nutrients Review Cow’s Milk Protein Allergy as a Model of Food Allergies Arianna Giannetti 1 , Gaia Toschi Vespasiani 2 , Giampaolo Ricci 3, Angela Miniaci 1, Emanuela di Palmo 1 and Andrea Pession 1,* 1 Pediatric Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; [email protected] (A.G.); [email protected] (A.M.); [email protected] (E.d.P.) 2 Specialty School of Paediatrics, Alma Mater Studiorum, University of Bologna, via G.Massarenti n 11, 40138 Bologna, Italy; [email protected] 3 Department of Medical and Surgical Sciences (DIMEC), University of Bologna, via G. Massarenti n.9, 40138 Bologna, Italy; [email protected] * Correspondence: [email protected]; Tel.: +39-051-214-4443; Fax: +39-051-346044 Abstract: Cow’s milk allergy (CMA) is one of the most common food allergies in infants, and its prevalence has increased over recent years. In the present paper, we focus on CMA as a model of food allergies in children. Understanding the diagnostic features of CMA is essential in order to manage patients with this disorder, guide the use of an elimination diet, and find the best moment to start an oral food challenge (OFC) and liberalize the diet. To date, no shared tolerance markers for the diagnosis of food allergy have been identified, and OFC remains the gold standard. Recently, oral immunotherapy (OIT) has emerged as a new therapeutic strategy and has changed the natural history of CMA. Before this, patients had to strictly avoid the food allergen, resulting in a decline in quality of life and subsequent nutritional, social, and psychological impairments. Thanks to the introduction of OIT, the passive approach involving rigid exclusion has changed to a proactive one. Citation: Giannetti, A.; Toschi Both the heterogeneity in the diagnostic process among the studies and the variability of OIT data Vespasiani, G.; Ricci, G.; Miniaci, A.; limit the comprehension of the real epidemiology of CMA, and, consequentially, its natural history. di Palmo, E.; Pession, A. Cow’s Milk Therefore, well-planned randomized controlled trials are needed to standardize CMA diagnosis, Protein Allergy as a Model of Food prevention, and treatment strategies. Allergies. Nutrients 2021, 13, 1525. https://doi.org/10.3390/nu13051525 Keywords: cow’s milk allergy; oral food challenge; oral immunotherapy; diet; skin prick test; serum-specific IgE; breastfeeding Academic Editors: Elvira Verduci, Gian Vincenzo Zuccotti and Diego Peroni Received: 30 March 2021 1. Introduction Accepted: 26 April 2021 The prevalence of food allergies (FAs) and especially cow’s milk allergy (CMA, cur- Published: 30 April 2021 rently one of the most common FAs among children [1,2]) has increased in recent decades. CMA is defined as a reproducible adverse reaction to one or more cow’s milk (CM) Publisher’s Note: MDPI stays neutral protein (usually casein or serum β-lactoglobulin) [3]. The underlying immunological with regard to jurisdictional claims in mechanism, presentation times, and organs involved differentiate CMA from other adverse published maps and institutional affil- reactions to CM such as lactose intolerance [4]. iations. CMA, like all FAs, can be divided into two main categories according to the type of immunological mechanism underlying it: immunoglobulin (Ig)E-mediated or non-IgE mediated [5] (Figure1). IgE-mediated reactions are the most common. On the other hand, there are non-IgE mediated reactions that can arise from other cellular processes involving Copyright: © 2021 by the authors. eosinophils or T-cells. Licensee MDPI, Basel, Switzerland. CMA usually occurs in the first 2 years of life and especially within the first year, This article is an open access article unlike other allergies, such as peanut, tree nuts, fish and shellfish allergies which may distributed under the terms and develop later in childhood or adulthood. Most allergies (including CM allergies) resolve conditions of the Creative Commons spontaneously during childhood or adolescence, whereas peanut and tree nut allergies are Attribution (CC BY) license (https:// more likely to persist into adulthood [6,7]. creativecommons.org/licenses/by/ 4.0/). Nutrients 2021, 13, 1525. https://doi.org/10.3390/nu13051525 https://www.mdpi.com/journal/nutrients NutrientsNutrients2021 2021, 13, 13, 1525, x FOR PEER REVIEW 22 ofof 21 21 FigureFigure 1. 