allergic reaction.

    Babies who own CMPA may own their growth and development impaired by the disorder; however, hydrolysed formula is shown to provide balanced nutrition and to restore normal growth and development[12, 13].

    If the symptoms persist on hydrolysed formula but a suspicion of CMPA remains, then attempt an amino acid formula.

    These include Nutramigen AA® and Neocate LCP®. Hydrolysed milks are cheaper and are also generally better tolerated, although the flavour and tolerability varies[14].

    If the kid is breast-fed and the mom wishes to continue breast-feeding, she must eliminate milk and milk products from her diet. This will include checking ingredients for anything derived from milk, such as casein, whey and lactose. The mom should make certain she is still getting adequate calcium in her diet.

    It is recommended that she be offered calcium and vitamin D tablets; however, calcium can also come from tinned fish, pulses, almonds, kale, oranges and soya products such as soya milk and tofu[8].

    Babies who are being weaned, and older children with persisting CMPA, will need to follow a cow’s milk-free diet as above. Parents must be advised about how to check the ingredients of processed foods for milk-derived constituents. Children should be referred to a paediatric dietician for advice about maintaining a balanced diet while excluding allergens.

    New treatments

    Immunotherapy, in which children are given a gradually increasing dose of milk over a period of several months, is one option which has been tried for children with persisting severe allergy.

    The results own been extremely promising, although a Cochrane review concluded that further studies of higher quality were necessary before it can be recommended without reservation[19].


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