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  Working group. It comprised 11 experts representing 4 paediatric societies: Sociedad Española de Gastroenterología, Hepatología y Nutrición Pediátrica (Spanish Society of Paediatric Gastroenterology, Hepatology and Nutrition, SEGHNP), Asociación Española de Pediatría de Atención Primaria (Spanish Association of Primary Care Paediatrics, AEPAP), Sociedad Española de Pediatría Extrahospitalaria y Atención Primaria (Spanish Society of Outpatient and Primary Care Paediatrics, SEPEAP) and Sociedad Española de Inmunología Clínica, Alergología y Asma Pediátrica (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.

• •

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

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  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.

The term allergy refers exclusively to adverse reactions involving one or several immune mechanisms—proven or highly suspected—and 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 usually 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.14–16 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 have 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), infant colic and constipation.17–21 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 child 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), 1–2 weeks in cases of eczema or rectal bleeding, and up to 2–4 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 usually 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).

Figure 1.

Diagnostic algorithm.

BF, breastfeeding; CMP, cow's milk protein; CMPA, cow's milk protein allergy; FPIES, food protein-induced enterocolitis syndrome; SC, specialty care.

1 Improvement with the elimination diet can be expected after a variable period of time depending on the clinical presentation: between 1 and 5 days in acute forms (acute FPIES, vomiting); 1–2 weeks in cases of eczema and gastrointestinal bleeding; 2–4 weeks in cases of constipation, diarrhoea and growth faltering.

2 Eliminate lactose as well in case of suspected lactose intolerance, enteropathy and/or growth faltering.

3 Patients with significant growth faltering (malnutrition, hypoalbuminaemia), rectal bleeding associated with haemodynamic instability or severe FPIES.

4 When symptoms develop with the first feeds of formula in infants that were previously breastfed and asymptomatic, BF should be recommended and elimination of CMP from the mother's diet is not necessary.

5 Switch to another extensively hydrolysed formula of different characteristics or a hydrolysed rice formula. Elimination of soy and egg (in the child and/or mother) if a concomitant food allergy is suspected.

6 An IgE-mediated mechanism should be suspected in case of immediate reactions (onset less than 2h after intake) and/or development of cutaneous and respiratory manifestations associated with IgE mechanisms (urticaria, erythema, oedema, bronchospasm).

7 In case it is not available at the primary care level, refer patient to specialty care.

8 The oral food challenge can be foregone in severe cases and cases meeting the diagnostic criteria for FPIES.

In patients with severe atopic dermatitis and/or FPIES, performance of a prick test or specific IgE tests is recommended before starting the challenge for diagnosis. In case the result of either test is positive, the oral challenge will be performed according to the protocol for IgE-mediated reactions.

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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 2–4 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 mother 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.2–11,25,26 Administration 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,27–29 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 have been proven efficacious and safe.2–11,30 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.2–11 Plant-based drinks made with soy, rice, oat, quinoa, tiger nut or almond are of little nutritional value and have low protein and energy contents, unlike plant-based infant 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 receive supplementation for both. Infants will be given vitamin D, and calcium supplementation will be considered in case of insufficient dietary intake.15,32,33

Most children with CMPA tolerate ingestion of well-cooked beef and other bovine meat (ox, bull, etc.). Thus, unless the child exhibits clinical manifestations associated to their consumption, these meats need not be avoided.10

The persistence or resolution of CMPA can only be established by testing for the development of tolerance, which involves the gradual reintroduction of CMP under medical supervision. Tolerance should be evaluated at regular intervals according to the clinical features and the severity of the response in previous challenges. Patients with mild forms manifesting with GOR, colic, constipation and proctocolitis may develop tolerance early, at ages 3–6 months, while patients with FPIES develop it later, and the oral challenge for tolerance testing should be deferred to ages 12, 18 or even 24 months in patients with the most severe forms.9,17

Before reintroducing CMP in the diet, the clinician should consider whether testing for specific IgE and/or a prick test are necessary. In so-called atypical FPIES, these tests may be positive at diagnosis or at a later time, and patients tend to develop tolerance later.9,34,35 Although most maintain a clinical presentation characteristic of non-IgE-mediated allergy, approximately 35% of patients also exhibit manifestations characteristic of IgE-mediated allergy.34 Furthermore, patients that have exhibited severe reactions, immediate reactions (onset within 2 hours from intake) or have a personal history of atopy (atopic dermatitis, recurrent bronchospasm, allergic rhinitis and/or IgE-mediated hypersensitivity to other foods) should be considered at high risk of developing IgE-mediated reactions after a prolonged period of elimination6 (Fig. 2).