1.Clinical Clinical presentation presentation of of IgE IgE and and non non IgE IgE CMA. CMA. 2. Cow’sCMA Milk usually Composition occurs in the first 2 years of life and especially within the first year, unlikeCM other contains allergies, from such 30 to as 35 peanut, g of protein tree nuts, per liter fish andand manyshellfish proteins, allergies which which are may all potentialdevelop allergenslater in childhood [8]. or adulthood. Most allergies (including CM allergies) resolve spontaneouslyThrough the during acidification childhood of raw or skimadolescence milk to, pHwhereas 4.6 at peanut 20 ◦C it and is possible tree nut to allergies obtain twoare differentmore likely fractions: to persist the into coagulum, adulthood containing [6,7]. the casein proteins which account for 80% of the fraction, and the lactoserum (whey proteins), representing 20% of the total milk proteins2. Cow’s [9 M].ilk These Composition proteins can also be divided into soluble and insoluble proteins [10]. TheCM major contains milk from allergens 30 to are 35 solubleg of protein proteins, per namedliter and whey many proteins, proteins, which which represent are all approximatelypotential allergens 20% of[8] total. proteins [11]. Allergens present in the serum fraction include α-lactalbuminThrough (Bosthe acidification d 4) and β -lactoglobulinof raw skim milk (Bos to dpH 5), 4.6 which at 20 are°C it the is possible most abundant, to obtain andtwo immunoglobulins different fractions: (Bos the dcoagulum, 7), serum albumincontaining (BSA, the Boscasein d 6), proteins and traces which of lactoferrin,account for lysozyme,80% of the proteose-peptone, fraction, and the lactoserum and transferrin (whey [9 ].proteins), In particular representing lactoferrin, 20% lactoperoxidase, of the total milk andproteins lysozyme [9]. These are important proteins can antimicrobial also be divided agents, in whileto soluble lactoferrin, and insolubleβ-lactoglobulin, proteins [10] and. α-lactalbuminThe major are milk important allergens tumor are soluble suppressors proteins, [12 ].named whey proteins, which represent approximatelyThe remaining 20% 80% of total is represented proteins [11] by. insolubleAllergens proteins present knownin the serum as caseins fraction (known include as Bosα-lactalbumin d 8). Total caseins (Bos d can4) and be divided β-lactoglobu into fourlin (Bos proteins, d 5), representingwhich are the different most abundant, percentages and ofimmunoglobulins the whole fraction: (Bosα S1-casein,d 7), serum which albumin is the (BSA, most Bos important d 6), and (Bos traces d 9,of 32%), lactoferrin, as well lyso- as αzyme,S2-casein proteose (Bos- dpeptone 10, 10%),, andβ-casein transferrin (Bos [9] d.11, In particular 28%), and lactoferrin,κ-casein (Bos lactoperoxidase d 12, 10%). The, and mainlysozyme role of are caseins important relates antimicrobial to their mineral agents, binding while and lactoferrin, carrier capacity, β-lactoglobulin specifically, and for α- calciumlactalbumin andphosphorus are important [12 tumor]. suppressors [12]. CMAsThe remaining are most 80% frequently is represented caused byby wheyinsoluble proteins, proteins but known they can as alsocaseins be promoted (known as byBos caseins d 8,). Total [13]. Ascaseins a matter can be of divided fact, most into patients four proteins, are sensitized representing to casein different (Bos dpercent- 8), β- lactoglobulinages of the whole (Bos fraction: d 5), and ααS1-lactalbumin-casein, which (Bos is dthe 4), most which important are the major(Bos d milk9, 32%), allergens. as well Thereas αS2 are-casein only (Bos a few d 10, studies 10%), thatβ-casein describe (Bos d allergies 11, 28%) to, and minor κ-casein serum (Bos proteins d 12, 10%). such The as immunoglobulin,main role of caseins bovine relates serum to their albumin, mineral or lactoferrin binding and [14 ].carrier capacity, specifically for calciumCM containsand phosphorus at least 20[12] potentially. allergenic proteins [15]. Most children with milk- allergyCMA are sensitizeds are most tofrequently more than caused one allergen, by whey with proteins, a greater but variabilitythey can also of symptoms. be promoted by caseinsTable1 provides[13]. As a shortmatter synthesis of fact, most of cow’s patients milk allergensare sensitized and their to casein characteristics. (Bos d 8), β- Nutrients 2021, 13, 1525 3 of 21 Table 1. Main characteristics of CM allergens, adapted from Hochwallner [8]. Allergen Protein Concentration Prevalence (% Allergenic Activity Name (g/L) Size (kDa) of Patients) (% of Patients) Bos d 4 α–Lactalbumin 1–1.5 14.2 0–67 12 Bos d 5 β–Lactoglobulin 3–4 18.3 13–62 19 Whey (20%) (5 g/L) Bos d 6 Bovine serum albumin 0.1–0.4 66.3 0–76 1 Bos d 7 Immunoglobulins 0.6–1 160 12–36 Lactoferrin 0.09 80 0–35 3 Bos d 9 αS1–casein 12–15 23.6 65–100 26 Whole Bos d 10 αS2–casein 3–4 25.2 casein (80%) (30 g/L) Bos d 11 β–casein 9–11 24 35–44 35 Bos d 12 k–casein 3–4 19 35–41 26 3. Subtypes of Immune-Mediated Reactions to CM CMAs have a range of clinical manifestations, with variable intensity. Moreover, clinical features can differ from “immediate” to “delayed” reactions, and this reflects the different pathogenesis (Figure1). Approximately 60% of CMA are IgE-mediated, although estimates change according to the study population and age [1]. The remaining 40% is divided into non IgE-mediated and mixed forms. The latter have different underlying mechanisms, presentations, and implications, which complicate the attempts to estimate the prevalence of CMA. Non IgE-mediated CMAs are caused by less clear immune mechanisms.