Figure 2.

Followup algorithm.

CMP, cow's milk protein; CMPA, cow's milk protein allergy; FPIES, food protein-induced enterocolitis syndrome.

1 The intervals between challenges for evaluation of tolerance will be determined by the clinician, and we recommend a higher frequency the milder the presentation. In case of dietary transgressions associated with symptoms, postpone challenge.

2 The patients considered at risk of developing an IgE-mediated response include those with a personal history of atopy and those that developed symptoms immediately after ingestion of CMP.

3 If not available at the primary care level, refer to specialty care.

4 Perform according to IgE-mediated protocol in case of positive prick/IgE test.

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The development of tolerance can be assessed at home with the gradual and controlled reintroduction of CMP in patients with non-IgE CMPA that have mild or moderate symptoms6,7,15 (Fig. 3), and should be assessed in a hospital setting if there is risk of a systemic reaction (FPIES or severe enteropathy) or an IgE-mediated reaction (children that have had positive results of testing for specific IgE and/or the prick test during the followup)9 (Table 4).

Figure 3.

Milk ladder challenge to assess tolerance at home. Adjust fed products to the patient's age.

BF, breastfeeding; CM, cow's milk.

1 Simple biscuits, such as María biscuits (no chocolate, custard, etc.). To feed infants, they can be puréed with fruit.

2 Adding fresh fruit or sweetening lightly with some milk of sugar is acceptable.

3 In children that continue to breastfeed, introduction of cow's milk will be delayed until breastfeeding is discontinued or supplementation becomes necessary.

4 Extensively hydrolysed formula, hydrolysed rice protein formula or soy-based formula.

5 Eventually, introduce a lactose-free formula, and later switch to an adapted formula.

6 In children that are not fed special formulas (for instance, fed plant-based milks) CMP could be reintroduced with low-fat milk (to facilitate acceptance), switching to whole milk 2 weeks later.

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The data on potential risk factors for non-IgE CMPA are scarce, as most studies have been conducted in patients with IgE-mediated allergy.36–38 At present, no intervention for preventing the development of non-IgE CMPA is backed by sufficient evidence.39–43 Exclusive breastfeeding is the optimal source of nutrition for infants up to age 6 months, and while the evidence on its protective effect against allergy development is inconsistent, it should still be recommended on account of the numerous benefits it offers.43

Beatriz Espín Jaime has participated in educational activities and symposiums sponsored by different infant and child food manufacturers: Mead Johnson, Hero, Nestlé, Nutricia, Ordesa, Nutribén, Lactalis. She has been a consultant in Nutricia advisory boards.

Juan J. Díaz Martín has received fees for participating in talks and symposia organised by different infant and child food manufacturers: Mead Johnson, Hero, Nestlé, Nutricia, Ordesa, Nutribén. He has received grants to attend scientific congresses from several corporations (Mead Johnson, Nestlé, Ordesa, Nutricia) and has been a consultant on Nutricia and Abbvie advisory boards.

Luis Carlos Blesa Baviera has received fees or support of various types (room and board, registration fees, travel) from most corporations related to infant and child foods for speaking, participating and/or attending a variety of workshops, congresses, conferences and meetings related to paediatrics.

Anselmo Hernández Hernández has participated in round tables and conferences sponsored by, and attended workshops and congresses for which he received financial support (for registration, travel and room and board) from infant and child food manufacturers and other corporations.

Cristóbal Coronel Rodríguez has participated as a facilitator or speaker in round tables, workshops and symposiums sponsored by infant and child food manufacturers.

Enriqueta Román Riechmann has participated in educational activities funded by Alter, Casen Fleet, Ferrer Internacional, Ferring, Hero, Mead Johnson and Nestlé.

Carmen Ribes Koninckx has received fees for participating in talks and symposiums organised by different manufacturers of infant and child foods: Mead Johnson, Nestlé, Nutricia. She has acted as a consultant in Nutritia, Nestlé and Mead Johnson advisory.

Ángela Claver Monzón, José Ignacio García Burriel, María José García Mérida and Celia Pinto Fernández have no conflicts of interest to declare.